WO2024040036A2

WO2024040036A2 - Adenosine receptor antagonists and compositions thereof for use in the treatment of disease associated with expression of at least one antibody-secreting cell marker

Info

Publication number: WO2024040036A2
Application number: PCT/US2023/072187
Authority: WO
Inventors: Maura ROSSETTI; Chiara MARTINOLI; Noemie WALD; Joanne LAGER; Sally ROSS
Original assignee: iTeos Belgium SA
Priority date: 2022-08-16
Filing date: 2023-08-15
Publication date: 2024-02-22
Also published as: WO2024040036A3

Abstract

The present disclosure relates to treatment of a subject who has been identified with an increased IRF4 gene expression or infiltration of MUM-1⁺ cells. The present disclosure also relates to treatment of a subject who has been identified with an increased gene expression of at least one antibody-secreting cell (ASC) marker or infiltration of cells positive for at least one ASC marker.

Description

ADENOSINE RECEPTOR ANTAGONISTS AND COMPOSITIONS THEREOF FOR USE IN THE TREATMENT OF DISEASE ASSOCIATED WITH EXPRESSION OF AT LEAST ONE ANTIBODY-SECRETING CELL MARKER CROSS-REFERENCE TO RELATED APPLICATIONS [001] This application claims priority to US Provisional Application Nos.63/398,381, filed on August 16, 2022, 63/425,924, filed November 16, 2022, 63/437,545, filed January 6, 2023, 63/451,414, filed March 10, 2023, and 63/457,589, filed April 6, 2023, the disclosures of each of which is incorporated herein by reference in their entirety for any purpose. FIELD OF THE PRESENT DISCLOSURE [002] The present disclosure includes treatment of a subject wherein the subject has been identified as having tumor-infiltrating immune cells (TILs) with high levels of IRF4/MUM-1 expression. The present disclosure also includes treatment of a subject wherein the subject has been identified as having tumor-infiltrating immune cells (TILs) with high levels of expression of at least one antibody-secreting cell (ASC) marker. Compounds of the present disclosure include, but are not limited to A_2AR antagonist(s), and are useful as therapeutic compounds, especially in the treatment of cancers. Compounds of the present disclosure may be used in combination with additional therapeutic agents for the treatment of cancer. BACKGROUND [003] Many of immunosuppressive mechanisms in tumors are common to physiological immunoregulation in normal tissues. Such immunoregulation can be very important in keeping the immune system under control in order to block a self-reactive immune response and to prevent an ongoing immune response from causing critical tissue damage. The lack of physiological immunoregulation often results in overwhelming immune activation that accompanies autoimmunity. Tumors, however, take advantage of such physiological immunoregulatory mechanisms to protect their tissue from immune attacks. Thus, these mechanisms intended to prevent inflammatory complication, now turn out to be major obstacles hampering spontaneous cancer regression and immunological cancer treatment. The identification of immunosuppressive mechanisms in tumors can lead to molecular targets to restore the antitumor immune response. Thus, these negative immunoregulatory mechanisms, so-called immune checkpoints, has become a focus in drug discovery. [004] Extracellular adenosine is known as an inhibitor of immune functions. (Chiarella et al., Trends in Cancer, 2021, 7(8), 731-750; Fredholm, Tissue Death and Differentiation, 2007, 14, 1315-1323; Allard et al., nature Reviews Clinical Oncology, 2020, 17, 611-629). While intracellular adenosine is involved in energy metabolism, nucleic acid metabolism, and the methionine cycle, extracellular adenosine plays an important role in intercellular signaling. Its signal is transmitted by G protein-coupled adenosine receptors on the cell surface, and it affects diverse physiological functions including neurological, cardiovascular, and immunological systems. [005] Many tumors produce high levels of extracellular adenosine which suppress anti- tumor immune responses, suggesting that tumor cells may benefit from its immunosuppressive effect and catabolic energy production (Allard et al., Curr. Opin. Pharmacol., 2016, 29, 7-16; Otta A., Frontiers in Immunology, 2016, 7: 109). This accumulation of adenosine in the tumor microenvironment (TME) mediates immune suppression mainly via adenosine receptors, causing dysregulation of innate and adaptative immune cell subsets and dampening the antitumor immune response. [006] Adenosine activates four G protein-coupled receptor subtypes (A₁, A_2A, A_2B, and A₃), which are widely expressed across many different organ systems. Of the four known types of adenosine receptors, A_2A adenosine receptor (A_2AR) is the predominantly expressed subtype in most immune cells (Gessi, Bencivenni et al., Front. Pharmacol., 2017, 8: 888). Stimulation of A_2AR generally provides an immunosuppressive signal that inhibits activities of T cells (proliferation, cytokine production, cytotoxicity), NK cells (cytotoxicity), NKT cells (cytokine production, CD40L upregulation), macrophages/dendritic cells (antigen presentation, cytokine production), and neutrophils (oxidative burst) (Staggs and Smyth, Oncogene, 2010, 29(39): 5346-58; Allard et al., Curr. Opin. Pharmacol., 2016, 29, 7-16). The presence of high levels of extracellular adenosine in tumors was found to play a significant role in the evasion of antitumor immune response. Especially, it was shown that genetic deletion of A_2A receptors in mice induced complete rejection of immunogenic tumors (Ohta et al., Proc. Natl. Acad. Sci. USA, 2006, 103(35):13132-7). Pharmacological inhibition of A_2A receptors on the surface of tumor-associated T cells improved the inhibition of tumor growth, destruction of metastases, and prevention of neo-vascularization in murine tumor models, either alone or in combination with immune checkpoint inhibitors or chemotherapy (Ohta et al., 2006; Beavis et al., Proc. Natl. Acad. Sci. USA, 2013, 110(36):14711-6; Loi et al., Proc. Natl. Acad. Sci. USA, 2013, 110(27):11091-6. Furthermore, deletion of A_2A receptors or A_2AR antagonist treatment in mice resulted in enhanced efficacy of chimeric antigen receptor T cells (Beavis et al., J. Clin. Invest., 2017, 127(3):929-941. [007] Therefore, given that A_2A receptor is expressed in most immune cells and particularly effector immune cells such as T cells and NK cells and given that A_2A receptor is engaged in tissues where adenosine is produced, blocking A_2A receptors, predominantly expressed on tumor-infiltrating immune cells, can reverse the immunosuppressive effect of adenosine. As such, the A_2A receptor represents a relevant target of interest for cancer immunotherapy. [008] Inupadenant is one such potent and highly selective small molecule antagonist of the A_2A receptor that remains active even at the high adenosine concentrations found in tumors. [009] However, there exists a need to better understand which immune cells express A2AR in the tumor microenvironment in order to develop a more targeted treatment of cancers with A_2AR inhibitors as well as prognosticators of treatment. [010] The adenosine field (and in general the immunotherapy field) has been so far heavily T cell-centric. It has been shown that T cell proliferation and cytokine production is suppressed in the presence of high adenosine concentrations as found in the tumor microenvironment. It has also been shown that A2A receptor antagonists can restore T cell activity in tumors with high adenosine concentrations. See, e.g., PCT Publication WO2018/178338, US Publication 2020/0102319, and PCT Publication WO2020/065036. [011] There is mounting evidence in the literature from the last few years that tumor- infiltrating B cells and plasma cells also have a crucial role in tumor control, synergistic to that of T cells. In many cancers, they have demonstrated strong predictive and prognostic significance (usually, but not always, positive) in the context of both standard treatments and immune checkpoint blockade (Edlund et al., Journal of Thoracic Oncology, 2019, 14(4): 628- 640). B cells and plasma cells may promote antitumor immunity through antigen presentation to T cells, recruitment and activation of other immune cells, and antibody-dependent mechanisms, usually directed to self-antigens. Rare subsets or pro-tumoral regulatory B cells has also been reported. [012] Antibody-secreting cells (ASC) are a specialized cell type that represents the end- stage of the B-cell differentiation program. They are any cell type that produces and secrets an antibody, such as plasmablasts and plasma cells. [013] ASC contribute to both the acute humoral response to infection by rapidly generating early antibodies at sites of infection as well as later secreting higher affinity antibodies produced by germinal center reactions to aid in pathogen clearance and protective immunity. While the ASC response is advantageous during infection and when co-opted for immunization, emergence of ASC secreting antibodies towards self-antigens is a deleterious factor in many autoimmune disorders. Aside of their key role in the humoral response, ASC can participate in the regulation of biological processes independent of immunoglobulins, for instance through cytokine production. [014] ASCs can typically be identified based on the expression of one or more markers, such as CD38, IRF4/MUM1, PRDM1/BLIMP1, SDC1/CD138, XBP1. While IRF4 is potentially indicated to be a prognostic factor in patients with a specific type of lung cancer, lung adenocarcinoma (LUAD) (a specific type of non-small-cell lung carcinoma (NSCLC)), there is conflicting evidence of whether IRF4 is a favorable or unfavorable prognostic factor in the broader category of NSCLC (Li et al., Front Oncol., 2021, 11: 698465 and Chen et al., N Engl J Med, 2007, 356(1): 11-20). Furthermore, in an analysis of prognostic value of IRF4 in LUAD patients with immunotherapy, no overall statistically beneficial effect of IRF4 was found (Li et al., Front Oncol., 2021, 11: 698465). Thus, there appears to be conflicting evidence of whether ASC markers such as IRF4 have prognostic significance for cancer patients or for immunotherapy-treated cancer patients. [015] Furthermore, while there is some literature which indicates that A2AR signaling may also be implicated in B cell viability, activation and antibody class switch in mice and humans (Allard et al., PLoS One, 2018, 13(1): e00191973; Sakata et al., J. Allergy Clin Immunol, 2000, 105(3): 522-531; Jeske et al., Cancer Immunology, Immunotherapy, 2020, 69, 1205-1216; Minguet et al., European Journal of Immunology, 2005, 35(1): 31-41), a connection between B cells and adenosine receptor expression is not clear. Thus, there exists a need to better understand the connection between B cells and adenosine receptor expression in the tumor microenvironment. SUMMARY [016] The present disclosure includes a method of treating cancer characterized by high levels of IRF4/MUM-1 expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a A_2AR antagonist, or a combination thereof. [017] The present disclosure also includes a method of treating cancer characterized by high levels of expression of at least one antibody-secreting cell (ASC) marker in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a A_2AR antagonist, or a combination thereof. In at least one embodiment, the ASC markers can include, but are not limited to, CD38, IRF4/MUM-1, SLAMF7, CD27, TNFSRF17, FAM30A, CD79A, and/or CD138. [018] The present disclosure is further defined in the appended claims. BRIEF DESCRIPTION OF THE DRAWINGS [019] FIG.1A is a box and whisker plot showing interferon regulatory factor 4 (IRF4) expression in progressive disease (PD) and partial response (PR) + stable disease (SD) patients as determined by Nanostring (a proprietary technology from NanoString Technologies). P=0.0023; N=19 PD, black dots; N=9 PR+SD, white and stripe dots, respectively. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from t test. [020] FIG.1B is a box and whisker plot showing intratumor density of multiple myeloma oncogene 1 (MUM-1⁺) cells in PD and PR+SD patients as determined by immunohistochemistry (IHC). N=16 PD, black dots; N=8 PR+SD, white and stripe dots, respectively. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from Mann- Whitney. [021] FIG.1C is a scatter plot correlating IRF4/MUM-1 detected by Nanostring and IHC. Spearman r=0.84, 95%CI: 0.69-0.92, P<0.0001; N=34. Each dot represents one biopsy for which both assessments were performed. [022] FIG.1D is a receiver operating characteristic (ROC) curve showing the relationship between true positive rate (sensitivity %) and false positive rate (100- specificity%), when baseline MUM-1+ cells were used for discriminating based on best response, as described in Example 4. N=24. [023] FIG.1E is a graph of Kaplan-Meier progression-free survival analysis by baseline density of MUM-1⁺ cells using the optimized cut-off. Hazard ratio (HR) with 95% confidence interval and p value from Log-rank test (N=25) are shown. [024] FIG.1F is a waterfall plot of best percent change in the sum of target lesion diameters in RECIST-evaluable subjects (N=38). Vertical stripe: subjects with low baseline density of MUM-1+ cells; black: subjects with high density of MUM-1+ cells; white: MUM- 1 data unavailable. For two patients with unavailable MUM-1 data, gene expression levels below (low) or above (high) the mean IRF4 levels assessed by Nanostring are indicated. [025] FIG.1G is a box and whisker plot showing intratumor density of MUM-1+ cells in a different set of data of PD and PR + SD patients as determined by IHC. N=18 PD, black dots; N=8 PR+SD, white and stripe dots, respectively. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from Mann-Whitney test. [026] FIG.1H is a scatter plot correlating IRF4/MUM-1 detected by Nanostring and IHC with additional data. Spearman r=0.84, 95%CI: 0.69-0.92, P<0.0001; N=34. Each dot represents one biopsy for which both assessments were performed. [027] FIG.1I is an ROC curve showing the relationship between true positive rate (sensitivity %) and false positive rate (100-specificity%), when baseline MUM-1+ cells were used for discriminating based on best response with additional data, as described in Example 4 (N=26). [028] FIG.1J is a graph of Kaplan-Meier progression-free survival analysis by baseline density of MUM-1+ cells with additional data, using the optimized cut-off. Hazard ratio (HR) with 95% confidence interval and p value from Log-rank test (N=27) are shown. [029] FIG.1K is a waterfall plot of best percent change in the sum of target lesion diameters in RECIST-evaluable subjects with additional data (N=38). Vertical stripe: subjects with low baseline density of MUM1+ cells; black: subjects with high density of MUM1+ cells; white: MUM1 data unavailable. For three patients with unavailable MUM1 data, gene expression levels below (low) or above (high) the mean IRF4 levels assessed by Nanostring are indicated. [030] FIG.2A is a graph showing correlation between density of MUM1+ cells obtained with clone MRQ-43 and clone MUM-1p in clinical samples. N=15. [031] FIG.2B is a graph showing correlation between density of MUM1+ cells obtained with clone MRQ-43 and clone MUM-1p with additional data. N=36, Spearman rho = 0.74, 95%CI: 0.54-0.86. [032] FIG.3A is a scatter plot showing correlation between A_2A receptor (A_2AR+) cell infiltration detected by IHC and expression of IRF4 detected by Nanostring. Each dot represents one biopsy (N= 52). Spearman rho correlation coefficient with 95% confidence interval and P value are shown. [033] FIG.3B is a scatter plot showing correlation between A_2AR+ cell infiltration detected by IHC, and expression of TNFRSF17 detected by Nanostring. Each dot represents one biopsy (N= 52). Spearman rho correlation coefficient with 95% confidence interval and P value are shown. [034] FIG.3C is a scatter plot showing correlation between A_2AR+ cell infiltration detected by IHC, and expression of CD38 detected by Nanostring. Each dot represents one biopsy (N= 52). Spearman rho correlation coefficient with 95% confidence interval and P value are shown. [035] FIG.3D is a scatter plot showing correlation between A_2AR+ cell infiltration detected by IHC, and expression of SLAMF7 detected by Nanostring. Each dot represents one biopsy (N= 52). Spearman rho correlation coefficient with 95% confidence interval and P value are shown. [036] FIG.3E is a scatter plot showing correlation between A_2AR+ cell infiltration detected by IHC, and expression of CD27 detected by Nanostring. Each dot represents one biopsy (N= 52). Spearman rho correlation coefficient with 95% confidence interval and P value are shown. [037] FIG.3F is a scatter plot showing correlation between A_2AR+ cell infiltration in the tumor area detected by IHC and expression of Nanostring B cell signature score. Each dot represents one biopsy (N= 52). Spearman rho correlation coefficient with 95% confidence interval and P value are shown. [038] FIG.3G is another scatter plot showing correlation between A_2AR+ cell infiltration in the tumor area detected by IHC, and expression of Nanostring B cell signature score. Each dot represents one biopsy (N= 52). Spearman rho correlation coefficient with 95% confidence interval and P value are shown. [039] FIG.4A is a scatter plot showing correlation between infiltration of A_2AR+ and MUM-1+ cells detected by IHC. Spearman r=0.68, 95%CI: 0.50-0.81, P<0.0001; N=54. Each dot represents one biopsy for which both assessments were performed. [040] FIG.4B is a scatter plot showing correlation between infiltration of A_2AR+ and CD38+ detected by IHC. Spearman r=0.54, 95%CI: 0.31-0.71, P<0.0001; N=55. Each dot represents one biopsy for which both assessments were performed. [041] FIG.5A is a box and whisker plot showing CD38⁺ cells in PD and PR + SD patients as determined by IHC. P=0.0026, N=16 PD, black dots; N=6 PR+SD, white and stripe dots, respectively. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from Mann-Whitney test. [042] FIG.5B is a box and whisker plot showing CD38 expression in PD and PR + SD patients as determined by Nanostring. N=19 PD, black dots; N=9 PR+SD, white and stripe dots, respectively. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. P from t test. [043] FIG.5C is a box and whisker plot showing SLAMF7 expression in PD and PR + SD patients as determined by Nanostring. N=19 PD, black dots; N=9 PR+SD, white and stripe dots, respectively. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. P from t test. [044] FIG.5D is a box and whisker plot showing CD27 expression in PD and PR + SD patients as determined by Nanostring. N=19 PD, black dots; N=9 PR+SD, white and stripe dots, respectively. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. P from t test. [045] FIG.5E is a box and whisker plot showing TNFRSF17 expression in PD and PR + SD patients as determined by Nanostring. N=19 PD, black dots; N=9 PR+SD, white and stripe dots, respectively. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. P from t test. [046] FIG.5F is a box and whisker plot showing baseline MUM1+ immune cells in PD (progressive disease) and nPD (non-progressive disease) patients treated with inupadenant monotherapy. P=0.0008, N=20 PD; N=8 nPD. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from Mann-Whitney test. [047] FIG.5G is a box and whisker plot showing baseline CD38+ immune cells in PD (progressive disease) and nPD (non-progressive disease) patients treated with inupadenant monotherapy. P=0.0242, N=20 PD; N=8 nPD. Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from Mann-Whitney test. [048] FIG.5H is a volcano plot showing differential expression of 780 genes according to best response to inupadenant. Names of B cell- and ASC-related genes are displayed on the plot. [049] FIG.6A is a graph showing change on MUM-1+ cell infiltration in subjects undergoing inupadenant monotherapy who had PD or PR + SD as best response as determined by IHC. PD (N=15, black dots); PR+SD (N=5, white and stripe dots, respectively). Each dot represents the mean of available biopsies for one subject. Matched samples are connected by a line. P from Wilcoxon test. [050] FIG.6B is another graph showing change on MUM-1+ cell infiltration in subjects undergoing inupadenant monotherapy who had PD (progressive disease) (N=15) or nPD (non-progressive disease) (N=5) as best response. Each dot represents the mean of available biopsies for one subject. Matched samples are connected by a line. P from Wilcoxon test. [051] FIG.7A is a graph showing frequency of CD19+, CD38+, or MUM1+ immune cells within A_2AR+ cells in tonsil as determined by multiplexed immune fluorescence (m(IF)). The graph in FIG.7A represents data from 3 selected regions of interest (ROIs) (circle: ROI 1, square: ROI 2, and triangle: ROI 3). [052] FIG.7B is a graph showing frequency of CD19+, CD38+, or MUM1+ immune cells within A_2AR+ cells in lung cancer tissue as determined by multiplexed immune fluorescence (m(IF)). The graph in FIG.7B represents data from 3 selected ROIs (circle: ROI 1, square: ROI 2, and triangle: ROI 3). [053] FIG 7C is a graph showing frequency of MUM1+CD38+ immune cells within A_2AR+ cells in lung cancer tissue as determined by multiplexed immune fluorescence (m(IF)). The graph in FIG.7C represents data from 3 selected ROIs (circle: ROI 1, square: ROI 2, and triangle: ROI 3). [054] FIG.7D is a graph showing frequency of different immune cells within A_2AR+ cells in tonsil tissue as determined by multiplexed immune fluorescence (m(IF)). Tonsil (n=1) samples were stained by multiplex (m)IF and co-expression of A_2AR was quantified. The mean is shown. pDC = plasmacytoid dendritic cell; cDC = conventional DC; PB = plasma blast; PC = plasma cell. Plasmacytoid (p)DCs were defined as CD123+, conventional (c)DCs as CD11c+, T cells as CD3+, B cells as CD19+MUM1-, ASCs as CD19+/- MUM1+CD123- CD11c-CD3-. [055] FIG.7E is a graph showing frequency of different immune cells within A_2AR+ cells in lung cancer tissue as determined by multiplexed immune fluorescence. Tumor samples (n=9) were stained by multiplex (m)IF and co-expression of A_2AR was quantified. The mean is shown. pDC = plasmacytoid dendritic cell; cDC = conventional; PB = plasma blast; PC = plasma cell. Plasmacytoid (p)DCs were defined as CD123+, conventional (c)DCs as CD11c+, T cells as CD3+, B cells as CD19+MUM1-, ASCs as CD19+/- MUM1+CD123- CD11c-CD3-. [056] FIG.7F is a representative mIF image of a lung tumor showing A_2AR+ ASCs, denoted by arrows. [057] FIG.8A is a graph showing quantification of expression of A_2AR on sorted tonsillar B cell subsets as determined by immunocytochemistry (ICC). [058] FIG.8B is a graph showing quantification of expression of MUM1 on sorted tonsillar B cell subsets as determined by immunocytochemistry (ICC). [059] FIG.8C is another graph showing quantification of the expression of A_2AR on sorted tonsillar B cell subsets as determined by immunocytochemistry (ICC). Sorted B cell subsets from tonsillar mononuclear cells (TMNC) were analyzed by ICC for A_2AR expression. Frequency of A_2AR+ cells on sorted B cell subsets from human TMNCs (n=3). Data are shown as mean ± SEM. ASCs = antibody secreting cells; PB = plasma blasts; PC = plasma cells. [060] FIG.8D is a graph showing quantification of the expression of A_2AR on sorted ascites B cell subsets as determined by immunocytochemistry (ICC). Sorted B cell subsets from ascites cells were analyzed by ICC for A_2AR expression. Frequency of A_2AR+ cells on sorted B cell subsets from human ascites (n=1). The mean is shown. ASCs = antibody secreting cells; PB = plasma blasts; PC = plasma cells. [061] FIG.8E and 8F are representative ICC image of A_2AR staining on memory B cells and plasma cells of a TMNC donor. [062] FIG.9A is a graph showing frequency of CD39+ cells within naïve B cells, memory B cells, and antibody-secreting cells, including plasma blasts and plasma cells, from tonsils (n=2), as determined by flow cytometry. Graph shows the mean ± SEM. [063] FIG.9B is a graph showing median fluorescence intensity (MFI) of CD39 on naïve B cells, memory B cells, and antibody-secreting cells, including plasma blasts and plasma cells, from 1 tonsil, as determined by flow cytometry. [064] FIG.9C is a graph showing MFI of CD39 on naïve B cells, memory B cells, and antibody-secreting cells, including plasma blasts and plasma cells, from another tonsil, as determined by flow cytometry. [065] FIG.10A is a graph showing percentage difference of the plasma cells (PC) within CD19+ cells after culturing healthy donor B cells (n=4) in the presence of CGS-21680 (A_2AR agonist) with or without inupadenant, normalized on the untreated condition for each donor, as determined by flow cytometry. [066] FIG.10B is a graph showing percentage of the viability of the plasma cells at the end of the culture, for control, and in the presence of CGS-21680 (A_2AR agonist) with or without inupadenant, as determined by flow cytometry. [067] FIG. 10C is a graph showing percent difference in frequency of plasma blasts (PB) and plasma cells (PC) within CD 19+ cells after culturing healthy donor B cells (n=4) in the presence of CGS-21680 (A_2AR agonist) with or without inupadenant. Data are shown as mean ± SEM. P from tukey adjusted for multiple comparison.

[068] FIG. 10D is a graph showing percent difference in viability of plasma blasts (PB) and plasma cells (PC) among CD 19+ cells after culturing healthy donor B cells (n=4) in the presence of CGS-21680 (A_2AR agonist) with or without inupadenant. Data are shown as mean ± SEM.

[069] FIG. 10E is a graph showing percent difference of Ki-67 expression in in plasma blasts (PB) and plasma cells (PC) after culturing healthy donor B cells (n=4) in the presence of CGS- 21680 (A_2AR agonist) with or without inupadenant. Data are shown as mean ± SEM.

[070] FIG. 11A is a table that shows measures of target lesions in a potential partial response with inupadenant monotherapy in a patient with a high level of MUM1+ cells having an adenocarcinoma tumor of unknown origin, where the patient had previous treatments of radiotherapy (left iliac zone), carboplatin+paclitaxel (with stable disease as the best response before progressing), and spartalizumab (antiPD1) (with a partial response as the best response prior to progressing).

[071] FIG. 11B (on left) shows an IHC MUM1 assessment in a patient with high levels of MUM1+ cells (>2000 cells/mm²) v. a threshold of 35 (corresponding to FIG. 11A).

[072] FIG. 11C (on right) shows hematoxylin and eosin (H&E) staining (showing architecture).

[073] FIG. 11D is a table that shows additional measures of target lesions in a confirmed partial response with inupadenant monotherapy in a patient with a high level of MUM1+ cells having an adenocarcinoma tumor of unknown origin, where the patient had previous treatments of radiotherapy (left iliac zone), carboplatin+paclitaxel (with stable disease as the best response before progressing), and spartalizumab (antiPDl) (with a partial response as the best response prior to progressing).

[074] FIG. 11E shows an additional IHC image for MUM1+ cells (>2000 cells/mm²) v. a threshold of 35 (corresponding to FIG. 11D).

[075] FIG. 12 is a volcano plot showing differential expression of 780 genes according to level of infiltration of A_2AR+ cells, and false discovery rate (FDR)-adjusted p values (q value, Benjamini and Yekutieli method). Names of B cell- and ASC-related genes are displayed on the plot. [076] FIG.13A is a graph showing frequency of CD39+ cells within B cell subsets from cancer peripheral blood mononuclear cells (PBMCs) (n=4), healthy donor tonsillar mononuclear cells (TMNCs) (n=5) and dissociated tumor cells (DTCs) (n=3). Graph shows the mean ± SEM. PB = plasma blast; PC = plasma cell. [077] FIG.13B is a graph showing frequency of CD73+ cells within B cell subsets from cancer PBMCs (n=4), healthy donor tonsillar mononuclear cells (TMNCs) (n=5) and dissociated tumor cells (DTCs) (n=3). Graph shows the mean ± SEM. PB = plasma blast; PC = plasma cell. [078] FIG.13C is a graph showing frequency of CD38+ cells within B cell subsets from cancer PBMCs (n=4), healthy donor tonsillar mononuclear cells (TMNCs) (n=5) and dissociated tumor cells (DTCs) (n=3). Graph shows the mean ± SEM. PB = plasma blast; PC = plasma cell. [079] FIG.13D is a graph showing median fluorescence intensity (MdFI) of CD39 on B cell subsets from cancer PBMCs (n=4), healthy donor tonsillar mononuclear cells (TMNCs) (n=5) and dissociated tumor cells (DTCs) (n=3). MdFI is calculated on total cells. Graph shows the mean ± SEM. PB = plasma blast; PC = plasma cell. [080] FIG.13E is a graph showing median fluorescence intensity (MdFI) of CD73 on B cell subsets from cancer PBMCs (n=4), healthy donor tonsillar mononuclear cells (TMNCs) (n=5) and dissociated tumor cells (DTCs) (n=3). MdFI is calculated on total cells. Graph shows the mean ± SEM. PB = plasma blast; PC = plasma cell. [081] FIG.13F is a graph showing median fluorescence intensity (MdFI) of CD38 on B cell subsets from cancer PBMCs (n=4), healthy donor tonsillar mononuclear cells (TMNCs) (n=5) and dissociated tumor cells (DTCs) (n=3). MdFI is calculated on total cells. Graph shows the mean ± SEM. PB = plasma blast; PC = plasma cell. [082] FIG.14 is a flow chart of a clinical study design to evaluate inupadenant hydrochloride in patients with metastatic nonsquamous non-small cell lung cancer (mNSCLC) or locally advanced, unresectable NSCLC. DEFINITIONS [083] In the present disclosure, the following terms have the following meanings: [084] The terms “adenosine A_2A receptor,” “A_2A receptor,” and “A_2AR” are used interchangeably to refer to a cell surface adenosine receptor with adenosine as the endogenous ligand. In human, A_2AR is encoded by the ADORA2A gene. An exemplary amino acid sequence of human A_2AR includes SEQ ID NO: 1.

[085] The term “aldehyde” refers to a group –CHO. [086] The term “alkenyl” refers to unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups comprise between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, still more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2- propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4- pentadienyl and the like. [087] The term “alkenylcarbonyl” refers to a group –(C=O)-alkenyl wherein alkenyl is as herein defined. [088] The term “alkenylcarbonylamino” refers to a group –NH-(C=O)-alkenyl wherein alkenyl is as herein defined. [089] The term “alkoxy” refers to a group –O-alkyl wherein alkyl is as herein defined. [090] The term “alkyl” refers to a hydrocarbyl radical of formula CnH2n+1 wherein n is a number greater than or equal to 1. Generally, alkyl groups of this disclosure comprise from 1 to 8 carbon atoms, more preferably, alkyl groups of this disclosure comprise from 1 to 6 carbon atoms. Alkyl groups may be linear or branched. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl. [091] The term “alkylaminoalkyl” refers to a group –alkyl-NH-alkyl wherein alkyl is as herein defined. [092] The term “alkylaminoalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl- NH-alkyl wherein alkyl is as herein defined. [093] The term “(alkylaminoalkyl)(alkyl)aminocarbonyl” refers to a group –(C=O)- NR¹R² wherein R¹ is an alkyl group and R² is a –alkyl-NH-alkyl group, wherein alkyl is as herein defined. [094] The term “alkylaminoalkylcarbonyl” refers to a group –(C=O)-alkyl-NH-alkyl wherein alkyl is as herein defined. [095] The term “alkylcarbonyl” refers to a group –(C=O)-alkyl wherein alkyl is as herein defined. [096] The term “alkylcarbonylamine” refers to a group –NH-(C=O)-alkyl wherein alkyl is as herein defined. [097] The term “alkylcarbonyloxyalkyl” refers to a group –alkyl-O-(C=O)-alkyl wherein alkyl is as herein defined. [098] The term “alkylheteroaryl” refers to any heteroaryl substituted by an alkyl group wherein alkyl is as herein defined. [099] The term “alkyloxyalkyl” refers to a group –alkyl-O-alkyl wherein alkyl is as herein defined. [100] The term “alkyloxyalkyloxy” refers to a group –O-alkyl-O-alkyl wherein alkyl is as herein defined. [101] The term “alkyloxycarbonyl” refers to a group –(C=O)-O-alkyl wherein alkyl is as herein defined. [102] The term “alkylsulfonyl” refers to a group –SO2-alkyl wherein alkyl is as herein defined. [103] The term “alkylsulfonylaminoalkyl” refers to a group –alkyl-NH-SO2-alkyl wherein alkyl is as herein defined. [104] The term “alkylsulfonealkyl” refers to a group –alkyl–SO₂-alkyl wherein alkyl is as herein defined. [105] The term “alkylsulfonimidoyl” refers to a group –S(=O)(=NH)-alkyl wherein alkyl is as herein defined. [106] The term “alkylsulfoxide” refers to a group –(S=O)-alkyl wherein alkyl is as herein defined. [107] The term “alkylsulfoxidealkyl” refers to a group –alkyl-SO-alkyl wherein alkyl is as herein defined. [108] The term “alkyne” refers to a class of monovalent unsaturated hydrocarbyl groups, wherein the unsaturation arises from the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above in relation to alkyl groups. Non-limiting examples of alkynyl groups are ethynyl, 2- propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers and the like. [109] The term “alkynealkyl” refers to a group –alkyl-alkyne wherein alkyl and alkyne are as herein defined. [110] The term “amino” refers to a group –NH2. [111] The term “aminoalkyl” refers to a group –alkyl-NH₂ wherein alkyl is as herein defined. [112] The term “aminoalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl-NH2 wherein alkyl is as herein defined. [113] The term “aminoalkylcarbonylamino” refers to a group –NH-(C=O)-alkyl-NH2 wherein alkyl is as herein defined. [114] The term “aminocarbonyl” or “aminocarboxy” refers to a group –(C=O)-NH₂. [115] The term “(aminocarbonylalkyl)(alkyl)amino” refers to a group –NR¹R² wherein R¹ is an alkyl group and R² is a –alkyl-(C=O)-NH2 group, wherein alkyl is as herein defined. [116] The term “aminocarbonylalkylamino” refers to a group –NH-alkyl-(C=O)-NH₂ wherein alkyl is as herein defined. [117] The term “aminosulfonyl” refers to a group –SO2-NH2. [118] The term “aryl” refers to a polyunsaturated, aromatic hydrocarbyl group having a single ring (i.e. phenyl) or multiple aromatic rings fused together (e.g. naphtyl), typically containing 5 to 12 atoms; preferably 5 to 10; more preferably the aryl is a 5- or 6-membered aryl. Non-limiting examples of aryl comprise phenyl, naphthalenyl. [119] The term “arylalkyl” refers to a group –alkyl–aryl wherein alkyl and aryl are as herein defined. [120] The term “aryloxyalkyl” refers to a group –alkyl-O-aryl wherein alkyl and aryl are as herein defined. [121] The term “carbonyl” refers to a group –(C=O)–. [122] The term “carbonylamino” refers to a group –NH-(C=O)–. [123] The term “cyano” refers to a group –CN. [124] The term “cyanoalkyl” refers to a group –alkyl-CN.= wherein alkyl is as herein defined. [125] The term “cycloalkyl” refers to a cyclic alkyl group, that is to say, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may comprise 3 or more carbon atoms in the ring and generally, according to this disclosure comprise from 3 to 10, more preferably from 3 to 8 carbon atoms; still more preferably more preferably the cycloalkyl is a 5- or 6-membered cycloalkyl. Examples of cycloalkyl groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. [126] The term “cycloalkyloxy” refers to a group –O-cycloalkyl wherein cycloalkyl is as herein defined. [127] The term “dialkylamino” refers to a group –NR¹R² wherein R¹ and R² are both independently alkyl group as herein defined. [128] The term “dialkylaminoalkyl” refers to a group –alkyl-NR¹R² wherein R¹ and R² are both independently alkyl group, as herein defined. [129] The term “dialkylaminoalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl- NR¹R² wherein R¹ and R² are both alkyl group, as herein defined. [130] The term “dialkylaminoalkylcarbonyl” refers to a group –(C=O)-alkyl-NR¹R² wherein R¹ and R² are both alkyl group, as herein defined. [131] The term “dihydroxyalkyl” refers to a group alkyl is as herein defined substituted by two hydroxyl (–OH) groups. [132] The term “halo” or “halogen” refers to fluoro, chloro, bromo, or iodo. [133] The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atom is replace by a halogen atom. [134] The term “haloalkyloxy” refers to a group –O-haloalkyl wherein alkyl is as herein defined. [135] The term “heteroaryl” refers to an aryl group as herein defined wherein at least one carbon atom is replaced with a heteroatom. In other words, it refers to 5 to 12 carbon- atom aromatic single rings or ring systems containing 2 rings which are fused together, typically containing 5 to 6 atoms; in which one or more carbon atoms is replaced by oxygen, nitrogen and/or sulfur atoms where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. Non-limiting examples of such heteroaryl, include: pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. The term “heteroarylalkyl” refers to a group –alkyl–heteroaryl wherein alkyl and heteroaryl are as herein defined. [136] The term “heterocyclyl” or “heterocycle” refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3 to 7 member monocyclic, 7 to 11 member bicyclic, or containing a total of 3 to 10 ring atoms) which have at least one heteroatom in at least one carbon atom-containing ring. Preferably the heterocyclyl is a 5- or 6-membered heterocyclyl. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom of the ring or ring system, where valence allows. The rings of multi-ring heterocycles may be fused, bridged and/or joined through one or more spiro atoms. Non limiting exemplary heterocyclic groups include piperidinyl, piperazinyl, azetidinyl, azocanyl, diazepanyl, diazocanyl, morpholin-4-yl, oxazepanyl, pyrrolidinyl, thiomorpholin-4-yl, tetrahydrofuranyl, tetrahydropyranyl,aziridinyl, oxiranyl, thiiranyl, 2- imidazolinyl, pyrazolidinyl imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, 4H-quinolizinyl, 2-oxopiperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H- pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 1-oxido-1-thiomorpholin-4-yl, 1-dioxido-1- thiomorpholin-4-yl, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H- pyrrolizinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, dihydrotriazolopyrazine, dihydroimidazopyrazine, hexahydropyrrolopyrrole, hexahydropyrrolopyrazine. [137] The term “heterocyclylalkyl” refers to a group –alkyl–heterocyclyl wherein alkyl and heterocyclyl are as herein defined. [138] The term “heterocyclylalkylaminocarbonyl” refers to a group –(C=O)-NH-alkyl-heterocyclyl, wherein alkyl and heterocyclyl are as herein defined. The term “(heterocyclyl)(alkyl)aminoalkyl” refers to a group –alkyl-NR¹R² wherein R¹ is an alkyl group and R² is a heterocyclyl group, wherein alkyl and heterocyclyl are as herein defined. [139] The term “heterocyclylalkyloxyalkyl” refers to a group –alkyl-O-alkyl– heterocyclyl wherein alkyl and heterocyclyl are as herein defined. [140] The term “heterocyclylcarbonyl” refers to a group –(C=O)-heterocyclyl wherein heterocyclyl is as herein defined. [141] The term “heterocyclyloxy” to a group –O-heterocyclyl wherein heterocyclyl is as herein defined. [142] The term “heterocyclylsulfonyl” refers to a group – SO₂-heterocyclyl wherein heterocyclyl is as herein defined. [143] The term “hydroxy” or “hydroxyl” refers to a group –OH. [144] The term “hydroxyalkyl” refers to a group –alkyl-OH wherein alkyl is as herein defined. [145] The term “hydroxyalkylaminoalkyl” refers to a group –alkyl-NH-alkyl-OH wherein alkyl is as herein defined. [146] The term “hydroxycarbonyl” refers to a group –C(=O)-OH wherein carbonyl is as herein defined. In other words, “hydroxycarbonyl” corresponds to a carboxylic acid group. [147] The term “oxo” refers to a =O substituent. [148] The term “sulfonylamino” refers to a group –NH-SO₂. [149] The term “intermediate” or “intermediate compound” refers to a compound which is produced in the course of a chemical synthesis, which is not itself the final product, but is used in further reactions which produce the final product. There may be many different intermediate compounds between the starting material and end product in the course of a complex synthesis. [150] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. [151] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(C_1-4alkyl)₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. [152] The term “about,” preceding a figure encompasses plus or minus 10%, or less, of the value of said figure. It is to be understood that the value to which the term “about” refers is itself also specifically, and preferably, disclosed. [153] The term “administration,” or a variant thereof (e.g. “administering”), means providing the active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition, to the patient in whom/which the condition, symptom, or disease is to be treated or prevented. [154] The term “antagonist” refers to a natural or synthetic compound which binds to the protein and blocks the biological activation of the protein, and thereby the action of the said protein. The protein may be a receptor, i.e. a protein molecule that receives chemical signals from outside a cell. Consequently, “an adenosine receptor antagonist” includes any chemical entity that, upon administration to a patient, results in inhibition or down-regulation of a biological activity associated with activation of an adenosine receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to an adenosine receptor of its natural ligand. Such adenosine receptor antagonists include any agent that can block activation of an adenosine receptor or any of the downstream biological effects of an adenosine receptor activation. [155] The term “inhibitor” refers to a natural or synthetic compound that has a biological effect to inhibit or significantly reduce or down-regulate the expression of a gene and/or a protein or that has a biological effect to inhibit or significantly reduce the biological activity of a protein. [156] As used herein, the term “combination” means, for instance, a combined occurrence of the two or more therapeutic agents. In some embodiments, a combination of the present disclosure may occur either as one composition, comprising all the components in one and the same mixture (e.g. a pharmaceutical composition), or may occur as a kit of parts, wherein the different components form different parts of such a kit of parts. Administration of each compound of a combination of the present disclosure may occur either simultaneously or timely staggered, with similar or different timing of administration (i.e. similar or different numbers of administration of each component), either at the same site of administration or at different sites of administration, under similar of different dosage form. [157] The term “chemotherapy" refers to a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents) as part of a standardized chemotherapy regimen. Chemotherapy may be given with a curative intent or it may aim to prolong life or to reduce symptoms. Chemotherapeutic agents are for example selected from anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds and any combination thereof. [158] The term “hormone therapy” refers to the use of hormones in medical treatment. In one embodiment, the hormone therapy is oncologic hormone therapy. [159] The term “human” refers to a subject of both genders and at any stage of development (i.e. neonate, infant, juvenile, adolescent, adult). [160] The term “subject” and “patient” are used interchangeably and refer to a mammal, for instance, a human, who/which is awaiting the receipt of, or is receiving medical care or is/will be the object of a medical procedure. In some embodiments, a subject has previously received treatment with a A_2AR antagonist. The term “subject” refers to a mammal, for instance a human. In one embodiment, the subject is diagnosed with a cancer. In one embodiment, the subject is a patient, preferably a human patient, who/which is awaiting the receipt of, or is receiving, medical care or was/is/will be the subject of a medical procedure or is monitored for the development or progression of a disease, such as a cancer. In one embodiment, the subject is a human patient who is treated and/or monitored for the development or progression of a cancer. In one embodiment, the subject is a male. In another embodiment, the subject is a female. In one embodiment, the subject is an adult. In another embodiment, the subject is a child. [161] The term “immunotherapy” refers to a therapy aiming at inducing and/or enhancing an immune response towards a specific target, for example towards cancer cells. Immunotherapy may involve the use of checkpoint inhibitors, checkpoint agonists (also called T-cell agonists), IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, adenosine-producing enzymes inhibitors, adoptive transfer, therapeutic vaccines, and combinations thereof. [162] The expression “pharmaceutically acceptable” refers to the ingredients of a pharmaceutical composition are compatible with each other and not deleterious to the subject to which it is administered. [163] The expression “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” or “excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. [164] The terms “prevent”, “preventing” and “prevention”, as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a patient from acquiring a condition or disease, or reducing a patient’s risk of acquiring a condition or disease. [165] The term “prodrug” as used herein means the pharmacologically acceptable derivatives of compounds of Formula (I), such as for example esters or amides, whose in vivo biotransformation product generates the biologically active drug. [166] The term “radiation therapy” refers to a method of treatment of cancer employing various radiations such as X-ray, gamma-ray, neutron ray, electron beam, proton beam and radiation sources. It is used as part of cancer treatment to control or kill malignant cells. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor. The three main divisions of radiation therapy are: external beam radiation therapy (EBRT or XRT); brachytherapy or sealed source radiation therapy; and systemic radioisotope therapy (RIT) or unsealed source radiotherapy. [167] The terms “therapeutically effective amount” or “effective amount” or “therapeutically effective dose” refer to the amount or dose of active ingredient that is aimed at, without causing significant negative or adverse side effects to the subject, (1) delaying or preventing the onset of a cancer in the subject; (2) reducing the severity or incidence of a cancer; (3) slowing down or stopping the progression, aggravation, or deterioration of one or more symptoms of a cancer affecting the subject; (4) bringing about ameliorations of the symptoms of a cancer affecting the subject; or (5) curing a cancer affecting the subject. A therapeutically effective amount may be administered prior to the onset of a cancer for a prophylactic or preventive action. Alternatively, or additionally, a therapeutically effective amount may be administered after initiation of a cancer for a therapeutic action. [168] The terms “treating” or “treatment” refer to therapeutic treatment; wherein the object is to prevent or slow down the targeted pathologic condition or disease. A subject or mammal is successfully “treated” for a disease or affection or condition if, after receiving the treatment according to the present disclosure, the subject or mammal shows observable and/or measurable reduction in or absence of one or more of the following: reduction of the number of cancer cells; and/or relief to some extent, for one or more of the symptoms associated with the specific disease or condition; reduced morbidity and mortality, and improvement in quality of life issues. The above parameters for assessing successful treatment and improvement in the disease are readily measurable by routine procedures familiar to a physician. [169] The term “stem cell transplant” refers to a procedure in which a patient receives healthy blood-forming cells (stem cells) to replace their own that have been destroyed by disease or by the radiation or high doses of anticancer drugs that are given as part of the procedure. The healthy stem cells may come from the blood or bone marrow of the patient, from a donor, or from the umbilical cord blood of a newborn baby. A stem cell transplant may be autologous (using a patient’s own stem cells that were collected and saved before treatment), allogeneic (using stem cells donated by someone who is not an identical twin), or syngeneic (using stem cells donated by an identical twin). [170] The term “tumor-infiltrating lymphocyte (TIL)” refers to a cell of the immune system that is capable of targeting at least one type of tumor or a cell present in a tumor or a sample thereof. TILs are a component of tumor-infiltrating immune cells, that can also include other leukocytes (e.g., neutrophils, eosinophils, basophils, monocytes, macrophages and dendritic cells). Lymphocytes include T cells, B cells, plasma cells, and natural killer (NK) cells among other less abundant immune cell subsets. [171] The term “Interferon Regulatory Factor 4 (IRF4)” refers to a transcription factor belonging to the Interferon Regulatory Factor (IRF) family of transcription factors, and is involved in immune responses in normal B and T cells. MUM-1 (multiple myeloma 1 or multiple myeloma oncogene 1) is a protein encoded by the gene IRF4. [172] Cell marker refers to a biochemical and/or genetic characteristic which allows to distinguish between different types of cells, tissues, or organs, and/or different states of cells, tissues or organs. The marker may broadly denote a biological molecule, such as an endogenous biological molecule, and/or a detectable portion thereof, whose qualitative and/or quantitative evaluation in a tested object (e.g., in or on a cell, cell population, tissue, organ, or organism, e.g., in a biological sample of a subject) is predictive or informative with respect to one or more aspects of the tested object's phenotype and/or genotype. Markers may be nucleic acid-based or peptide-, polypeptide- and/or protein-based. For example, a marker may be comprised of peptide(s), polypeptide(s) and/or protein(s) encoded by a given gene, or of detectable portions thereof. Further, whereas the term “nucleic acid” generally encompasses DNA, RNA and DNA/RNA hybrid molecules, in the context of markers the term may refer to heterogeneous nuclear RNA (hnRNA), pre-mRNA, messenger RNA (mRNA), or complementary DNA (cDNA), or detectable portions thereof. Such nucleic acid species can be useful as markers, since they contain qualitative and/or quantitative information about the expression of the gene. In an embodiment, a nucleic acid-based marker may encompass mRNA of a given gene, or cDNA made of the mRNA, or detectable portions thereof. [173] Markers may be extracellular or cell surface markers, as methods to measure extracellular or cell surface marker(s) need not disturb the integrity of the cell membrane and may not require fixation/permeabilization of the cells. [174] Unless otherwise apparent from the context, reference herein to any marker, such as a peptide, polypeptide, protein, or nucleic acid, may generally also encompass modified forms of said marker, such as bearing post-expression modifications including, for example, phosphorylation, glycosylation, lipidation, methylation, cysteinylation, sulphonation, glutathionylation, acetylation, oxidation of methionine to methionine sulphoxide or methionine sulphone, and the like. [175] When a cell is said to be positive for or to express or comprise expression of a given marker, a skilled person would conclude the presence or evidence of a distinct signal for the marker when carrying out a measurement capable of detecting or quantifying the marker in or on the cell. Suitably, the presence or evidence of the distinct signal for the marker would be concluded based on a comparison of the measurement result obtained for the cell to a result of the same measurement carried out for a negative control (for example, a cell known to not express the marker) and/or a positive control (for example, a cell known to express the marker). The cell may be conventionally denoted as positive (“+”) for a particular marker when a cell expresses that marker, and applies to the protein as measured, for instance, by IHC or flow cytometry. [176] The term “antibody secreting cell (ASC)” refers to any cell type that produces and secretes an antibody. ASC is typically a specialized cell type that represents the end-stage of the B-cell differentiation program. Plasma cells (also referred to as "plasma B cells" or "plasmocytes") are terminally differentiated, and are one type of ASC. Other include plasma blasts, plasma cell precursors generated through the expansion of memory B cells, cell lines that express recombinant monoclonal antibodies, hybridoma cell lines. As ASCs differentiate and mature, they alter their surface protein and carbohydrate expression profile, which can be used as phenotypic markers for identifying subsets within the ASC population. [177] “Expression” includes all the functions by which a gene’s coded information is converted into structures present and operating in a cell. Such structures include, but are not limited to, the products of transcription and translation. DETAILED DESCRIPTION [178] Applicant has demonstrated that T cell proliferation and cytokine production is suppressed in the presence of high adenosine concentrations as found in the tumor microenvironment. Applicant has also demonstrated that A_2A receptor antagonists can restore T cell activity in tumors with high adenosine concentrations (see, e.g., PCT Publication WO2018/178338 “2-Oxo-Thiazole Derivatives as A2A Inhibitors and Compounds for Use in the Treatment of Cancers,” US Publication 2020/0102319 “Non Brain Penetrant A2A Inhibitors and Methods for Use in the Treatment of Cancers,” and PCT Publication WO2020/065036. [179] “Thiocarbamate Derivatives as A2A Inhibitors, Pharmaceutical Composition Thereof and Combinations with Anticancer Agents,” each of which is incorporated by reference in its entirety). In particular, the present disclosure shows among other things that using A_2A receptor as a biomarker is associated with clinical benefit. The present disclosure also shows A_2A receptor antagonists can also affect B cell activity, antibody-secreting cell activity, plasma cell activity, and/or tertiary lymphoid structure in tumors with high adenosine concentrations. Detection of Antibody-secreting cell (ASC) markers [180] In some embodiments, the antibody-secreting cells are lymphocytes. In some embodiments, the antibody-secreting cells are tumor-infiltrating lymphocytes. In some embodiments, the antibody-secreting cells are plasma cells or plasma blasts. [181] In some embodiments, the ASC markers can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD 138. [182] In some embodiments, the present disclosure provides a method to determine if a subject has an elevated level of expression of at least one ASC marker comprising: (a) detecting the level of expression of at least one ASC marker in a sample from the subject using an in vitro assay and (b) comparing the level of expression of at least one ASC marker to a suitable reference level of expression of at least one ASC marker. In some embodiments, a subject with elevated expression of at least one ASC marker is administered a compound or a combination of compounds effective for treatment of a patient having an elevated level of expression of at least one ASC marker. In some embodiments, a subject with elevated expression of at least one ASC marker is selected for treatment with a combination of compounds effective for treatment of a patient having an elevated level of expression of at least one ASC marker. In some embodiments, the compound or combination of compounds include an adenosine receptor antagonist, as further defined below. In some embodiments, the adenosine receptor antagonist is an antagonist of A₁ receptor, A_2A receptor, A_2B receptor, A3 receptor or of a combination thereof; preferably the adenosine receptor antagonist is an antagonist of A_2A receptor, A_2B receptor or of a combination thereof; more preferably the adenosine receptor antagonist is an A_2A receptor antagonist. [183] In some embodiments, the present disclosure provides a method to determine if a subject has an elevated density of cells positive for at least one ASC marker comprising: (a) detecting the density of cells positive for at least one ASC marker in a sample from the subject using an in vitro assay and (b) comparing the density of cells positive for at least one ASC marker to a suitable reference level of cells positive for at least one ASC marker. In some embodiments, a subject with a tumor with elevated density of cells positive for at least one ASC marker is administered a compound or a combination of compounds effective for treatment of a patient with a tumor having an elevated density of cells positive for at least one ASC marker. In some embodiments, a subject with a tumor with cells positive for elevated density of at least one ASC marker is selected for treatment with a compound or a combination of compounds effective for treatment of a patient with a tumor having cells positive for an elevated density of at least one ASC marker. In some embodiments, the compound or combination of compounds include an adenosine receptor antagonist, as further defined below. In some embodiments, the adenosine receptor antagonist is an antagonist of A₁ receptor, A_2A receptor, A_2B receptor, A₃ receptor or of a combination thereof; preferably the adenosine receptor antagonist is an antagonist of A_2A receptor, A_2B receptor or of a combination thereof; more preferably the adenosine receptor antagonist is an A_2A receptor antagonist. [184] In some embodiments, the present disclosure provides a method to determine if a subject has an elevated infiltration of cells positive for at least one ASC marker comprising: (a) detecting the infiltration of cells positive for at least one ASC marker in a sample from the subject using an in vitro assay and (b) comparing the infiltration of cells positive for at least one ASC marker to a suitable reference level of infiltration of cells positive at least one ASC marker. In some embodiments, a subject with a tumor with elevated infiltration of cells positive at least one ASC marker is administered a compound or a combination of compounds effective for treatment of a patient with a tumor having an elevated infiltration of cells positive at least one ASC marker. In some embodiments, a subject with a tumor with elevated infiltration of cells positive at least one ASC marker is selected for treatment with a compound or a combination of compounds effective for treatment of a patient with a tumor having an elevated infiltration of positive cells for at least one ASC marker. In some embodiments, the compound or combination of compounds include an adenosine receptor antagonist, as further defined below. In some embodiments, the adenosine receptor antagonist is an antagonist of A₁ receptor, A_2A receptor, A_2B receptor, A3 receptor or of a combination thereof; preferably the adenosine receptor antagonist is an antagonist of A_2A receptor, A_2B receptor or of a combination thereof; more preferably the adenosine receptor antagonist is an A_2A receptor antagonist. [185] In some embodiments, the gene expression of at least one ASC marker or density of cells positive for at least one ASC marker may be determined using a suitable in vitro assay. In some embodiments, the gene expression of at least one ASC marker or density of cells positive for at least one ASC marker may be determined by measuring the levels, amount or concentration of at least one ASC marker at the RNA or protein levels. In some embodiments, the gene expression of at least one ASC marker or density of cells positive for at least one ASC marker may be determined by measuring a RNA or protein level in a sample. In vitro assays for measuring the level, amount or concentration of at least one ASC marker at the RNA level include, without limitation, reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), in situ hybridization (ISH), RNA microarrays, Nanostring technology, and the like. In vitro assays for measuring the level, amount or concentration of at least one ASC marker at the protein level include, without limitation, immunohistochemistry (IHC), fluorescent IHC, flow cytometry, Western blotting, enzyme-linked immunosorbent assay (ELISA), and the like. [186] In some embodiments, gene expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker may be determined using a suitable in vitro assay. In some embodiments, gene expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker may be determined by measuring the levels, amount or concentration of at least one ASC marker at the RNA or protein levels. In some embodiments, gene expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker may be determined by measuring a RNA or protein level in a sample. In vitro assays for measuring the level, amount or concentration of at least one ASC marker at the RNA level include, without limitation, reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), in situ hybridization (ISH), DNA microarrays, Nanostring technology, and the like. In vitro assays for measuring the level, amount or concentration of at least one ASC marker at the protein level include, without limitation, immunohistochemistry (IHC), fluorescent IHC, flow cytometry, Western blotting, enzyme-linked immunosorbent assay (ELISA), and the like. [187] In some embodiments, gene expression of at least one ASC marker or density of cells positive for at least one ASC marker in a tumor is compared to a control, i.e., a suitable reference standard. In some embodiments, gene expression of at least one ASC marker or density of cells positive for at least one ASC marker in a tumor is compared to a control, i.e., a suitable reference standard. [188] In some embodiments, gene expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a tumor is compared to a control, i.e., a suitable reference standard. In some embodiments, gene expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a tumor is compared to a control, i.e., a suitable reference standard. In some embodiments, infiltration refers to an accumulation of cells into a tissue or other location as a result of migration from their sources of origin. [189] The terms “control” and “cutoff” refers to any reference standard suitable to provide a comparison to the expression products in the test sample. In one embodiment, the control comprises obtaining a “control sample” from which expression product levels are detected and compared to the expression product levels from the test sample. Such a control sample may comprise any suitable sample, including but not limited to a sample from a control cancer patient (can be stored sample or previous sample measurement) with a known outcome; normal tissue or cells isolated from a subject, such as a normal patient or the cancer patient, cultured primary cells/tissues isolated from a subject such as a normal subject or the cancer patient, adjacent normal cells/tissues obtained from the same organ or body location of the cancer patient, a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository. In another preferred embodiment, the control may comprise a reference standard expression product level from any suitable source, including but not limited to housekeeping genes, an expression product level range from normal tissue (or other previously analyzed control sample), a previously determined expression product level range within a test sample from a group of patients, or a set of patients with a certain outcome (for example, survival for one, two, three, four years, etc.) or receiving a certain treatment (for example, standard of care cancer therapy). It will be understood by those of skill in the art that such control samples and reference standard expression product levels can be used in combination as controls in the methods of the present disclosure. In one embodiment, the control may comprise normal or non-cancerous cell/tissue sample. In another preferred embodiment, the control may comprise an expression level for a set of patients, such as a set of cancer patients, or for a set of cancer patients receiving a certain treatment, or for a set of patients with one outcome versus another outcome. In the former case, the specific expression product level of each patient can be assigned to a percentile level of expression, or expressed as either higher or lower than the mean or average of the reference standard expression level. In another preferred embodiment, the control may comprise normal cells, cells from patients treated with combination chemotherapy, and cells from patients having benign cancer. In another embodiment, the control may also comprise a measured value for example, average level of expression of a particular gene in a population compared to the level of expression of a housekeeping gene in the same population. Such a population may comprise normal subjects, cancer patients who have not undergone any treatment (i.e., treatment naive), cancer patients undergoing standard of care therapy, or patients having benign cancer. In another preferred embodiment, the control comprises a ratio transformation of expression product levels, including but not limited to determining a ratio of expression product levels of two genes in the test sample and comparing it to any suitable ratio of the same two genes in a reference standard; determining expression product levels of the two or more genes in the test sample and determining a difference in expression product levels in any suitable control; and determining expression product levels of the two or more genes in the test sample, normalizing their expression to expression of housekeeping genes in the test sample, and comparing to any suitable control. In particularly preferred embodiments, the control comprises a control sample which is of the same lineage and/or type as the test sample. In another embodiment, the control may comprise expression product levels grouped as percentiles within or based on a set of patient samples, such as all patients with cancer. In one embodiment a control expression product level is established wherein higher or lower levels of expression product relative to, for instance, a particular percentile, are used as the basis for predicting outcome. In another preferred embodiment, a control expression product level is established using expression product levels from cancer control patients with a known outcome, and the expression product levels from the test sample are compared to the control expression product level as the basis for predicting outcome. As demonstrated by the data below, the methods of the disclosure are not limited to use of a specific cut-point in comparing the level of expression product in the test sample to the control. [190] In some embodiments, a suitable control or reference standard is gene expression of at least one ASC marker or density of cells positive for at least one ASC marker in a subject not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is the mean gene expression of at least one ASC marker or mean density of cells positive for at least one ASC marker in a population of subjects not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is gene expression of at least one ASC marker or density of cells positive for at least one ASC marker of a sample from the subjects themselves. In some embodiments, a suitable reference standard is gene expression of at least one ASC marker or density of cells positive for at least one ASC marker in a non-cancerous cellular sample adjacent to a tumor from the subject themselves. [191] In some embodiments, the present disclosure includes determining a level of gene expression of at least one ASC marker or density of cells positive for at least one ASC marker in a tumor in a subject comprising obtaining or having obtained a biological sample from the subject; and performing an assay on the biological sample to determine if the tumor has an elevated level of gene expression or density of cells positive for at least one ASC marker. [192] In some embodiments, the methods of determining a level of gene expression of at least one ASC marker or density of cells positive for at least one ASC marker disclosed herein are in vitro method. In some embodiments, the methods are performed on a sample previously obtained from the subject. [193] In some embodiments, a suitable control or reference standard is gene expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a subject not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is the mean gene expression of at least one ASC marker or mean infiltration of cells positive for at least one ASC marker in a population of subjects not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is gene expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker of a sample from the subjects themselves. In some embodiments, a suitable reference standard is gene expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a non-cancerous cellular sample adjacent to a tumor from the subject themselves. [194] In some embodiments, the present disclosure includes determining a level of gene expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a tumor in a subject comprising obtaining or having obtained a biological sample from the subject; and performing an assay on the biological sample to determine if the tumor has an elevated level of gene expression of at least one ASC marker or infiltration of at least one ASC marker. [195] In some embodiments, the methods of determining a level of at least one ASC marker expression or infiltration of cells positive for at least one ASC marker disclosed herein are in vitro method. In some embodiments, the methods are performed on a sample previously obtained from the subject. [196] In some embodiments, the sample is a bodily fluid. In some embodiments, the sample is a bodily tissue. In some embodiments, the sample is a tumor tissue sample. In some embodiments, the tumor tissue sample comprises tumor cells. In some embodiments, the tumor tissue sample further comprises tumor infiltrating immune cells. In some embodiments, the tumor tissue sample does not comprise tumor infiltrating immune cells. [197] In some embodiments, the level of ASC marker expression is considered as “elevated” or “increased” or “higher” when said level is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more higher than the level of ASC marker expression in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves. [198] In some embodiments, ASC marker log2 expression is considered as “elevated” or “increased” or “higher” when said ASC marker log2 expression is above about -5.0, -5.1, - 5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, or -5.9. In some embodiments, the level of ASC marker expression is considered as “elevated” or “increased” or “higher” when said level is above about -5.56. In some embodiments, the level of ASC marker expression is considered as “elevated” or “increased” or “higher” when the ASC marker log2 expression value relative to the reference value is greater than -5.0 to -6.0. In some embodiments, the level of ASC marker expression is considered as “elevated” or “increased” or “higher” when the ASC marker log2 expression value relative to the reference value is greater than about -5.2 to -5.8. In some embodiments, the level of ASC marker expression is considered as “elevated” or “increased” or “higher” when the ASC marker log2 expression value relative to the reference value is greater than about -5.4 to -5.6. In some embodiments, the level of ASC marker expression is considered as “elevated” or “increased” or “higher” when the ASC marker log2 expression value relative to the reference value is greater than about -5.0, -5.1, -5.2, -5.3, - 5.4, -5.5, -5.6, -5.7, -5.8, or -5.9. In some embodiments, the level of ASC marker expression is considered as “elevated” or “increased” or “higher” when the ASC marker log2 expression value relative to the reference value is greater than about -5.56. [199] In some embodiments, the density of cells positive for at least one ASC marker is considered as “elevated” or “increased” or “higher” when said density is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more higher than the density of cells positive for the ASC marker in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves. [200] In some embodiments, the infiltration of cells positive for the ASC marker is considered as “elevated” or “increased” or “higher” when said infiltration is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more higher than the infiltration of cells positive for the ASC marker in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves. In some embodiments, the density of cells positive for at least one ASC marker may be determined in a 4-to-5 µm-thick section of a bodily tissue, in particular of a tumor tissue. Detection of MUM-1 [201] MUM-1 is a protein coded by the gene IRF4. [202] In some embodiments, the present disclosure provides a method to determine if a subject has an elevated level of IRF4 expression comprising: (a) detecting the level of IRF4 expression in a sample from the subject using an in vitro assay and (b) comparing the level of the IRF4 expression to a suitable reference level of IRF4 expression. In some embodiments, a subject with elevated IRF4 expression is administered a compound or a combination of compounds effective for treatment of a patient having an elevated level of IRF4 expression. In some embodiments, a subject with elevated IRF4 expression is selected for treatment with a combination of compounds effective for treatment of a patient having an elevated level of IRF4 expression. In some embodiments, the compound or combination of compounds include an adenosine receptor antagonist, as further defined below. In some embodiments, the adenosine receptor antagonist is an antagonist of A₁ receptor, A_2A receptor, A_2B receptor, A3 receptor or of a combination thereof; preferably the adenosine receptor antagonist is an antagonist of A_2A receptor, A_2B receptor or of a combination thereof; more preferably the adenosine receptor antagonist is an A_2A receptor antagonist. [203] In some embodiments, the present disclosure provides a method to determine if a subject has an elevated density of MUM-1⁺ cells comprising: (a) detecting the density of MUM-1⁺ cells in a sample from the subject using an in vitro assay and (b) comparing the density of MUM-1⁺ cells to a suitable reference level of density of MUM-1⁺ cells. In some embodiments, a subject with a tumor with elevated density of MUM-1⁺ cells is administered a compound or a combination of compounds effective for treatment of a patient with a tumor having an elevated density of MUM-1⁺ cells. In some embodiments, a subject with a tumor with elevated density of MUM-1⁺ cells is selected for treatment with a compound or a combination of compounds effective for treatment of a patient with a tumor having an elevated density of MUM-1⁺ cells. In some embodiments, the compound or combination of compounds include an adenosine receptor antagonist, as further defined below. In some embodiments, the adenosine receptor antagonist is an antagonist of A₁ receptor, A_2A receptor, A_2B receptor, A₃ receptor or of a combination thereof; preferably the adenosine receptor antagonist is an antagonist of A_2A receptor, A_2B receptor or of a combination thereof; more preferably the adenosine receptor antagonist is an A_2A receptor antagonist. [204] In some embodiments, the present disclosure provides a method to determine if a subject has an elevated infiltration of MUM-1⁺ cells comprising: (a) detecting the infiltration of MUM-1⁺ cells in a sample from the subject using an in vitro assay and (b) comparing the infiltration of MUM-1⁺ cells to a suitable reference level of infiltration of MUM-1⁺ cells. In some embodiments, a subject with a tumor with elevated infiltration of MUM-1⁺ cells is administered a compound or a combination of compounds effective for treatment of a patient with a tumor having an elevated infiltration of MUM-1⁺ cells. In some embodiments, a subject with a tumor with elevated infiltration of MUM-1⁺ cells is selected for treatment with a compound or a combination of compounds effective for treatment of a patient with a tumor having an elevated infiltration of MUM-1⁺ cells. In some embodiments, the compound or combination of compounds include an adenosine receptor antagonist, as further defined below. In some embodiments, the adenosine receptor antagonist is an antagonist of A₁ receptor, A_2A receptor, A_2B receptor, A₃ receptor or of a combination thereof; preferably the adenosine receptor antagonist is an antagonist of A_2A receptor, A_2B receptor or of a combination thereof; more preferably the adenosine receptor antagonist is an A_2A receptor antagonist. [205] In some embodiments, MUM-1⁺ cells are lymphocytes. In some embodiments, MUM-1⁺ cells are tumor-infiltrating lymphocytes. [206] In some embodiments, IRF4 expression or density of MUM-1⁺ cells may be determined using a suitable in vitro assay. In some embodiments, IRF4 expression or density of MUM-1⁺ cells may be determined by measuring the levels, amount or concentration of IRF4/MUM-1 at the RNA or protein levels. In some embodiments, IRF4 expression or density of MUM-1⁺ cells may be determined by measuring a RNA or protein level in a sample. In vitro assays for measuring the level, amount or concentration of IRF4 at the RNA level include, without limitation, reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), in situ hybridization (ISH), DNA microarrays, Nanostring technology, and the like. In vitro assays for measuring the level, amount or concentration of IRF4/MUM-1 at the protein level include, without limitation, immunohistochemistry (IHC), fluorescent IHC, flow cytometry, Western blotting, enzyme-linked immunosorbent assay (ELISA), and the like. [207] In some embodiments, IRF4 expression or infiltration of MUM-1⁺ cells may be determined using a suitable in vitro assay. In some embodiments, IRF4 expression or infiltration of MUM-1⁺ cells may be determined by measuring the levels, amount or concentration of MUM-1 at the RNA or protein levels. In some embodiments, IRF4 expression or infiltration of MUM-1⁺ cells may be determined by measuring a RNA or protein level in a sample. In vitro assays for measuring the level, amount or concentration of IRF4 at the RNA level include, without limitation, reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR), in situ hybridization (ISH), DNA microarrays, Nanostring technology, and the like. In vitro assays for measuring the level, amount or concentration of IRF4/MUM-1 at the protein level include, without limitation, immunohistochemistry (IHC), fluorescent IHC, flow cytometry, Western blotting, enzyme-linked immunosorbent assay (ELISA), and the like. [208] In some embodiments, IRF4 expression or density of MUM-1⁺ cells in a tumor is compared to a control, i.e., a suitable reference standard. In some embodiments, IRF4 expression or density of MUM-1⁺ cells in a tumor is compared to a control, i.e., a suitable reference standard. [209] In some embodiments, IRF4 expression or infiltration of MUM-1⁺ cells in a tumor is compared to a control, i.e., a suitable reference standard. In some embodiments, IRF4 expression or infiltration of MUM-1⁺ cells in a tumor is compared to a control, i.e., a suitable reference standard. In some embodiments, infiltration refers to an accumulation of cells into a tissue or other location as a result of migration from their sources of origin. [210] The terms “control” and “cutoff” refers to any reference standard suitable to provide a comparison to the expression products in the test sample. In one embodiment, the control comprises obtaining a “control sample” from which expression product levels are detected and compared to the expression product levels from the test sample. Such a control sample may comprise any suitable sample, including but not limited to a sample from a control cancer patient (can be stored sample or previous sample measurement) with a known outcome; normal tissue or cells isolated from a subject, such as a normal patient or the cancer patient, cultured primary cells/tissues isolated from a subject such as a normal subject or the cancer patient, adjacent normal cells/tissues obtained from the same organ or body location of the cancer patient, a tissue or cell sample isolated from a normal subject, or a primary cells/tissues obtained from a depository. In another preferred embodiment, the control may comprise a reference standard expression product level from any suitable source, including but not limited to housekeeping genes, an expression product level range from normal tissue (or other previously analyzed control sample), a previously determined expression product level range within a test sample from a group of patients, or a set of patients with a certain outcome (for example, survival for one, two, three, four years, etc.) or receiving a certain treatment (for example, standard of care cancer therapy). It will be understood by those of skill in the art that such control samples and reference standard expression product levels can be used in combination as controls in the methods of the present disclosure. In one embodiment, the control may comprise normal or non-cancerous cell/tissue sample. In another preferred embodiment, the control may comprise an expression level for a set of patients, such as a set of cancer patients, or for a set of cancer patients receiving a certain treatment, or for a set of patients with one outcome versus another outcome. In the former case, the specific expression product level of each patient can be assigned to a percentile level of expression, or expressed as either higher or lower than the mean or average of the reference standard expression level. In another preferred embodiment, the control may comprise normal cells, cells from patients treated with combination chemotherapy, and cells from patients having benign cancer. In another embodiment, the control may also comprise a measured value for example, average level of expression of a particular gene in a population compared to the level of expression of a housekeeping gene in the same population. Such a population may comprise normal subjects, cancer patients who have not undergone any treatment (i.e., treatment naive), cancer patients undergoing standard of care therapy, or patients having benign cancer. In another preferred embodiment, the control comprises a ratio transformation of expression product levels, including but not limited to determining a ratio of expression product levels of two genes in the test sample and comparing it to any suitable ratio of the same two genes in a reference standard; determining expression product levels of the two or more genes in the test sample and determining a difference in expression product levels in any suitable control; and determining expression product levels of the two or more genes in the test sample, normalizing their expression to expression of housekeeping genes in the test sample, and comparing to any suitable control. In particularly preferred embodiments, the control comprises a control sample which is of the same lineage and/or type as the test sample. In another embodiment, the control may comprise expression product levels grouped as percentiles within or based on a set of patient samples, such as all patients with cancer. In one embodiment a control expression product level is established wherein higher or lower levels of expression product relative to, for instance, a particular percentile, are used as the basis for predicting outcome. In another preferred embodiment, a control expression product level is established using expression product levels from cancer control patients with a known outcome, and the expression product levels from the test sample are compared to the control expression product level as the basis for predicting outcome. As demonstrated by the data below, the methods of the disclosure are not limited to use of a specific cut-point in comparing the level of expression product in the test sample to the control. [211] In some embodiments, a suitable control or reference standard is IRF4 expression level or density of MUM-1⁺ cells in a subject not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is the mean IRF4 expression level or mean density of MUM-1⁺ cells in a population of subjects not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is IRF4 expression level or density of MUM-1⁺ cells of a sample from the subjects themselves. In some embodiments, a suitable reference standard is IRF4 expression level or density of MUM-1⁺ cells in a non- cancerous cellular sample adjacent to a tumor from the subject themselves. [212] In some embodiments, the present disclosure includes determining a level of IRF4 expression or density of MUM-1⁺ cells in a tumor in a subject comprising obtaining or having obtained a biological sample from the subject; and performing an assay on the biological sample to determine if the tumor has an elevated level of IRF4 expression or density of MUM-1⁺ cells. [213] In some embodiments, the methods of determining a level of IRF4 expression or density of MUM-1⁺ cells disclosed herein are in vitro method. In other words, the methods are non-invasive and do not include a step of taking a sample from the subject. In some embodiments, the methods are performed on a sample previously obtained from the subject. [214] In some embodiments, a suitable control or reference standard is IRF4 expression level or infiltration of MUM-1⁺ cells in a subject not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is the mean IRF4 expression level or mean infiltration of MUM-1⁺ cells in a population of subjects not affected and/or diagnosed with cancer. In some embodiments, a suitable reference standard is IRF4 expression level or infiltration of MUM-1⁺ cells of a sample from the subjects themselves. In some embodiments, a suitable reference standard is IRF4 expression level or infiltration of MUM- 1⁺ cells in a non-cancerous cellular sample adjacent to a tumor from the subject themselves. [215] In some embodiments, the present disclosure includes determining a level of IRF4 expression or infiltration of MUM-1⁺ cells in a tumor in a subject comprising obtaining or having obtained a biological sample from the subject; and performing an assay on the biological sample to determine if the tumor has an elevated level of IRF4 expression or infiltration of MUM-1⁺ cells. [216] In some embodiments, the methods of determining a level of IRF4 expression or infiltration of MUM-1⁺ cells disclosed herein are in vitro method. In other words, the methods are non-invasive and do not include a step of taking a sample from the subject. In some embodiments, the methods are performed on a sample previously obtained from the subject. [217] In some embodiments, the sample is a bodily fluid. In some embodiments, the sample is a bodily tissue. In some embodiments, the sample is a tumor tissue sample. In some embodiments, the tumor tissue sample comprises tumor cells. In some embodiments, the tumor tissue sample further comprises tumor infiltrating immune cells. In some embodiments, the tumor tissue sample does not comprise tumor infiltrating immune cells. [218] In some embodiments, the level of IRF4 expression is considered as “elevated” or “increased” or “higher” when said level is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, or more higher than the level of IRF4 expression in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves. [219] In some embodiments, IRF4 log2 expression is considered as “elevated” or “increased” or “higher” when said IRF4 log2 expression is above about -5.0, -5.1, -5.2, -5.3, - 5.4, -5.5, -5.6, -5.7, -5.8, or -5.9. In some embodiments, the level of IRF4 expression is considered as “elevated” or “increased” or “higher” when said level is above about -5.56. In some embodiments, the level of IRF4 expression is considered as “elevated” or “increased” or “higher” when the IRF4 log2 expression value relative to the reference value is greater than -5.0 to -6.0. In some embodiments, the level of IRF4 expression is considered as “elevated” or “increased” or “higher” when the IRF4 log2 expression value relative to the reference value is greater than about -5.2 to -5.8. In some embodiments, the level of IRF4 expression is considered as “elevated” or “increased” or “higher” when the IRF4 log2 expression value relative to the reference value is greater than about -5.4 to -5.6. In some embodiments, the level of IRF4 expression is considered as “elevated” or “increased” or “higher” when the IRF4 log2 expression value relative to the reference value is greater than about -5.0, -5.1, -5.2, -5.3, -5.4, -5.5, -5.6, -5.7, -5.8, or -5.9. In some embodiments, the level of IRF4 expression is considered as “elevated” or “increased” or “higher” when the IRF4 log2 expression value relative to the reference value is greater than about -5.56. [220] In some embodiments, the density of MUM-1⁺ cells is considered as “elevated” or “increased” or “higher” when said density is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more higher than the density of MUM-1⁺ cells in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves. [221] In some embodiments, the infiltration of MUM-1⁺ cells is considered as “elevated” or “increased” or “higher” when said infiltration is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100% or more higher than the infiltration of MUM-1⁺ cells in a control subject or population, e.g., in a subject or a population of subjects not affected and/or diagnosed with cancer, or in a sample such as a non-cancerous sample from the subject themselves. In some embodiments, the density of MUM-1⁺ cells is considered as “elevated” or “increased” or “higher” when said density is equal or above about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 or more MUM-1⁺ cells/mm², preferably equal or above about 35 MUM-1⁺ cells/mm². In some embodiments, the density of MUM-1⁺ cells is considered as “elevated” or “increased” or “higher” when said density is equal or above about 20-50 cells/mm². In some embodiments, the density of MUM-1⁺ cells is considered as “elevated” or “increased” or “higher” when said density is equal or above about 25-45 cells/mm². In some embodiments, the density of MUM-1⁺ cells is considered as “elevated” or “increased” or “higher” when said density is equal or above about 30-40 cells/mm². In some embodiments, the density of MUM-1⁺ cells may be determined in a 4-to-5 µm-thick section of a bodily tissue, in particular of a tumor tissue. Adenosine Receptor Antagonists and Methods of Use Thereof [222] As defined above, “adenosine receptor antagonist” refers to a compound that, upon administration to a patient, results in inhibition or down-regulation of a biological activity associated with activation of an adenosine receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to an adenosine receptor of its natural ligand. Such adenosine receptor antagonists include any agent that can block activation of an adenosine receptor or any of the downstream biological effects of an adenosine receptor activation. [223] Adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as endogenous ligand. There are four known types of adenosine receptors in humans: A₁, A_2A, A_2B and A₃; each is encoded by a different gene (ADOARA1, ADORA2A, ADORA2B, and ADORA3 respectively). [224] In one embodiment, an adenosine receptor antagonist is an antagonist of A₁ receptor, A_2A receptor, A_2B receptor, A₃ receptor or of a combination thereof. [225] In one embodiment, an adenosine receptor antagonist is an antagonist of A_2A receptor, A_2B receptor or of a combination thereof. In one embodiment, an adenosine receptor antagonist is an A_2A or A_2B receptor antagonist. [226] In one embodiment, an adenosine receptor antagonist is an antagonist of A_2A receptor (A_2AR antagonist). In one embodiment, the adenosine receptor antagonist is an antagonist of A_2B receptor (A_2BR antagonist). [227] In one embodiment, an adenosine receptor antagonist is an antagonist that is selective of A_2A receptor with respect to other adenosine receptors. In one embodiment, the adenosine receptor antagonist is an antagonist that is selective of A_2A receptor with respect to A_2B receptor. [228] In one embodiment, an adenosine receptor antagonist is an antagonist that is selective of A_2B receptor with respect to other adenosine receptors. In one embodiment, an adenosine receptor antagonist is an antagonist that is selective of A_2B receptor with respect to A_2A receptor. A_2A receptor Antagonists [229] An “A_2AR antagonist” refers to a compound that, upon administration to a subject, results in inhibition or down-regulation of a biological activity associated with activation of A_2A receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to A_2A receptor of its natural ligand. Such A_2AR antagonists include any agent that can block activation of A_2A receptor or any of the downstream biological effects of A_2A receptor activation. [230] In some embodiments, an A_2AR antagonist includes, but is not limited to, Preladenant (SCH-420,814), Vipadenant (BIIB-014), Tozadenant (SYK-115), ATL-444, Istradefylline (KW-6002), MSX-3, SCH-58261, SCH-412,348, SCH-442,416, ST-1535, Caffeine, VER-6623, VER-6947, VER-7835, ZM-241,385, theophylline. In some embodiments, an A_2AR antagonist includes, but is not limited to, compounds disclosed in WO2018/178338, WO2011/121418, WO2009/156737, WO2011/095626 or WO2018/136700, the contents of which are herein incorporated by reference. [231] In one embodiment, an A_2AR antagonist is a thiocarbamate disclosed in WO2018/178338. In some embodiments, an A_2AR antagonist is a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ represents a 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein the heteroaryl or aryl groups are optionally substituted by one or more substituent selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R¹ represents a 5-membered heteroaryl; more preferably R¹ a represents furyl; R² represents a 6-membered aryl or 6-membered heteroaryl, wherein the heteroaryl or aryl groups are optionally substituted by one or more substituent selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino and alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl alkylsulfonyl and alkylsulfonealkyl; or the heteroaryl or aryl groups are optionally substituted with two substituents that form together with the atoms to which they are attached a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring; optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl. [232] In one embodiment, an A_2AR antagonist is a compound of Formula (Ia):

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ represents a 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein the heteroaryl or aryl groups are optionally substituted by one or more substituent selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R¹ represents a 5-membered heteroaryl; more preferably R¹ represents a furyl; X¹ and X² represent each independently C or N; R^1’ is absent when X¹ is N; or when X¹ is C, R^1’ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyl; said R^1’being optionally substituted where appropriate by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; R^2’ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl; said R^2’ being optionally substituted where appropriate by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; or R^1’ and R^2’ form together with the atoms to which they are attached a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring; optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl; R^3’ is absent when X² is N; or when X² is C, R^3’ represents H or halo, preferably H or F; R^4’ represents H or halo, preferably H or F; and R^5’ represents H or halo, preferably H or F. [233] In some embodiments, an A_2AR antagonist is a compound of Formula (Ia-1):

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹, R^1’, R^2’, R^3’, R^4’ and R^5’ are as defined in Formula (Ia). [234] In some embodiments, an A_2AR antagonist is a compound of Formula (Ia-1a):

(Ia-1a) or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ and R^3’ are as defined in Formula (Ia); and R^1” represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl. [235] In one embodiment, a A_2AR antagonist is a compound of Formula (Ia-1b):

(Ia-1b) or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ and R^3’ are as defined in Formula (Ia); R^1’ represents H or halo, preferably H or F; and R^2” represents an alkyl or heterocyclyl group substituted by one or more group selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl. [236] In one embodiment, an A_2AR antagonist is a compound of Formula (Ia-1c) or (Ia- 1d):

or a pharmaceutically acceptable salt or solvate thereof, wherein: R¹ and R^3’ are as defined in Formula (Ia); R^1’ represents H or halo, preferably H or F; R^2’ represents H or halo, preferably H or F; R¹ⁱ and R¹ⁱⁱ represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl; and R²ⁱ and R²ⁱⁱ represent each independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl. [237] In some embodiments, an A_2AR antagonist is a compound of Formulae (Ia-2) or (IIa-3):

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹, R^2’, R^3’, R^4’ and R^5’ are as defined in Formula (Ia). [238] In some embodiments an A_2AR antagonist is a compound selected from the group consisting of: 3-(2-(4-(4-((1H-1,2,3-triazolo-4-yl)methoxy-2-fluorophenyl)piperazine-1-yl)ethyl)-5-amino- (8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidine-2(3H)-one; 5-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)-1,3,4-oxadiazol-2(3H)-one; 5-amino-3-(2-(4-(3-fluoropyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo [1,5-c] pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetamide; (S)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)- 8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)- 8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2-hydroxyethoxy) phenyl)piperazin-1- yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)acetic acid; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)acetamide; 5-amino-3-(2-(4-(4-(2,3-dihydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(4-(2-aminoethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e] [1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl) ethyl)piperazin-1-yl)benzamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-methylbenzamide; 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2-morpholinoethoxy)phenyl)piperazin-1- yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(4-(2-(dimethylamino)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)benzenesulfonamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c] pyrimidin-3(2H)- yl)ethyl) piperazin-1-yl)-N-methylbenzenesulfonamide; 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfonyl) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfinyl) phenyl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)benzamide; 5-amino-8-(furan-2-yl)-3-(2-(4-(3-(2-hydroxyethoxy) phenyl)piperazin-1- yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-ylmethoxy) phenyl)piperazin-1-yl)ethyl)-8-(furan- 2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(piperazine-1-carbonyl) phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan- 2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(piperazin-1-ylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(methylsulfonyl)phenyl) piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-aminoethyl)-3-fluorobenzamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylamino)ethyl) benzamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluorobenzamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-3-fluorobenzamide; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetic acid; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl) piperazin-1-yl)-3,5-difluorophenoxy) acetic acid; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid; (S)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-2-methylpropanoic acid; 3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)propanoic acid; 4-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)butanoic acid; 2-(3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,6-difluorophenoxy) acetic acid; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetic acid; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluorobenzoic acid; 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl) amino)acetamide; 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)(methyl)amino)acetamide; 5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-yloxy) phenyl)piperazin-1-yl) ethyl)-8-(furan-2-yl) thiazolo[5,4-e][1,2,4] triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(pyrrolidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 3-(2-(4-(4-((1H-1,2,4-triazol-3-yl)methoxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-5-amino-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(methylamino)ethyl) acetamide; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl) ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(dimethylamino)ethyl) acetamide; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-aminoethyl)acetamide; (R)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl) ethyl)piperazin-1-yl)-3-fluorophenoxy)acetamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-methyl-N-(2-(methylamino)ethyl) benzamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluoro-N-methylbenzamide; (R)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl) ethyl)piperazin-1-yl)-N-(1-(dimethylamino) propan-2-yl)-3-fluorobenzamide; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl) ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-methyl-N-(2-(methylamino)ethyl) acetamide; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-2-methylpropanoic acid; (S)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) propanoic acid; (R)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) propanoic acid; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(methylamino)ethyl) acetamide; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(dimethylamino)ethyl) acetamide; 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluoro-N-methylbenzamide; 4-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo [5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) butanoic acid; 3-(2-(4-(5-((1H-tetrazol-5-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-5-amino-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy) phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl) methoxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl) ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methyl (oxetan-3-yl)amino)ethyl) benzamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-((2-hydroxyethyl)amino)ethyl)benzamide; 2-amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl) acetamide; (S)-2-amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)-3-methylbutanamide; ethyl 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e] [1,2,4]triazolo[1,5-c] pyrimidin-3(2H)-yl) ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetate; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy) acetonitrile; 5-amino-8-(furan-2-yl)-3-(2-(4-(pyridin-4-yl) piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-8-(furan-2-yl)-3-(2-(4-(pyrimidin-4-yl)piperazin-1-yl)ethyl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(6-fluoro-2-oxoindolin-5-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(S-methylsulfonimidoyl)phenyl)piperazin-1-yl)ethyl)-8-(furan- 2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluorobenzamide; 5-amino-3-(2-(4-(5-fluoro-2-methylpyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin- 1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(3,3,3-trifluoro-2-hydroxypropoxy)phenyl)piperazin-1-yl)ethyl)- 8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-5-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)- 8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-morpholinoethyl)acetamide; 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(morpholin-3-ylmethyl)benzamide; 5-amino-3-(2-(4-(2-fluoro-4-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan- 2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan- 2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-morpholinoethyl)acetamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-morpholinoethyl)benzamide; 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)- yl)ethyl)piperazin-1-yl)-3-fluoro-N-(morpholin-3-ylmethyl)benzamide; 5-amino-3-(2-(4-(4-(azetidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one; (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide; (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide; (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2- (methylsulfinyl)ethyl)benzamide; (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2- (methylsulfinyl)ethyl)benzamide; 5-amino-3-(2-(4-(2,4-difluoro-5-(1-oxidothiomorpholine-4-carbonyl)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2,4-difluoro-5-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4- yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5- c]pyrimidin-2(3H)-one; (S)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide; (R)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide; 5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholine-4-carbonyl)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(furan- 2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8- (furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide; (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin- 3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide; 5-amino-3-(2-(4-(4-(azetidin-3-yloxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-amino-3-(2-(4-(5-(azetidin-3-yloxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2- yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; and (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(3-(methylsulfinyl)propoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof. [239] In some embodiments, an A_2AR antagonist is selected from the group consisting of: (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; and (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof. [240] In some embodiments, an A_2AR antagonist is selected from the group consisting of: (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; and (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt or solvate thereof. [241] In some embodiments, an A_2AR antagonist is (R,S)-5-amino-3-(2-(4-(2,4-difluoro- 5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt or solvate thereof. [242] In some embodiments, an A_2AR antagonist is (+)-5-amino-3-(2-(4-(2,4-difluoro-5- (2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt or solvate thereof. [243] In some embodiments, an A_2AR antagonist is (-)-5-amino-3-(2-(4-(2,4-difluoro-5- (2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt or solvate thereof. [244] In some embodiments, an A_2AR antagonist is (R)-5-amino-3-(2-(4-(2,4-difluoro-5- (2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt or solvate thereof. [245] In some embodiments, an A_2AR antagonist is (S)-5-amino-3-(2-(4-(2,4-difluoro-5- (2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt or solvate thereof. [246] In some embodiments, an A_2AR antagonist is (R)-5-amino-3-(2-(4-(2,4-difluoro-5- (2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt thereof. [247] In some embodiments, an A_2AR antagonist is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2- (methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharmaceutically acceptable salt thereof. [248] In some embodiments, an A_2AR antagonist is (R)-5-amino-3-(2-(4-(2,4-difluoro-5- (2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one. [249] In some embodiments, an A_2AR antagonist is (S)-5-amino-3-(2-(4-(2,4-difluoro-5- (2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4- e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one. [250] In another embodiment, an A_2AR antagonist is an A_2AR antagonist disclosed in WO2011/121418. Especially, an A_2AR antagonist is the compound of example 1 of WO2011/121418, namely 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine, also known as NIR178:

. [251] In another embodiment, an A_2AR antagonist is an A_2AR antagonist disclosed in WO2009/156737. Especially, an A_2AR antagonist is the compound of example 1S of WO2009/156737, namely (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3- yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine, also known as CPI-444:

. [252] In another embodiment, an A_2AR antagonist is an A_2AR antagonist disclosed in WO2011/095626. Especially, the A_2AR antagonist is the compound (cxiv) of WO2011/095626, namely 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4- triazin-3-amine, also known as AZD4635:

[253] In another embodiment, an A_2AR antagonist is an A_2AR antagonist disclosed in WO2018/136700. Especially, the A_2AR antagonist is the compound of example 1 of WO2018/136700, namely 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)- 1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile, also known as AB928:

[254] In another embodiment, an A_2AR antagonist is Preladenant (SCH-420,814), namely 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H- pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine:

[255] In another embodiment, an A_2AR antagonist is Vipadenant (BIIB-014), namely 3- (4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidine-5-amine:

[256] In another embodiment, an A_2AR antagonist is Tozadenant (SYK-115), namely 4- hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1- carboxamide:

. [257] In one embodiment, an adenosine receptor antagonist is selected from: 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2- yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4- yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H- pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidine-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidine-5- amine; and 4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1- carboxamide; (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; or a pharmaceutically acceptable salts thereof. [258] In one embodiment, an adenosine receptor antagonist is 5-bromo-2,6-di-(1H- pyrazol-1-yl)pyrimidin-4-amine. In one embodiment, an adenosine receptor antagonist is (S)- 7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H- [1,2,3]triazolo[4,5-d]pyrimidin-5-amine. In one embodiment, an adenosine receptor antagonist is 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine. In one embodiment, an adenosine receptor antagonist is 3-(2-amino-6-(1-((6-(2-hydroxypropan- 2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile. A_2B and A3 receptor antagonists [259] An “A_2BR antagonist” refers to a compound that, upon administration to a patient, results in inhibition or down-regulation of a biological activity associated with activation of A_2B receptor in the patient, including any of the downstream biological effects otherwise resulting from the binding to A_2B receptor of its natural ligand. Such A_2BR antagonists include any agent that can block activation of A_2B receptor or any of the downstream biological effects of A_2B receptor activation. [260] Examples of A_2BR antagonists include: Vipadenant (BIIB-014), CVT-6883, MRS- 1706, MRS-1754, PSB-603, PSB-0788, PSB-1115, OSIP-339,391, ATL-801, theophylline, or Caffeine. [261] Examples of inhibitors of A_2B receptor include ATL-801, CVT-6883, MRS-1706, MRS-1754, OSIP-339,391, PSB-603, PSB-0788 and PSB-1115. [262] Examples of inhibitors of A₃ receptor include KF-26777, MRS-545, MRS-1191, MRS-1220, MRS-1334, MRS-1523, MRS-3777, MRE-3005-F20, MRE-3008-F20, PSB-11, OT-7999, VUF-5574 and SSR161421. Methods [263] In some embodiments, the present disclosure includes a method of treating cancer characterized by increased IRF4 expression or infiltration of MUM-1⁺ cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased IRF4 expression or infiltration of MUM-1⁺ cells in a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist. [264] In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased IRF4 expression or infiltration of MUM-1⁺ cells. [265] In some embodiments, a subject has previously been identified as having increased IRF4 expression or infiltration of MUM-1⁺ cells in a tumor microenvironment as compared to a reference. [266] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist, wherein the subject has previously been identified as having increased IRF4 expression or infiltration of MUM-1⁺ cells in a tumor of the subject. In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased IRF4 expression or infiltration of MUM-1⁺ cells, and wherein the subject has previously been identified as having increased IRF4 expression or infiltration of MUM-1⁺ cells in a tumor of the subject. In some embodiments, a subject has previously been identified as having increased IRF4 expression or infiltration of MUM-1⁺ cells in the tumor microenvironment as compared to a reference. In some embodiments, a subject has previously been identified as having increased IRF4 expression or infiltration of MUM-1⁺ cells in the tumor microenvironment as compared to a reference. [267] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising: selecting a subject with cancer having a diagnosis of an increased IRF4 expression or infiltration of MUM-1⁺ cells in a tumor of the subject; and treating the patient with an adenosine receptor antagonist. [268] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising: detecting the level of IRF4 expression or the infiltration of MUM-1⁺ cells in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an adenosine receptor antagonist based on a comparison of said level or infiltration with a reference level or infiltration. [269] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising: detecting the level of IRF4 expression or the infiltration of MUM-1⁺ cells in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an adenosine receptor antagonist when the level of IRF4 expression or the infiltration of MUM-1⁺ cells is increased. [270] In some embodiments, level of IRF4 expression or the infiltration of MUM-1⁺ cells is increased as compared to a reference. In some embodiments, the level of IRF4 expression or the infiltration of MUM-1⁺ cells is increased in the tumor microenvironment as compared to a reference. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased IRF4 expression or density of MUM-1⁺ cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased IRF4 expression or density of MUM-1⁺ cells in a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist. [271] In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased IRF4 expression or density of MUM-1⁺ cells. [272] In some embodiments, a subject has previously been identified as having increased IRF4 expression or density of MUM-1⁺ cells in a tumor microenvironment as compared to a reference. [273] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist, wherein the subject has previously been identified as having increased IRF4 expression or density of MUM-1⁺ cells in a tumor of the subject. In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased IRF4 expression or density of MUM-1⁺ cells, and wherein the subject has previously been identified as having increased IRF4 expression or density of MUM-1⁺ cells in a tumor of the subject. In some embodiments, a subject has previously been identified as having increased IRF4 expression or density of MUM-1⁺ cells in the tumor microenvironment as compared to a reference. In some embodiments, a subject has previously been identified as having increased IRF4 expression or density of MUM-1⁺ cells in the tumor microenvironment as compared to a reference. [274] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising: selecting a subject with cancer having a diagnosis of an increased IRF4 expression or density of MUM-1⁺ cells in a tumor of the subject; and treating the patient with an adenosine receptor antagonist. [275] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising: detecting the level of IRF4 expression or the density of MUM-1⁺ cells in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an adenosine receptor antagonist based on a comparison of said level or density with a reference level or density. [276] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising: detecting the level of IRF4 expression or the density of MUM-1⁺ cells in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an adenosine receptor antagonist when the level of IRF4 expression or the density of MUM-1⁺ cells is increased. [277] In some embodiments, level of IRF4 expression or the density of MUM-1⁺ cells is increased as compared to a reference. In some embodiments, the level of IRF4 expression or the density of MUM-1⁺ cells is increased in the tumor microenvironment as compared to a reference. [278] In some embodiments, the present disclosure includes a method of treating cancer characterized by increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist. In some embodiments, the ASC markers can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [279] In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker. In some embodiments, the ASC markers can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [280] In some embodiments, a subject has previously been identified as having increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a tumor microenvironment as compared to a reference. In some embodiments, the ASC markers can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD 138. [281] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist, wherein the subject has previously been identified as having increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a tumor of the subject. In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker, and wherein the subject has previously been identified as having increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a tumor of the subject. In some embodiments, a subject has previously been identified as having increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in the tumor microenvironment as compared to a reference. In some embodiments, a subject has previously been identified as having increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in the tumor microenvironment as compared to a reference. In some embodiments, the ASC markers can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [282] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising: selecting a subject with cancer having a diagnosis of an increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a tumor of the subject; and treating the patient with an adenosine receptor antagonist. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [283] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising: detecting the level of expression of at least one ASC marker or the infiltration of cells positive for at least one ASC marker in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an adenosine receptor antagonist based on a comparison of said level or infiltration with a reference level or infiltration. In some embodiments, the ASC markers can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [284] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising: detecting the level of expression of at least one ASC marker or the infiltration of cells positive for at least one ASC marker in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an adenosine receptor antagonist when the level of expression of at least one ASC marker or the infiltration of cells positive for at least one ASC marker is increased. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [285] In some embodiments, level of expression of at least one ASC marker or the infiltration of cells positive for at least one ASC marker is increased as compared to a reference. In some embodiments, the level of expression of at least one ASC marker expression or the infiltration of cells positive for at least one ASC marker is increased in the tumor microenvironment as compared to a reference. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in a tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [286] In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased expression of at least one ASC marker or density of cells positive for at least one ASC marker. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [287] In some embodiments, a subject has previously been identified as having increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in a tumor microenvironment as compared to a reference. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [288] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist, wherein the subject has previously been identified as having increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in a tumor of the subject. In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased expression of at least one ASC marker or density of cells positive for at least one ASC marker, and wherein the subject has previously been identified as having increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in a tumor of the subject. In some embodiments, a subject has previously been identified as having increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in the tumor microenvironment as compared to a reference. In some embodiments, a subject has previously been identified as having increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in the tumor microenvironment as compared to a reference. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [289] In some embodiments, the present disclosure includes a method of treating cancer in a subject in need thereof, comprising: selecting a subject with cancer having a diagnosis of an increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in a tumor of the subject; and treating the patient with an adenosine receptor antagonist. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [290] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising: detecting the level of expression of at least one ASC marker or the density of cells positive for at least one ASC marker in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an adenosine receptor antagonist based on a comparison of said level or density with a reference level or density. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [291] In some embodiments, the present disclosure includes a method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising: detecting the level of expression of at least one ASC marker or the density of cells positive for at least one ASC marker in a sample from the subject, such as in a tumor sample from the subject; selecting the subject for treatment with an adenosine receptor antagonist when the level of expression of at least one ASC marker or the density cells positive for of at least one ASC marker is increased. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A and/or CD138. [292] In some embodiments, level of expression of at least one ASC marker or the density of cells positive for at least one ASC marker is increased as compared to a reference. In some embodiments, the level of expression of at least one ASC marker or the density of cells positive for at least one ASC marker is increased in the tumor microenvironment as compared to a reference. In some embodiments, the ASC marker can include, but are not limited to, MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A, and/or CD138. [293] In some embodiments, the subject is to be treated with an adenosine receptor antagonist as a first line therapy, i.e., the subject has not received prior anticancer treatment. In some embodiments, the subject is to be treated with an adenosine receptor antagonist as a second, third or more line therapy, i.e., the subject has received prior anticancer treatment with another anticancer agent. [294] Without being bound by theory, the adenosine receptor antagonist can modulate various functions and/or various subsets of ASCs, for example, blocking adenosine receptors, such as A2aR, may modulate ASC terminal differentiation and migration to the bone marrow, antibody production/ class switch, cytokine production, and/or antigen presentation. Combinations [295] In some embodiments, the present disclosure includes a method of treating cancer characterized by increased IRF4 expression or density of MUM-1⁺ cells in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased IRF4 expression or density of MUM-1⁺ cells in a tumor in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent. In some embodiments, the present disclosure includes a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased IRF4 expression or density of MUM-1⁺ cells. In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased IRF4 expression or density of MUM-1⁺ cells, and wherein the subject is further to be administered with an anticancer agent. [296] Ins some embodiments, the present disclosure includes a method of treating cancer characterized by increased IRF4 expression or infiltration of MUM-1⁺ cells in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased IRF4 expression or infiltration of MUM-1⁺ cells in a tumor in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent. In some embodiments, the present disclosure includes a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased IRF4 expression or infiltration of MUM-1⁺ cells. In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased IRF4 expression or infiltration of MUM-1⁺ cells, and wherein the subject is further to be administered with an anticancer agent. [297] In some embodiments, the present disclosure includes a method of treating cancer characterized by increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased expression of at least one ASC marker or density of cells positive for at least one ASC marker in a tumor in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent. In some embodiments, the present disclosure includes a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased expression of at least one ASC marker expression or density of cells positive for at least one ASC marker. In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased expression of at least one ASC marker or density of cells positive for at least one ASC marker, and wherein the subject is further to be administered with an anticancer agent. [298] In some embodiments, the present disclosure includes a method of treating cancer characterized by increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent. In some embodiments, the present disclosure includes a method of treating cancer characterized by increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker in a tumor in a subject in need thereof, comprising administering to the subject a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent. In some embodiments, the present disclosure includes a combination of a therapeutically effective amount of an adenosine receptor antagonist and a therapeutically effective amount of an anticancer agent, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker. In some embodiments, the present disclosure includes an adenosine receptor antagonist, for use in the treatment of cancer in a subject in need thereof, wherein the cancer is characterized by increased expression of at least one ASC marker or infiltration of cells positive for at least one ASC marker, and wherein the subject is further to be administered with an anticancer agent. [299] In one embodiment, an anticancer agent is selected from immunotherapeutic agents, chemotherapeutic agents, antiangiogenic agents, multidrug resistance-associated proteins inhibitors, radiotherapeutic agents, and any combination thereof. [300] In one embodiment, a combination of comprises a single anticancer agent. In another embodiment, a combination comprises a plurality of anticancer agents; preferably two, three or four anticancer agents as defined below. In case of use of a combination of anticancer agents in a combination, an anticancer agents may be of the same class of agents or of different classes of agents. For example, a combination of an immunotherapeutic agent and of a chemotherapeutic agent may be used with an adenosine receptor antagonist. [301] In the context of the present disclosure, administration of an anticancer agent and an adenosine receptor antagonist may occur either simultaneously or timely staggered, either at the same site of administration or at different sites of administration, under similar or different dosage forms as further outlined below. [302] In one embodiment, an anticancer agent is administered prior to, concomitant with, or subsequent to administration of an adenosine receptor antagonist. To ensure that the separate mechanisms elicited by an anticancer agent and an adenosine receptor antagonist are not negatively influenced by each other, an adenosine receptor antagonist and an anticancer agent may be administered separated in time (in a time-staggered manner), i.e. sequentially, and/or are administered at different administration sites. This means that the adenosine receptor antagonist may be administrated e.g. prior, concurrent or subsequent to an anticancer agent, or vice versa. Alternatively, or additionally, an adenosine receptor antagonist and an anticancer agent may be administered at different administration sites, or at the same administration site, preferably, when administered in a time staggered manner. [303] In one embodiment, an adenosine receptor antagonist is to be administered prior to and/or concomitantly with an anticancer agent. In one embodiment, an adenosine receptor antagonist is to be administered prior to the day or on the same day that an anticancer agent is administered. In another embodiment, an anticancer agent is to be administered prior to and/or concomitantly with an adenosine receptor antagonist. In one embodiment, an anticancer agent is to be administered prior to the day or on the same day that an adenosine receptor antagonist is administered. In one embodiment, an adenosine receptor antagonist is to be administered prior to and/or concomitantly with an anticancer agent and continuously thereafter. In another embodiment, an anticancer agent is to be administered prior to and/or concomitantly with an adenosine receptor antagonist and continuously thereafter. [304] Depending on the condition to be prevented or treated and the form of administration, an anticancer agent and the adenosine receptor antagonist may be administered as a single daily dose, divided over one or more daily doses. [305] It will be understood that the total daily usage of adenosine receptor antagonist and anticancer agent will be decided by the attending physician within the scope of sound medical judgment. The specific dose for any particular subject will depend upon a variety of factors such as the cancer to be treated; the age, body weight, general health, sex and diet of the patient; and like factors well-known in the medical arts. Immunotherapeutic agent [306] In one embodiment, a combination includes an immunotherapeutic agent as anticancer agent. [307] In such case the present disclosure relates to a combination comprising: (a) at least one adenosine receptor antagonist, and (b) at least one immunotherapeutic agent. [308] In the present disclosure, “immunotherapy” refers to a therapy aiming at inducing and/or enhancing an immune response towards a specific target, for example towards cancer cells. In such last case, it is referred to as cancer immunotherapy. [309] In some embodiments, immunotherapeutic agent is, for example, selected from checkpoint inhibitors, checkpoint agonists (also called T-cell agonists), IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, adenosine-producing enzymes inhibitors, CD40 agonists, IL2 variants, immune cells (for conducting adoptive transfer), therapeutic vaccines, and combinations thereof. In a specific embodiment, the immunotherapeutic agent is a checkpoint inhibitor. [310] In one embodiment, an immunotherapeutic agent to be combined with adenosine receptor antagonist as described hereinabove comprises or consists of checkpoint inhibitors, checkpoint agonists, IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, adenosine-producing enzymes inhibitors, CD40 agonists, IL2 variants, immune cells (for conducting adoptive transfer), therapeutic vaccines, or any mixes thereof. Checkpoint inhibitors [311] In one embodiment, a combination includes at least one checkpoint inhibitor as immunotherapeutic agent. [312] In some embodiments, checkpoint inhibitors (CPI), that may also be referred to as immune checkpoint inhibitors (ICI), block the interactions between inhibitory receptors expressed on T cells and their ligands. As a cancer treatment, use of checkpoint inhibitor aims at preventing the activation of inhibitory receptors expressed on T cells by ligands expressed by a tumor. Use of checkpoint inhibitors thus aims at preventing inhibition of T cells present in the tumor, i.e., tumor infiltrating T cells, and thus at enhancing the subject immune response towards a tumor. [313] Thus, a combination of the present disclosure can restore immune functions in tumor environments by using as a first component an A_2AR inhibitor, and to antagonize checkpoint pathway signaling by preferably inhibiting or suppressing signal transduction by using as second component a checkpoint inhibitor as immunotherapeutic agent. [314] Examples of checkpoint inhibitors include, without being limited to: − inhibitors of the cell surface receptor PD-1 (programmed cell death protein 1), also known as CD279 (cluster differentiation 279); − inhibitors of the ligand PD-L1 (programmed death-ligand 1), also known as CD274 (cluster of differentiation 274) or B7-H1 (B7 homolog 1); − inhibitors of the cell surface receptor CTLA4 or CTLA-4 (cytotoxic T-lymphocyte- associated protein 4), also known as CD152 (cluster of differentiation 152); − inhibitors of LAG-3 (lymphocyte-activation gene 3), also known as CD223 (cluster differentiation 223); − inhibitors of TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), also known as HAVCR2 (hepatitis A virus cellular receptor 2) or CD366 (cluster differentiation 366); − inhibitors of TIGIT (T cell immunoreceptor with Ig and ITIM domains), also known as VSIG9 (V-Set And Immunoglobulin Domain-Containing Protein 9) or VSTM3 (V- Set And Transmembrane Domain-Containing Protein 3); − inhibitors of BTLA (B and T lymphocyte attenuator), also known as CD272 (cluster differentiation 272); − inhibitors of CEACAM-1 (carcinoembryonic antigen-related cell adhesion molecule 1) also known as CD66a (cluster differentiation 66a); and − inhibitors of GITR (glucocorticoid-induced TNFR-related protein) also known as TNFRSF18 (tumor necrosis factor receptor superfamily member 18) or AITR (activation-inducible TNFR family receptor). [315] In one embodiment, a checkpoint inhibitor is selected from the group comprising or consisting of inhibitors of PD-1, inhibitors of PD-L1, inhibitors of CTLA4, inhibitors of LAG-3, inhibitors of TIM-3, inhibitors of TIGIT, inhibitors of BTLA, inhibitors of CEACAM-1, inhibitors of GITR and any mixtures thereof. [316] In one embodiment, a checkpoint inhibitor is selected from the group comprising or consisting of inhibitors of PD-1, inhibitors of PD-L1, inhibitors of CTLA-4, inhibitors of TIGIT and any mixtures thereof. [317] In one embodiment, a checkpoint inhibitor is selected from the group comprising or consisting of inhibitors of PD-1, inhibitors of PD-L1, inhibitors of CTLA-4 and any mixtures thereof. [318] In one embodiment, a checkpoint inhibitor is an inhibitor of PD-1, also referred to as an anti-PD-1. Inhibitors of PD-1 may include antibodies targeting PD-1, in particular monoclonal antibodies, and non-antibody inhibitors such as small molecule inhibitors. [319] Examples of inhibitors of PD-1 include, without being limited to, pembrolizumab, nivolumab, cemiplimab, tislelizumab, spartalizumab, ABBV-181, JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034. Pembrolizumab is also known as MK-3475, MK03475, lambrolizumab, or SCH-900475. The trade name of pembrolizumab is Keytruda®. Nivolumab is also known as ONO-4538, BMS-936558, MDX1106, or GTPL7335. The trade name of nivolumab is Opdivo®. Cemiplimab is also known as REGN2810 or REGN-2810. Tislelizumab is also known as BGB-A317. Spartalizumab is also known as PDR001 or PDR- 001. [320] In one embodiment, a checkpoint inhibitor is selected from the group comprising or consisting of pembrolizumab, nivolumab, cemiplimab, tislelizumab, spartalizumab, ABBV-181, JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034, and any mixtures thereof. [321] In one embodiment, a checkpoint inhibitor is an inhibitor of PD-L1, also referred to as an anti-PD-L1. Inhibitors of PD-L1 may include antibodies targeting PD-L1, in particular monoclonal antibodies, and non-antibody inhibitors such as small molecule inhibitors. [322] Examples of inhibitors of PD-L1 include, without being limited to, avelumab, atezolizumab, durvalumab and LY3300054. Avelumab is also known as MSB0010718C, MSB-0010718C, MSB0010682, or MSB-0010682. The trade name of avelumab is Bavencio®. Atezolizumab is also known as MPDL3280A (clone YW243.55.S70), MPDL- 3280A, RG-7446 or RG7446. The trade name of atezolizumab is Tecentriq®. Durvalumab is also known as MEDI4736 or MEDI-4736. The trade name of durvalumab is Imfinzi®. [323] In one embodiment, a checkpoint inhibitor is selected from the group comprising or consisting of avelumab, atezolizumab, durvalumab, LY3300054, and any mixtures thereof. [324] In one embodiment, a checkpoint inhibitor is an inhibitor of CTLA-4, also referred to as an anti-CTLA-4. [325] Inhibitors of CTLA-4 may include antibodies targeting CTLA-4, in particular monoclonal antibodies, and non-antibody inhibitors such as small molecule inhibitors. [326] Examples of inhibitors of CTLA-4 include, without being limited to, ipilimumab and tremelimumab. Ipilimumab is also known as BMS-734016, MDX-010, or MDX-101. The trade name of ipilimumab is Yervoy®. Tremelimumab is also known as ticilimumab, CP-675, or CP-675,206. [327] In one embodiment, at least one checkpoint inhibitor is selected from the group comprising or consisting of ipilimumab, tremelimumab, and any mixtures thereof. [328] In one embodiment, a checkpoint inhibitor is an inhibitor of TIGIT, also referred to as an anti-TIGIT. [329] In one embodiment of various methods, pharmaceutical compositions, kits, or uses provided herein, an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof is BMS-986207 (Bristol-Myers Squibb, New York, NY). [330] In another embodiment of various methods, pharmaceutical compositions, kits, or uses provided herein, an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof is OMP-313M32 (OncoMed Pharmaceuticals, Redwood city, CA). [331] In another embodiment of various methods, pharmaceutical compositions, kits, or uses provided herein, an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof is MK-7684 (Merck & Co., Kenilworth, NJ). [332] In yet another embodiment of various methods, pharmaceutical compositions, kits, or uses provided herein, an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof is MTIG7192A (also known as RG6058, U.S. Publ. No.2017/0088613). [333] In still another embodiment of various methods, pharmaceutical compositions, kits, or uses provided herein, an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof is PTZ-201 (Potenza Therapeutics, Cambridge, MA; also known as ASP8374, Astellas Pharma, Tokyo, Japan). [334] In another embodiment of various methods, pharmaceutical compositions, kits, or uses provided herein, an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof is COM902 (Compugen LTD, Holon, IL). [335] In yet another embodiment of various methods, pharmaceutical compositions, kits, or uses provided herein, an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof is described in WO2018/160704 (Seattle Genetics, Seattle, WA). [336] In yet another embodiment of various methods, pharmaceutical compositions, kits, or uses provided herein, an anti-human TIGIT monoclonal antibody or antigen binding fragment thereof is described in WO2019/023504 (iTeos Therapeutics). In certain preferred embodiments, an anti-human TIGIT antibody or antigen binding fragment comprises a combination of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein: HCDR1 comprises or consists of SEQ ID NO: 2 (YTFTSYYMH), HCDR2 comprises or consists of SEQ ID NO: 3 (VIGPSGASTSYAQKFQG), HCDR3 comprises or consists of SEQ ID NO: 4 (ARDHSDYWSGIMEV), LCDR1 comprises or consists of SEQ ID NO: 5 (RASQSVRSSYLA), LCDR2 comprises or consists of SEQ ID NO: 6 (GASSRAT), and LCDR3 comprises or consists of SEQ ID NO: 7 (QQYFSPPWT). Checkpoint agonists (T-cell agonists) [337] In one embodiment, a combination of the present disclosure includes at least one checkpoint agonist (also referred to as T-cell agonist) as immunotherapeutic agent. [338] T-cell agonists act by activating stimulatory receptors expressed on immune cells, such as T cells. As used herein, the term “stimulatory receptors” refer to receptors that induce a stimulatory signal upon activation, and thus lead to an enhancement of the immune response. As a cancer treatment, T-cell agonist therapy aims at activating stimulatory receptors expressed on immune cells present in a tumor. In particular, T-cell agonist therapy aims at enhancing the activation of T cells present in a tumor, i.e., tumor infiltrating T cells, and thus at enhancing the subject immune response towards A tumor. [339] Examples of T-cell agonists include, without being limited to: − agonists of CD137 (cluster differentiation 137) also known as 4-1BB or TNFRS9 (tumor necrosis factor receptor superfamily, member 9); − agonists of OX40 receptor also known as CD134 (cluster differentiation 134) or TNFRSF4 (tumor necrosis factor receptor superfamily, member 4). [340] In one embodiment, a checkpoint agonist is selected from the group comprising or consisting of agonists of CD137, agonists of OX40 and any mixtures thereof. [341] Examples of agonists of CD137 include, without being limited, utomilumab and urelumab. IDO inhibitors [342] In one embodiment, a combination of the present disclosure includes at least one inhibitor of indoleamine-2,3-dioxygenase (IDO) as immunotherapeutic agent. [343] Indoleamine 2,3-dioxygenase enzyme catalyzes the first and rate-limiting step of L-tryptophan (Trp) catabolism. IDO is implicated in immune modulation through its ability to limit T cell function and engage mechanisms of immune tolerance. IDO activity in a tumor serves to impair anti-tumor responses. Inhibiting IDO thus enables to restore tumor immune surveillance. [344] Examples of IDO inhibitors include beta-carboline (also known as norharmane), rosmarinic acid, 1-methyl-L-tryptophan (also known as L-1-MT), epacadostat, navoximod or those disclosed in WO2015/173764, and more preferably those of formula II, II’ or II’’. [345] In a preferred embodiment, an IDO inhibitor is selected among those disclosed in WO2015/173764, and more preferably those of formula II, II’ or II’’. PI3Kgamma inhibitors [346] In one embodiment, a combination of the present disclosure includes at least one PI3K inhibitor as immunotherapeutic agent. [347] A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a class of medical drug that functions by inhibiting one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K/AKT/mTOR pathway, an important signaling pathway for many cellular functions such as growth control, metabolism and translation initiation. Many types of cancers have activated PI3K pathway, which prohibit tumor cells from cell death. [348] There are a number of different classes and isoforms of PI3Ks. Class 1 PI3Ks have a catalytic subunit known as p110, with four types (isoforms) – p110 alpha, p110 beta, p110 gamma and p110 delta. [349] In a preferred embodiment, a PI3K inhibitor is a PI3K-gamma inhibitor. [350] Examples of PI3K inhibitors include wortmannin, LY294002, demethoxyviridon, hibiscone C, Idelalisib, Copanlisib, Duvelisib, Taselisib, Buparlisib, Alpelisib, Umbralisib, Dactolisib, Voxtalisib, IPI-549, RP6530, IC87114 and TG100-115. [351] Examples of PI3K-gamma inhibitors include Copanlisib, Duvelisib, IPI-549, RP6530, IC87114 and TG100-115. CD40 agonists [352] In one embodiment, a combination of the present disclosure includes at least one CD40 agonist as immunotherapeutic agent. [353] CD40 is a cell surface receptor member of the tumor necrosis factor (TNF) receptor superfamily. It mediates both indirect tumor cell killing through the activation of the immune system and direct tumor cell apoptosis. Similar to the endogenous CD40 ligand (CD40L or CD154), CD40 agonists bind to CD40 on a variety of immune cell types. This triggers the cellular proliferation and activation of antigen-presenting cells (APCs), and activates B-cells, and effector and memory T-cells. This results in an enhanced immune response against tumor cells. [354] Examples of CD40 agonists include CD40 agonistic antibodies and recombinant CD40 agonists (i.e. proteins, but not antibodies). Examples of CD40 agonistic antibodies include selicrelumab (formely known as RO7009789 and CP-870,893), APX005M, JNJ- 64457107 (formerly ADC-1013), SEA-CD40, ChiLob 7/4, CDX-1140H, dacetuzumab (SGN-40) and ABBV-428. Examples of recombinant CD40 agonists include MEDI5083 and HERA-CD40L. Adenosine-producing enzymes inhibitors [355] In one embodiment, a combination of the present disclosure includes at least one adenosine-producing enzymes inhibitor as immunotherapeutic agent. [356] Ectonucleotidases are families of nucleotide metabolizing enzymes that metabolize nucleotides to nucleosides. Subfamilies of ectonucleotidases include: CD39/NTPDases (ecto-nucleotide triphosphate diphosphohydrolases), nucleotide pyrophosphatase/phosphodiesterase (NPP)-type ecto-phosphodiesterases, alkaline phosphatases and ecto-5’-nucleotidases/CD73. [357] Among other functions, ectonucleotidases generate extracellular adenosine, a first step involving the conversion of ATP/ADP to AMP, carried out by ENTPD1, also known as CD39. a second step involves the conversion of AMP to adenosine. It is carried out by NT5E, also known as CD73. Thus ectonucleotidases are adenosine-producing enzymes. [358] Examples of adenosine-producing enzymes inhibitors include: − inhibitors of CD39, also known as ENTPD1 or Ecto-nucleoside triphosphate diphosphohydrolases (EC 3.6.1.5, apyrase), − inhibitors of CD73, also known as 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase or NT5E, − inhibitors of Ecto-nucleotide pyrophosphatase/PDEs (EC 3.6.1.9 and EC 3.1.4.1) and − inhibitors of alkaline phosphatases (APs; EC 3.1.3.1), − inhibitors of CD38, also known as cyclic ADP ribose hydrolase or ADP-ribosyl cyclase/cyclic ADP-ribose (cADPR) hydrolase). [359] Examples of adenosine-producing enzymes inhibitors include IPH5201, A001485, SRF617, ARL67156, POM-1, IPH5301, A000830, A001190, A001421, SRF373/NZV930, Darutumumab. More precisely, examples of CD39 inhibitors include IPH5201, A001485, SRF617, ARL67156 and POM-1; examples of CD73 inhibitors include IPH5301, A000830, A001190, A001421 and SRF373/NZV930; and examples of CD38 inhibitors include Darutumumab. IL2 variants [360] In one embodiment, a combination of the present disclosure includes at least one IL2 variant as immunotherapeutic agent. [361] Interleulin-2 (IL-2) is a powerful immune growth factor that plays an important role in sustaining T cell response. The potential of IL-2 in expanding T cells without loss of functionality has led to its early use in cancer immunotherapy. [362] Examples of IL2 variants include recombinant, PEGylated and/or mutated IL2 variants, such as for example aldesleukin, monomethoxy PEG IL2, NKTR-214, MDNA-109, RO6874281 and ALKS-4230. Immune cells - Adoptive cell transfer [363] According to one embodiment, an immunotherapeutic agent is immune cells to be used in an adoptive transfer of cells, also referred to as adoptive cell therapy (both also referred to as ACT), particularly an adoptive transfer of T cells, also referred to as adoptive T cell therapy. [364] As used herein, an adoptive transfer of cells or adoptive cell therapy is defined as the transfer, for example as an infusion, of immune cells to a subject. As a cancer treatment, an adoptive transfer of immune cells to a subject aims at enhancing the subject immune response towards the cancer cells. [365] In one embodiment, immune cells are T cells, in particular effector T cells. Examples of effector T cells include CD4⁺ T cells and CD8⁺ T cells. [366] In one embodiment, transferred T cells are cytotoxic cells. Examples of cytotoxic T cells include CD8⁺ T cells and natural killer (NK) cells, in particular natural killer (NK) T cells. [367] In one embodiment, transferred immune cells as described hereinabove are antigen-specific cells. In one embodiment, transferred immune cells as described hereinabove are antigen-specific immune cells, wherein said antigen is specifically and/or abundantly expressed by cancer cells. In one embodiment, transferred immune cells as described hereinabove are cancer-specific immune cells, in other words the transferred immune cells as described hereinabove specifically recognize cancer cells through an antigen specifically and/or abundantly expressed by said cancer cells. In one embodiment, transferred immune cells as described hereinabove are cancer-specific effector T cells. In one embodiment, transferred immune cells as described hereinabove are cancer-specific CD8⁺ effector T cells, in particular cancer-specific cytotoxic CD8⁺ T cells. In one embodiment, transferred immune cells as described hereinabove are cancer-specific cytotoxic cells. In one embodiment, transferred immune cells as described hereinabove are cancer-specific NK cells. In one embodiment, transferred immune cells as described hereinabove are tumor-specific immune cells, in other words transferred immune cells as described hereinabove specifically recognize tumor cells through an antigen specifically and/or abundantly expressed by said tumor cells. In one embodiment, transferred immune cells as described hereinabove are tumor-specific effector T cells. In one embodiment, transferred immune cells as described hereinabove are tumor-specific CD8⁺ effector T cells, in particular tumor-specific cytotoxic CD8⁺ T cells. In one embodiment, transferred immune cells as described hereinabove are tumor-specific cytotoxic cells. In one embodiment, transferred immune cells as described hereinabove are tumor-specific NK cells. [368] In one embodiment, transferred immune cells as described hereinabove are autologous immune cells, in particular autologous T cells. In another embodiment, transferred immune cells as described hereinabove are allogenic (or allogenous) immune cells, in particular allogenic NK cells. [369] Methods to isolate T cells from a subject, in particular antigen-specific T cells, e.g., tumor-specific T cells, are well-known in the art (see for example Rosenberg & Restifo, 2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs & Rosenberg, 2014, Immunol Rev 257, 56-71). Methods to expand T cells ex vivo are well- known in the art (see for example Rosenberg & Restifo, 2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs & Rosenberg, 2014, Immunol Rev 257, 56-71). Protocols for infusion of T cells in a subject, including pre-infusion conditioning regimens, are well-known in the art (see for example Rosenberg & Restifo, 2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs & Rosenberg, 2014, Immunol Rev 257, 56-71). [370] In one embodiment, immune cells are CAR immune cells, in particular a CAR T cells, in the context respectively of CAR immune cell therapy and CAR T cell therapy. [371] As used herein, CAR immune cell therapy is an adoptive cell therapy wherein transferred cells are immune cells as described hereinabove, such as T cells or NK cells, genetically engineered to express a chimeric antigen receptor (CAR). As a cancer treatment, the adoptive transfer of CAR immune cells to a subject aims at enhancing the subject immune response towards the cancer cells. [372] CARs are synthetic receptors consisting of a targeting moiety that is associated with one or more signaling domains in a single fusion molecule or in several molecules. In general, the binding moiety of a CAR consists of an antigen-binding domain of a single-chain antibody (scFv), comprising the light and variable fragments of a monoclonal antibody joined by a flexible linker. Binding moieties based on receptor or ligand domains have also been used successfully. The signaling domains for first generation CARs are usually derived from the cytoplasmic region of the CD3zeta or the Fc receptor gamma chains. First generation CARs have been shown to successfully redirect T cell cytotoxicity, however, they failed to provide prolonged expansion and anti-tumor activity in vivo. Thus, signaling domains from co-stimulatory molecules including CD28, OX-40 (CD134), and 4-1BB (CD137) have been added alone (second generation) or in combination (third generation) to enhance survival and increase proliferation of CAR modified T cells. [373] Thus, in one embodiment, transferred T cells as described hereinabove are CAR T cells. Expression of a CAR allows the T cells to be redirected against a selected antigen, such as an antigen expressed at the surface of cancer cells. In one embodiment, transferred CAR T cells recognize a tumor-specific antigen. [374] In another embodiment, transferred NK cells as described hereinabove are CAR NK cells. Expression of a CAR allows the NK cells to be redirected against a selected antigen, such as an antigen expressed at the surface of cancer cells. In one embodiment, the transferred CAR NK cells recognize a tumor-specific antigen. [375] In one embodiment, CAR immune cells as described hereinabove are autologous CAR immune cells, in particular autologous CAR T cells. In another embodiment, CAR immune cells as described hereinabove are allogenic (or allogenous) CAR immune cells, in particular allogenic CAR NK cells. Therapeutic vaccines [376] According to one embodiment, an immunotherapeutic agent is a therapeutic vaccine (sometimes also referred to as a treatment vaccine). [377] As used herein, a therapeutic vaccine is defined as the administration of at least one tumor-specific antigen (e.g., synthetic long peptides or SLP), or of the nucleic acid encoding said tumor-specific antigen; administration of recombinant viral vectors selectively entering and/or replicating in tumor cells; the administration of tumor cells; and/or administration of immune cells (e.g., dendritic cells) engineered to present tumor-specific antigens and trigger an immune response against these antigens. [378] As a cancer treatment, therapeutic vaccines aim at enhancing a subject immune response towards the tumor cells. [379] Examples of therapeutic vaccines aiming at enhancing a subject immune response towards the tumor cells include, without being limited to, viral-vector based therapeutic vaccines such as adenoviruses (e.g., oncolytic adenoviruses), vaccinia viruses (e.g., modified vaccinia Ankara (MVA)), alpha viruses (e.g., Semliki Forrest Virus (SFV)), measles virus, Herpes simplex virus (HSV), and coxsackievirus; synthetic long peptide (SLP) vaccines; and dendritic cell vaccines. Chemotherapeutic agent [380] In one embodiment, a combination of the present disclosure includes at least one chemotherapeutic agent as anticancer agent. [381] A chemotherapeutic agent is for example selected from anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, Parp inhibitors, anti-hormone-sensitive cancer agents and any combination thereof. [382] In one embodiment, a chemotherapeutic agent to be combined with the A_2AR inhibitor of Formula (I) as described hereinabove comprises or consists of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, Parp inhibitors, anti-hormone-sensitive cancer agents and any combination thereof. Anticancer alkylating agent [383] In one embodiment, a combination of the present disclosure includes at least one anticancer alkylating agent as chemotherapeutic agent. [384] An anticancer alkylating agent refers to an alkylating agent having anticancer activity, and the term “alkylating agent” herein generally refers to an agent giving an alkyl group in the alkylation reaction in which a hydrogen atom of an organic compound is substituted with an alkyl group. [385] Examples of anticancer alkylating agents include nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, rammustine, nimustine, temozolomide and carmustine. Anticancer antimetabolite [386] In one embodiment, a combination of the present disclosure includes at least one anticancer antimetabolite as chemotherapeutic agent. [387] An anticancer antimetabolite refers to an antimetabolite having anticancer activity, and the term "antimetabolite" herein includes, in a broad sense, substances which disturb normal metabolism and substances which inhibit the electron transfer system to prevent the production of energy-rich intermediates, due to their structural or functional similarities to metabolites that are important for living organisms (such as vitamins, coenzymes, amino acids and saccharides). [388] Examples of anticancer antimetabolites include methotrexate, 6-mercaptopurine riboside, rnercaptopurine, 5-fluorouracil (also called “5-FU”), tegafur, doxifluridine, carrnofur, cytarabine, cytarabine ocfosfate, enocitabine, S-1, gemcitabine, fludarabine and pemetrexed disodium. Preferably the anticancer antimetabolite is selected from 5-FU, gemcitabine and pemetrexed. Anticancer antibiotic [389] In one embodiment, a combination of the present disclosure includes at least one anticancer antibiotic as chemotherapeutic agent. [390] An “anticancer antibiotic” refers to an antibiotic having anticancer activity, and the “antibiotic” herein includes substances that are produced by microorganisms or by partial or total synthesis, and derivatives thereof; and inhibit cell growth and other functions of microorganisms and of other living organisms. [391] Examples of anticancer antibiotic include actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zinostatin stimalamer, idarubicin, sirolimus and valrabicin. Preferably, thenanticancer antibiotic is doxorubicin. Plant-derived anticancer agent [392] In one embodiment, a combination of the present disclosure includes at least one plant-derived anticancer agent as chemotherapeutic agent. [393] A “plant-derived anticancer agent” as used in the specification includes compounds having anticancer activities which originate from plants, or compounds prepared by applying chemical modification to the foregoing compounds. [394] Examples of plant-derived anticancer agent include vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel, nab-paclitaxel and vinorelbine. Preferably, the plant-derived anticancer agent is docetaxel. Anticancer platinum coordination compound [395] In one embodiment, a combination of the present disclosure includes at least one anticancer platinum coordination compound as chemotherapeutic agent. [396] An “anticancer platinum coordination compound” refers to a platinum coordination compound having anticancer activity, and the term “platinum coordination compound” herein refers to a platinum coordination compound which provides platinum in ion form. [397] Preferred platinum compounds include cisplatin; cis- diamminediaquoplatinum (O)-ion; chloro(diethylenetriamine)-platinum (II) chloride; dichloro(ethylenediamine)- platinum (II); diamine( 1 , 1 -cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; diamine(2-ethylmalonato)platinum (II); ethylenediaminemalonatoplatinum (H); aqua(l,2-diaminodicyclohexane)sulfatoplatinum (II); aqua(l,2-diaminodicyclohexane)malonatoplatinum (II); (1,2- diaminocyclohexane)malonatoplatinum (II); (4-carboxyphthalato)(l ,2-diaminocyclohexane) platinum (II); (l,2-diaminocyclohexane)-(isocitrato)platinum (II); (1,2- diaminocyclohexane)oxalatoplatinum (II); ormaplatin; tetraplatin; carboplatin, nedaplatin and oxaliplatin. Preferably the anticancer platinum coordination compound is selected from carboplatin and oxaliplatin. Parp inhibitors [398] In one embodiment, a combination of the present disclosure includes at least one Parp inhibitor as chemotherapeutic agent. [399] A “Parp inhibitor” refers to an inhibitor of the enzyme poly ADP ribose polymerase (PARP). This enzyme is important for repairing single-strand breaks in the DNA. If such breaks remain unrepaired until DNA is replicated, then the replication can cause double strand breaks to form. PARP inhibitors thus enable to cause multiple double strand breaks to form in tumors, leading to the death of the tumor cells. [400] Examples of Parp inhibitors include olaparib, rucaparib, niraparib, veliparib, pamiparib, iniparib, and talazoparib. Anti-hormone-sensitive cancer agent [401] In one embodiment, a combination of the present disclosure includes at least one anti-hormone-sensitive cancer agent as chemotherapeutic agent. [402] An “anti-hormone-sensitive cancer agent” refers to an anticancer agent having an activity against hormone-sensitive cancers. Examples of anti-hormone-sensitive cancer agents include anti-androgens, GnRH agonists and GnRH antagonists. [403] “Anti-androgens” refer to a class of drugs that prevent androgens like testosterone and dihydrotestosterone (DHT) from mediating their biological effects in the body. Anti-androgens may be used for example to treat prostate cancer. Examples of anti-androgens include bicalutamide, flutamide, nilutamide, apalutamide, enzalutamide and abiraterone. [404] “Gonadotropin-releasing hormone agonists” (GnRH agonist) refer to a class of drugs which affects gonadotropins and sex hormones. They may be used to lower sex hormone levels in the treatment of hormone-sensitive cancers such as prostate cancer and breast cancer. Examples of GnRH agonists include goserelin, leuprorelin and triptorelin. [405] “Gonadotropin-releasing hormone antagonists” (GnRH antagonist) refer to a class of drugs that antagonize the action of gonadotropin-releasing hormone (GnRH). They may be used for example in the treatment of prostate cancer. An example of GnRH antagonist is degarelix. Combinations of chemotherapeutic agents [406] Combinations of chemotherapeutic agents may be used as a second component of a combination of the present disclosure. [407] For example, a combination known as folfox may be used. Folfox comprises the combined use of fluorouracil (antimetabolite), oxaliplatin (platinum compound) and folinic acid (chemoprotectant). [408] A combination consisting of carboplatin (platinum compound) and paclitaxel (plant-derived agent) may alternatively be used. Another example is a combination consisting of gemcitabine (antimetabolite) and nab-paclitaxel (plant-derived agent). [409] In one embodiment, a combination of chemotherapeutic agents is selected from: (i) a combination consisting of folinic acid, fluorouracil and oxaliplatin (folfox); (ii) a combination consisting of carboplatin and paclitaxel; and (iii) a combination consisting of gemcitabine and nab-paclitaxel. Antiangiogenic agent [410] In one embodiment, a combination of the present disclosure includes at least one antiangiogenic agent as anticancer agent. [411] Angiogenesis, i.e. growth of new blood vessels, plays an important role in the development of tumors and the progression of malignancies. Inhibiting angiogenesis has been shown to suppress tumor growth and metastasis. The most prominent target of antiangiogenic agents is vascular endothelial growth factor (VEGF) and its receptors. Several other factors are of interest as well, including integrins, matrix metalloproteinases, and endogenous antiangiogenic factors. [412] Antiangiogenic agents thus include VEGF inhibitors, integrins inhibitors and matrix metalloproteinases inhibitors. [413] Examples of antiangiogenic agents include Ramucirumab, IMC-18F1, Bevacizumab, Ziv-aflibercept, Sorafenib, Sunitinib, Axitinib, Nintedanib, Regorafenib, Pazobanib, Cabozantinib, Vandetanib and Thalidomide. In a specific embodiment, the antiangiogenic agent is a VEGF inhibitor, for example Ramucirumab. Multidrug resistance-associated proteins inhibitors [414] In one embodiment, a combination of the present disclosure includes at least one multidrug resistance-associated protein inhibitor as anticancer agent. [415] Multidrug resistance-associated proteins (MRP/ABCC) are a subfamily of ATP- binding cassette transporters, which are capable of actively pumping a wide variety of organic anionic compounds across the plasma membrane against their concentration gradient. These proteins are involved in multi-drug resistance by transporting a wide variety of drugs outside cells, among which anticancer drugs. Inhibiting multidrug resistance-associated proteins can thus improve efficacy of anticancer drugs. [416] Examples of multidrug resistance-associated protein inhibitor include inhibitors of MRP4/ABCC4, inhibitors of MRP5/ABCC5 and inhibitors of MRP8/ABCC11. Radiotherapeutic agents – Radiation therapy [417] In one embodiment, a combination of the present disclosure includes at least one radiotherapeutic agent as anticancer agent. [418] “Radiation therapy” refers to a method of treatment of cancer employing various radiations such as X-ray, γ-ray, neutron ray, electron beam, proton beam and radiation sources. It is used as part of cancer treatment to control or kill malignant cells. Radiation therapy may be curative in a number of types of cancer if they are localized to one area of the body. It may also be used as part of adjuvant therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor. [419] The three main divisions of radiation therapy are: external beam radiation therapy (EBRT or XRT); brachytherapy or sealed source radiation therapy; and systemic radioisotope therapy (RIT) or unsealed source radiotherapy. The differences relate to the position of the radiation source; external is outside the body, brachytherapy uses sealed radioactive sources placed precisely in the area under treatment, and systemic radioisotopes are given by infusion or oral ingestion. Particle therapy is a special case of external beam radiation therapy where the particles are protons or heavier ions. Radiations may be delivered by a linear accelerator. [420] Systemic radioisotope therapy (RIT) is a form of targeted therapy. Targeting can be due to the chemical properties of the isotope such as radioiodine which is specifically absorbed by the thyroid gland a thousand fold better than other bodily organs. Targeting can also be achieved by attaching the radioisotope to another molecule or antibody to guide it to the target tissue, forming a radiopharmaceutical agent. [421] In order to enhance the radiosensitivity of the cancer, radiosensitizing agents may be administered during a radiation therapy. Examples of radiosensitizing agents include: Cisplatin, Nimorazole, and Cetuximab. [422] Thus, in one embodiment, radiotherapeutic agent is selected from sealed radiation sources, radioisotopes, radiopharmaceutical agents, radiosensitizing agents and the like useful in the course of radiation therapy. [423] In another embodiment, the present disclosure also provides the use of adenosine receptor antagonist as described above, in combination with radiation therapy, including radiation therapy performed by external beam radiations or X-ray radiations; brachytherapy; and systemic radioisotope therapy. Specific Combinations [424] In one embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above and at least one anticancer agent as defined above. [425] In a specific embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above and at least one immunotherapeutic agent as defined above. [426] In a specific embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above and at least one checkpoint inhibitor as defined above, preferably an inhibitor of PD-1, PD-L1, CTLA-4 or of TIGIT, or any mixture thereof. [427] In a specific embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above and at least one adenosine-producing enzymes inhibitor as defined above, preferably at least one inhibitor of CD39, such as for example ARL67156 and POM-1. [428] In a specific embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above and at least one chemotherapeutic agent as defined above. [429] In a specific embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above and at least one anticancer antibiotic as defined above, such as for example doxorubicin. [430] In a specific embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above and at least one anticancer platinum coordination compound as defined above, such as for example oxaliplatin. [431] In a specific embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above, at least one immunotherapeutic agent as defined above and at least one chemotherapeutic agent as defined above. [432] In a specific embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above, at least one checkpoint inhibitor as defined above and at least one chemotherapeutic agent as defined above. In a specific embodiment, the combination of the present disclosure comprises at least one A_2AR inhibitor as defined above, at least one inhibitor of PD-L1, CTLA-4 or TIGIT and at least one chemotherapeutic agent as defined above. In a specific embodiment, the combination of the present disclosure comprises at least one A_2AR inhibitor as defined above, at least one checkpoint inhibitor as defined above and at least one anticancer antibiotic as defined above. In a specific embodiment, the combination of the present disclosure comprises at least one A_2AR inhibitor as defined above, at least one inhibitor of PD-L1, CTLA-4 or TIGIT as defined above and at least one anticancer antibiotic as defined above, such as for example doxorubicin. [433] In a specific embodiment, a combination of the present disclosure comprises at least one A_2AR inhibitor as defined above and at least two checkpoint inhibitor as defined above. In a specific embodiment, the combination of the present disclosure comprises at least one A_2AR inhibitor as defined above, at least one inhibitor of PD-L1 as defined above and at least one inhibitor of TIGIT as defined above. Diseases and Disorders [434] In some embodiments, the present disclosure includes the methods of treating proliferative disorders, including cancers. In some embodiments, the present disclosure includes a compound for use in the treatment and/or prevention of proliferative disorders, including cancers. Thus, in one embodiment, the present disclosure provides use of a compound for the manufacture of a medicament for treating and/or preventing cancer. The present disclosure also provides a method of treatment of cancer, which comprises administering to a mammal species in need thereof a therapeutically effective amount of a compound. [435] The present disclosure also provides for a method for delaying in patient the onset of cancer comprising the administration of a pharmaceutically effective amount of a compound of the disclosure to a patient in need thereof. [436] Various cancers are known in the art. Cancers that can be treated using methods of the disclosure include solid cancers and non-solid cancers, especially benign and malignant solid tumors and benign and malignant non-solid tumors. Cancer may be metastatic or non- metastatic. The cancer may be familial or sporadic. [437] In some embodiments, cancer is a solid cancer. As used herein, the term “solid cancer” encompasses any cancer (also referred to as malignancy) that forms a discrete tumor mass, as opposed to cancers (or malignancies) that diffusely infiltrate a tissue without forming a mass. [438] Examples of solid tumors include, but are not limited to: biliary tract cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, carcinoid, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms (including Bowen’s disease and Paget’s disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, renal cancer (including adenocarcinoma and Wilms tumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi’s sarcoma, basocellular cancer and squamous cell cancer), testicular cancer including germinal tumors (seminomas, and non- seminomas such as teratomas and choriocarcinomas), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma) and urothelial cancer. [439] In some embodiments, cancer is selected from the group consisting of colorectal cancer, stomach cancer, liver cancer, prostate cancer, breast cancer, endometrial cancer, and ovarian cancer. [440] In another embodiment, cancer is a non-solid cancer. Examples of non-solid tumors include but are not limited to hematological neoplasms. As used herein, a hematologic neoplasm is a term of art which includes lymphoid disorders, myeloid disorders, and AIDS associated leukemias. [441] Lymphoid disorders include but are not limited to acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin’s disease, non-Hodgkin’s lymphoma lymphomas, and lymphocytic lymphomas). Chronic lymphoid leukemias include, for example, T cell chronic lymphoid leukemias and B cell chronic lymphoid leukemias. [442] In a specific embodiment, cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, renal, gastric, thyroid and urothelial cancers. [443] In a specific embodiment, cancer is breast cancer. In a specific embodiment, cancer is carcinoid cancer. In a specific embodiment, cancer is cervical cancer. In a specific embodiment, cancer is colorectal cancer. In a specific embodiment, cancer is endometrial cancer. In a specific embodiment, cancer is glioma. In a specific embodiment, cancer is head and neck cancer. In a specific embodiment, cancer is liver cancer. In a specific embodiment, cancer is lung cancer. In a specific embodiment, the cancer is melanoma. In a specific embodiment, the cancer is ovarian cancer. In a specific embodiment, the cancer is pancreatic cancer. In a specific embodiment, cancer is prostate cancer. In a specific embodiment, cancer is renal cancer. In a specific embodiment, the cancer is gastric cancer. In a specific embodiment, cancer is thyroid cancer. In a specific embodiment, cancer is urothelial cancer. [444] In another specific embodiment, cancer is selected from the group consisting of: leukemia and multiple myeloma. [445] In one embodiment, a subject has previously received at least one prior therapeutic treatment, and has progressed subsequent to the administration of at least one prior therapeutic treatment and prior to administration of a therapeutic agent. In one embodiment, a prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplant, hormone therapy, and surgery. Formulations [446] The present disclosure also provides pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant. [447] The present disclosure also provides a medicament comprising at least one compound disclosed herein, or a pharmaceutically acceptable salt and solvate thereof, as active ingredient. [448] Generally, for pharmaceutical use, a compound disclosed herein may be formulated as a pharmaceutical preparation comprising at least one compound disclosed and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant, and optionally one or more further pharmaceutically active compounds. Details regarding the presence of further pharmaceutically active compounds are provided hereafter. [449] By means of non-limiting examples, such a formulation may be in a form suitable for oral administration, for parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), for topical administration (including ocular), for administration by inhalation, by a skin patch, by an implant, by a suppository, etc. Such suitable administration forms – which may be solid, semi-solid or liquid, depending on the manner of administration – as well as methods and carriers, diluents and excipients for use in the preparation thereof, will be clear to the skilled person; reference is made to the latest edition of Remington’s Pharmaceutical Sciences. [450] Some preferred, but non-limiting examples of such preparations include tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments, cremes, lotions, soft and hard gelatin capsules, suppositories, drops, sterile injectable solutions and sterile packaged powders (which are usually reconstituted prior to use) for administration as a bolus and/or for continuous administration, which may be formulated with carriers, excipients, and diluents that are suitable per se for such formulations, such as lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol, cellulose, (sterile) water, methylcellulose, methyl- and propylhydroxybenzoates, talc, magnesium stearate, edible oils, vegetable oils and mineral oils or suitable mixtures thereof. Formulations can optionally contain other substances that are commonly used in pharmaceutical formulations, such as lubricating agents, wetting agents, emulsifying and suspending agents, dispersing agents, disintegrants, bulking agents, fillers, preserving agents, sweetening agents, flavoring agents, flow regulators, release agents, etc. Compositions may also be formulated so as to provide rapid, sustained or delayed release of the active compound(s) contained therein. [451] Pharmaceutical preparations of the disclosure are preferably in a unit dosage form, and may be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which may be properly labeled); optionally with one or more leaflets containing product information and/or instructions for use. [452] Depending on the condition to be prevented or treated and the route of administration, a compound disclosed may be administered as a single daily dose, divided over one or more daily doses, or essentially continuously, e.g. using a drip infusion. [453] Another object of this disclosure is the use of the combination as a medicament, i.e. for medical use. Thus, in one embodiment, the disclosure provides the use of the combination of the disclosure for the manufacturing of a medicament. Especially, the disclosure provides the use of the combined pharmaceutical composition of the disclosure or the kit of the disclosure for the manufacturing of a medicament. EXAMPLES [454] High levels of extracellular adenosine, often found in the tumor microenvironment (TME), promote immune suppression mainly through the A_2A receptor (A_2AR) expressed by tumor-infiltrating immune cells. Inupadenant is an oral, non-brain penetrant, potent and highly selective small molecule antagonist of A_2AR. In a clinical trial, inupadenant as monotherapy showed initial evidence of clinical benefit in subjects with advanced solid tumors (Example 1). As disclosed herein, tumor biopsies with a high number of A_2AR-expressing immune cells at baseline were associated with response or stable disease. [455] Infiltration of A_2AR+ cells was found to be strongly correlated with the expression of B- and antibody-secreting cell (ASC)-related genes, as assessed by Nanostring and immunohistochemistry (IHC), which suggested a role for A_2AR in B cell biology (Examples 2 and 3). Therefore, the expression and function of A_2AR was explored in human B cells. Immunocytochemistry staining of A_2AR on sorted tonsillar B cell subsets showed that A_2AR was predominantly expressed on ASCs, including plasma cells and plasma blasts, versus naïve or memory B cells (Example 8(2)). The preferential expression of A_2AR by ASCs was confirmed on non-small cell lung cancer (NSCLC) tissues by multiplex immunofluorescence (Example 8(1)). In addition to A_2AR, ASCs expressed other adenosine pathway markers such as CD39, suggesting that the adenosine pathway is a key mechanism through which ASC functions may be modulated (Example 9). Using B cells derived from peripheral blood, the A_2AR agonist CGS-21680 was shown to inhibit the maturation of B cells into plasma cells, and that maturation could be fully restored by inupadenant (Example 10). CGS-21680 did not affect B cell or plasma cell viability, indicating that the effect of A_2AR signaling on plasma cell differentiation is not due to preferential plasma cell death in culture (Example 10). [456] B cells, plasma cells, and tertiary lymphoid structures are shown to be associated with favorable responses to cancer immunotherapy. Further, four out of five non-progressors treated with inupadenant as monotherapy showed a reduction in ASC infiltration after inupadenant treatment (Example 6), suggesting that inupadenant may promote terminal plasma cell differentiation and migration out of the tumor tissue and to the bone marrow. [457] Altogether, the Examples demonstrate that antibody secreting cells (ASCs) are a cellular target of inupadenant and A_2AR antagonism and thus a plasma cell-centric mechanism of action of inupadenant, which may complement its reported T cell-mediated anti-tumor activity. Example 1 – Dose Escalation of Inupadenant [458] A Phase I portion of an ongoing multi-center, first-in-human, clinical trial to evaluate safety/tolerability, pharmacokinetic, pharmacodynamic and anti-tumor activity of inupadenant in adult patients with solid tumors who have exhausted standard treatment options was conducted. In addition, tumor biomarkers, including adenosine-pathway markers by immunohistochemistry (IHC), are being evaluated. [459] Results: Overall, 42 patients (21 patients in the dose escalation and an additional 21 patients in a monotherapy expansion) with a median of 3 prior regimens were treated as of the data cut off. The dose levels investigated, along with the most frequent (>15%) treatment-emergent adverse events (TEAEs) across all dose levels are presented in Table 1. There were 7 AEs leading to discontinuation, of which 2 (atrial fibrillation and myocardial infarction) were considered to be possibly related to study drug by the investigator. No dose reductions were required. Two partial responses (PRs) were reported in patients with melanoma and prostate cancer. The patient with melanoma (NRAS-mutant) had received prior immunotherapy treatment with pembrolizumab and ipilumimab, and the patient with prostate cancer had received antiandrogen therapy and 2 prior lines of chemotherapy. At the date cut-off, both PRs were ongoing with a duration of response >230 days. Stable disease as best response was observed in 12 patients and prolonged SD (>6 months) was observed in 3 patients with head & neck cancers, and non-small cell lung cancer. Response and stable disease were associated with a higher number of cells expressing MUM-1 within the tumor at baseline, as measured by IHC. Conclusions: Inupadenant monotherapy was generally well-tolerated as of the date cut-off at a dose of 80 mg twice daily with initial evidence of clinical benefit, including 2 durable partial responses in patients who have exhausted standard treatment options. Analysis of pre- treatment tumor biopsies has identified the MUM-1 as a biomarker which may be associated with clinical benefit. Table 1: Most frequent TEAEs (>15%) in dose escalation and monotherapy expansion

Example 2 – Assessment of A_2AR expression and antibody-secreting cell marker expression in clinical tumor samples collected Methods [460] Tumor biopsies (1-3 per subject) were collected 1-28 days before inupadenant therapy, formalin-fixed and paraffin-embedded (FFPE), sectioned at 4 µm, and assessed for A_2AR expression using immunohistochemistry (IHC), and for the expression of several antibody-secreting cell (ASC) markers at RNA level using Nanostring technology (a customized Nanostring IO360 panel) (a proprietary technology from NanoString Technologies). [461] For A_2AR protein expression analysis, sections were stained with an anti- human A_2AR antibody (clone 7F6-G5-A2, ref#NBP1-39474) on a Ventana Discovery Ultra. Stained slides were digitalized and analyzed with Visiopharm software to determine the number of A_2AR+ cells. [462] For gene expression analysis, RNA was extracted from macrodissected tumor areas using High Pure FFPET RNA extraction kit and quantified using Quant-iT RiboGreen RNA Reagent and Kit. Total RNA (100 ng) was assayed using a customized nCounter PanCancer IO360 panel, and proprietary Nanostring gene signature scores were calculated. IRF4, CD38, SLAMF7, CD27 and TNFRSF17 expression was analyzed using QCed, normalized data. Results [463] Baseline A_2AR cell infiltration was significantly correlated with the expression of IRF4, CD38, SLAMF7, CD27 and TNFRSF17 genes (FIG.3A-3E), as well as with the Nanostring B cell signature score (FIG.3F-3G). Each dot represents one biopsy (N= 52). Spearman rho correlation coefficient with 95% confidence interval and P value are shown. Example 3 – Assessment of A_2AR+, MUM-1+, and CD38+ immune cell infiltration in clinical tumor samples collected Methods [464] Tumor biopsies (1-3 per subject) were collected 1-28 days before inupadenant therapy, formalin-fixed and paraffin-embedded (FFPE), sectioned at 4 µm, and assessed for A_2AR, MUM-1 and CD38 expression using immunohistochemistry (IHC). [465] Sections were stained with an anti-human A_2AR antibody (clone 7F6-G5-A2, ref#NBP1-39474), anti-human MUM1 antibody (Clone MRQ-43, Roche), or anti-CD38 antibody (clone SP149), digitalized and analyzed with Visiopharm software as described above. Results [466] Baseline A_2AR and MUM-1 immune cell infiltration assessed by IHC are significantly correlated (FIG.4A) (Spearman r=0.68, 95%CI: 0.50-0.81, P<0.0001; N=54). Each dot represents one biopsy for which both assessments were performed. [467] Baseline A_2AR and CD38 immune cell infiltration assessed by IHC are significantly correlated (FIG.4B) (Spearman r=0.54, 95%CI: 0.31-0.71, P<0.0001; N=55). Each dot represents one biopsy for which both assessments were performed. Example 4 – Assessment of A_2AR+ cell infiltration and B cell and antibody-secreting cell (ASC) related genes expression in clinical tumor samples collected Methods [468] Tumor biopsies (1-3 per subject) were collected 1-28 days before inupadenant therapy, formalin-fixed and paraffin-embedded (FFPE), sectioned at 4 µm, and assessed for A_2AR expression using immunohistochemistry (IHC), and for the gene expression using Nanostring technology (a customized Nanostring IO360 panel). [469] For gene expression analysis, RNA was extracted from macrodissected tumor areas using High Pure FFPET RNA extraction kit and quantified using Quant-iT RiboGreen RNA Reagent and Kit. Total RNA (100 ng) was assayed using a customized nCounter PanCancer IO360 panel. [470] For A2AR protein expression analysis, sections were stained with an anti-human A_2AR antibody (clone 7F6-G5-A2, ref#NBP1-39474) on a Ventana Discovery Ultra. Stained slides were digitalized and analyzed with Visiopharm software to determine the number of A_2AR+ cells. The receiver operating characteristics (ROC) curve analysis was used to select the optimal cut-off value of A_2AR for determining non-PD in subjects receiving inupadenant monotherapy. [471] Differential expression of 780 genes in subjects with low or high A_2AR+ cell infiltration was evaluated. Results [472] FIG. 12 is a volcano plot showing differential expression of 780 genes according to level of infiltration of A_2AR+ cells, and false discovery rate (FDR)-adjusted p values (q value, Benjamini and Yekutieli method). Names of B cell- and ASC-related genes are displayed on the plot. All genes differentially expressed between patients with low vs high A_2AR+ cell density are B cell- or antibody-secreting cell (ASC)-related. [473] A_2AR+ cell infiltration is shown to correlate with expression of B cell and antibody secreting cell (ASC) related genes. Example 5 - Assessment of IRF4 expression in clinical tumor samples collected Methods [474] Tumor biopsies (1-3 per subject) were collected 1-28 days before inupadenant therapy, formalin-fixed and paraffin-embedded (FFPE), sectioned at 4 μm, and assessed for IRF4/MUM-1 expression at RNA and protein level using Nanostring technology (customized Nanostring IO360 panel) and immunohistochemistry (IHC), respectively. [475] For IRF4 gene expression analysis, RNA was extracted from macrodissected tumor areas using High Pure FFPET RNA extraction kit and quantified using Quant-iT RiboGreen RNA Reagent and Kit. Total RNA (100 ng) was assayed using a customized nCounter PanCancer IO360 panel, and proprietary Nanostring gene signature scores were calculated. IRF4 was analyzed using QCed, normalized data. [476] For IRF4/MUM-1 protein expression analysis, sections were stained by IHC with a rabbit anti-human MUM-1 antibody (Clone MRQ-43, Roche) on a DAKO Link autostainer. Stained slides were digitalized and analyzed with Visiopharm software to determine the density of MUM-1⁺ cells (cells/mm2) in the tumor areas. [477] Tumor assessment was performed every 8 weeks, and tumor responses were evaluated using RECIST or PCWG3 criteria. The best percent change from baseline size of target lesions was calculated. Subjects were grouped based on their best overall response (BOR) to inupadenant (PD: progressive disease; SD: stable disease; PR: partial response). Association of baseline IRF4/MUM-1 expression (continuous variable) with BOR was evaluated using t test or Mann-Whitney test, as appropriate. [478] The receiver operating characteristics (ROC) curve analysis was used to select the optimal cut-off value of MUM-1 for determining non-PD in subjects receiving inupadenant monotherapy (training cohort). Association of baseline MUM-1 expression (categorical variable) with BOR was evaluated using chi-squared test. [479] Progression free survival (PFS) was calculated from first inupadenant dose to disease progression (event) or last patient visit (censored). PFS curve was estimated with the Kaplan-Meier method, and survival distributions according to baseline MUM-1 were compared using the log-rank test. Results [480] Results demonstrated that IRF4/MUM1 expression is associated with increased benefit from inupadenant therapy. • Baseline IRF4 gene expression as measured by Nanostring was shown to be significantly associated with BOR of subjects treated with inupadenant monotherapy (FIG.1A) (P=0.0023; N=19 PD, black dots; N=9 PR+SD, white and stripe dots, respectively). Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from t test. • Baseline MUM-1+ cell density as measured by IHC was shown to be significantly associated with BOR of subjects treated with inupadenant monotherapy (FIG. 1B) (N=16 PD, black dots; N=8 PR+SD, white and stripe dots, respectively). Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from Mann-Whitney test. • Baseline IRF4/MUM-1 detected by Nanostring and IHC are significantly correlated (FIG. 1C) (Spearman r=0.84, 95%CI: 0.69-0.92, P<0.0001; N=34). Each dot represents one biopsy for which both assessments were performed. • The optimal cut-off of MUM-1+ cells for non-PD was 35 MUM-1+ cells/mm2, as determined with ROC curve analysis (N=24) (FIG.1D). The area under the curve (AUC) is 0.88 (95% confidence interval: 0.74-1.00). With the optimal threshold, sensitivity is 87.5% (95% CI: 53-99%) and specificity is 75% (95% CI: 51-90%). • High baseline density of MUM-1+ cells is associated with improved PFS of subjects treated with inupadenant monotherapy (FIG 1E). Hazard ratio (HR) with 95% confidence interval and p value from Log-rank test (N=25) are shown. • Waterfall plot of best percent change in the sum of target lesion diameters in RECIST-evaluable subjects (N=38) (FIG.1F). vertical stripe: subjects with low baseline density of MUM-1+ cells; black: subjects with high density of MUM- 1+ cells; white: MUM-1 data unavailable. For two patients with unavailable MUM-1 data, gene expression levels below (low) or above (high) the mean IRF4 levels assessed by Nanostring are indicated. [481] Additional testing with additional subjects/data points added to previous data as set forth in FIG.1B-1F also confirmed correlation of IRF4/MUM1 expression with increased benefit from inupadenant therapy. • Baseline MUM1+ cell density was significantly associated with BOR of subjects treated with inupadenant monotherapy (FIG. 1G) (N=18 PD, black dots; N=8 PR+SD, white and stripe dots, respectively). Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from Mann-Whitney test. • Baseline IRF4/MUM1 detected by Nanostring and IHC were significantly correlated (FIG. 1H) (Spearman r=0.84, 95%CI: 0.69-0.92, P<0.0001; N=34). Each dot represents one biopsy for which both assessments were performed. • The optimal cut-off of MUM1+ cells for non-PD was 35 MUM1+ cells/mm2, as determined with ROC curve analysis (N=26) (FIG. 1I). The area under the curve (AUC) is 0.92 (95% confidence interval: 0.82-1.00). With the optimal threshold, sensitivity is 87.5% (95% CI: 53-99%) and specificity is 83% (95% CI: 61-94%). • High baseline density of MUM1+ cells was associated with improved PFS of subjects treated with inupadenant monotherapy (FIG. 1J). Hazard ratio (HR) with 95% confidence interval and p value from Log-rank test (N=27) are shown. • Waterfall plot of best percent change in the sum of target lesion diameters in RECIST-evaluable subjects (N=38) (FIG.1K). vertical stripe: subjects with low baseline density of MUM1+ cells; black: subjects with high density of MUM1+ cells; white: MUM1 data unavailable. For three patients with unavailable MUM1 data, gene expression levels below (low) or above (high) the mean IRF4 levels assessed by Nanostring are indicated. Example 6 - Assessment of expression of antibody-secreting cell markers in association with response to inupadenant in clinical tumor samples collected Methods [482] Tumor biopsies (1-3 per subject) were collected 1-28 days before inupadenant therapy, formalin-fixed and paraffin-embedded (FFPE), sectioned at 4 µm, and assessed for CD38 expression using immunohistochemistry (IHC), and for the expression of other antibody-secreting cell (ASC) markers at RNA level using Nanostring technology (customized Nanostring IO360 panel). [483] For CD38 protein expression analysis, sections were stained with a rabbit anti- CD38 antibody (clone SP149) on a Ventana Benchmark XT. Stained slides were digitalized and analyzed with Visiopharm software to determine the fractional area covered by CD38+ immune cells. [484] For gene expression analysis, RNA was extracted from macrodissected tumor areas using High Pure FFPET RNA extraction kit and quantified using Quant-iT RiboGreen RNA Reagent and Kit. Total RNA (100 ng) was assayed using a customized nCounter PanCancer IO360 panel, and proprietary Nanostring gene signature scores were calculated. CD38, SLAMF7, CD27 and TNFRSF17 expression was analyzed using QCed, normalized data. [485] Tumor assessment was performed every 8 weeks, and tumor responses were evaluated using RECIST or PCWG3 criteria. The best percent change from baseline size of target lesions was calculated. Subjects were grouped based on their best overall response (BOR) to inupadenant (PD: progressive disease; SD: stable disease; PR: partial response). Association of baseline marker expression (continuous variable) with BOR was evaluated using t test or Mann-Whitney test, as appropriate. Results [486] Baseline CD38+ immune cells were significantly associated with BOR of subjects treated with inupadenant monotherapy (FIG.5A) (P=0.0026, N=16 PD, black dots; N=6 PR+SD, white and stripe dots, respectively). Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from Mann-Whitney test. [487] Baseline gene expression of CD38, SLAMF7, CD27 and TNFSRF17 was significantly associated with BOR of subjects treated with inupadenant monotherapy (FIG. 5B-5E) (N=19 PD, black dots; N=9 PR+SD, white and stripe dots, respectively). Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from t test. [488] Updated additional testing also shows that baseline MUM1+ (FIG. 5F) and CD38+ (FIG. 5G) immune cells were significantly associated with BOR of subjects treated with inupadenant monotherapy (N=20 PD; N=8 nPD). Each dot represents the mean of available biopsies for one subject. Box plot showing median and quartiles, with whiskers from min to max. + is the mean. P from Mann-Whitney test. ASC markers are shown to be associated with response to inupadenant therapy. Example 7 - Assessment of expression of B cell and ASC related genes in association with response to inupadenant in clinical tumor samples collected [489] Differential expression of 780 genes according to best response to inupadenant was assessed (FIG. 5H). The same method as described in the methods section of Example 6, entitled “Assessment of expression of antibody-secreting cell markers in association with response to inupadenant in clinical tumor samples collected”, was performed. [490] Expression of B cell and antibody secreting cell (ASC) related genes is shown to be associated with response to inupadenant. Example 8 – Assessment of MUM-1+ cell infiltration in clinical tumor samples collected Methods [491] Tumor biopsies (1-3 per subject) were collected 1-28 days before inupadenant therapy (SCR), or after 3-4 weeks of therapy (C1D21), formalin-fixed and paraffin-embedded (FFPE), sectioned at 4 µm, and assessed for IRF4/MUM1 using immunohistochemistry (IHC). [492] Sections were stained by IHC with a rabbit anti-human MUM1 antibody (Clone MRQ-43, Roche) on a DAKO Link autostainer. Stained slides were digitalized and analyzed with Visiopharm software to determine the density of MUM1+ cells (cells/mm2) in the tumor areas. [493] Tumor assessment was performed every 8 weeks, and tumor responses were evaluated using RECIST or PCWG3 criteria. The best percent change from baseline size of target lesions was calculated. Subjects were grouped based on their best overall response (BOR) to inupadenant (PD: progressive disease; SD: stable disease; PR: partial response). Association of baseline IRF4/MUM1 expression with BOR was evaluated using Wilcoxon test for matched samples. Results [494] FIG.6A showed change on MUM-1+ cell infiltration in subjects undergoing inupadenant monotherapy who had PD (N=15, black dots) or PR+SD (N=5, white and stripe dots, respectively) as best response. Each dot represents the mean of available biopsies for one subject. Matched samples are connected by a line. P from Wilcoxon test. [495] FIG.6B showed another analysis of the change on MUM-1+ cell infiltration in subjects undergoing inupadenant monotherapy who had PD (progressive disease) (N=15) or nPD (non-progressive disease) (N=5, white and stripe dots) as best response. Each dot represents the mean of available biopsies for one subject. Matched samples are connected by a line. P from Wilcoxon test. [496] MUM-1+ cell infiltration was reduced post-inupadenant treatment in the 4/5 patients in the PD + SD or nPD group. Example 9 – Validation of MUM-1 clone MUM-1p IHC assay for predictive use in clinical studies Methods [497] FFPE tonsils and tumor samples (a mixture of lung, head, and neck squamous cancer, or endometrial cancer origin), sectioned at 4 μm, were assessed for IRF4/MUM-1 expression by IHC with clone MRQ-43 (Roche), or mouse anti-human MUM-1 antibody clone MUM-1p (Agilent). Briefly, after antigen retrieval, sections were incubated with anti- human MUM-1 antibodies, or isotype controls, followed by Flex HRP for detection and DAB as chromogen. Sections were finally counterstained with hematoxilin. [498] A pathologist performed qualitative evaluation to confirm subcellular and cellular staining pattern in normal (n=2 tonsils) and tumor (n=18) samples. Clone MUM-1p specificity was tested using positive and negative control tissues (n=3 tonsils and n=2 colon samples). Cross-reactivity in normal tissues was evaluated using a tissue microarray with 33 normal/anatomic sites. [499] Positivity range using the pre-determined cut-off of 35 MUM-1+ cells/mm² was evaluated using 71 carcinoma specimens of various origin, including non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) and endometrial carcinoma. Stained slides were digitalized and analyzed with Visiopharm integrator system to determine the density of MUM-1+ cells (cells/mm2) in the tumor areas. [500] Staining profiles of clone MRQ-43 and clone MUM-1p were compared in one tonsil and 33 tumor samples. [501] Finally, MUM-1p assay precision was tested using 12 tumor samples with different MUM-1 expression levels. The intra-run and inter-run agreement of the precision study was 100% and 97.5%, respectively. Results [502] Correlation was determined between clone MRQ-43 and clone MUM-1p in clinical samples (FIG.2A). Spearman correlation coefficient (rho) is shown. [503] An additional 21 samples were added, and strong correlation (N=36, Spearman rho = 0.74, 95%CI: 0.54-0.86) between staining profiles of clone MRQ-43 and clone MUM1p in clinical samples was confirmed (FIG.2B). Example 10 – Expression of A_2AR and antibody-secreting cell markers in clinical samples collected [504] Antibody-secreting cells (ASCs) are the major fraction of immune cells expressing A_2AR in both tonsil and tumor, as assessed by two methods as set forth below. 1. Multiplex Immunofluorescence (mIF) [505] Two similar analyses were done for this method as follows: A. First Analysis: Methods [506] FFPE tonsil and lung tumor samples were sectioned at 4 µm and the expression of several markers including PCK, A_2AR, MUM-1, CD19, and CD38 was evaluated by multiplexed immune fluorescence using Leica Bond and Akoya reagents. Images of the immunostained sections were captured using a Vectra Polaris (Automated Quantitative Pathology Imaging System – Akoya).20X resolution (0.5μm/pixel) images encompassing the whole slide were acquired using the DAPI, FITC, Cy3, Texas Red and Cy5 channels. Three Regions of interest (ROIs) were selected from the whole slide scanned images and further multispectral images (MSIs) were captured using Vectra Polaris. MSIs were unmixed using 103nform® software v6.4.2 (Akoya Biosciences) based on a library created from single color controls and the autofluorescent (AF) signal was subtracted. Following unmixing, multispectral images were analyzed with HALO® image analysis platform (Indicalabs) using Highplex FL module.

Results [507] FIG.7A-B show the frequency of CD19+, CD38+ or MUM1+ immune cell populations within A_2AR+ cells in tonsil and lung cancer tissue, respectively. FIG.7C showed frequency of MUM1+CD38+ immune cells within A_2AR+ cells in lung cancer tissue. The graphs in FIG.7A-7C represent data from 3 selected ROIs (circle: ROI 1, square: ROI 2, and triangle: ROI 3). [508] A_2AR was shown to be mainly expressed on MUM1+CD38+ cells. B. Second Analysis: Methods [509] FFPE blocks from adult tonsil and from lung tumors were sectioned at 4 µm and analyzed by multiplexed immune fluorescence for the expression of PCK, A_2AR, MUM-1, CD19, CD3, CD11c, CD123, and CD38 in 6 mm² over 39 regions of interest using Leica Bond and Akoya reagents. Images of the immunostained sections were captured using a Vectra Polaris (Automated Quantitative Pathology Imaging System – Akoya). 20X resolution (0.5μm/pixel) images encompassing the whole slide were acquired using the DAPI, FITC, Cy3, Texas Red and Cy5 channels. Multispectral images (MSIs) were unmixed using 104nform® software v6.4.2 (Akoya Biosciences) based on a library created from single color controls and the autofluorescent (AF) signal was subtracted. Following unmixing, multispectral images were analyzed with HALO® image analysis platform (Indicalabs) using Highplex FL module.

Results [510] Tonsil (n=1) (FIG.7D) and tumor samples (n=9) (FIG.7E) were stained by multiplex (m)IF and co-expression of A_2AR was quantified. A representative mIF image of a lung tumor showing A2AR+ ASCs, denoted by arrows, is shown at FIG.7F. Data are shown as mean ± SEM. pDC = plasmacytoid dendritic cell; cDC = conventional; PB = plasma blast; PC = plasma cell. Plasmacytoid (p)DCs were defined as CD123⁺, conventional (c)DCs as CD11c⁺, T cells as CD3⁺, B cells as CD19⁺MUM1-, ASCs as CD19^+/- MUM1⁺CD123- CD11c-CD3-. [511] A_2AR was shown to be mainly expressed on ASCs. 2. A_2AR and/or MUM1 immunocytochemistry of sorted tonsillar and ascites B cell subsets Two similar analyses were done for this method as follows: A. First Analysis: Methods [512] Human tonsil tissue samples were purchased from Discovery Life Science and obtained from adult patients who had tonsillectomies due to inflammation. Tonsillar mononuclear cells (TMNC) were obtained after mechanical dissociation followed by Lymphoprep gradient centrifugation and frozen in liquid nitrogen until further use. Thawed TMNC were enriched or not for B cells using the EasySep™ Human Pan-B Cell Enrichment Kit (StemCell, Cat 19554) previous staining with an antibody mix and naïve B cells (CD45+CD19+IgD+CD27-), memory B cells (CD45+CD19+IgD-CD27+without CD38++CD27++ cells), and antibody-secreting cells, including plasma blasts (CD45+CD19+IgD-CD38++CD27++HLADR+), and plasma cells (CD45+CD19+IgD- CD38++CD27++HLADR-), were sorted (3000-200000 cells) on a FACS Aria III cell sorter. Summary of reagents for cell sorting for A_2AR staining by immunocytochemistry:

Summary of reagents for cell sorting for MUM1 immunocytochemistry:

[513] Formalin-fixed cells coated on poly-L-lysine slides were prepared after sorting the populations of interest. [514] A_2AR expression was assessed by ICC. After antigen retrieval with RiboCC (Roche) and a blocking step with the Antibody block reagent (Roche), cells were incubated with mouse anti-human A_2AR antibody (clone 7F6G5A2, Novus Biologicals, lot E, 0.4 ug/ml final), followed by anti-mouse HQ (Roche) and anti-HQ-HRP (Roche) for detection and DAB was used (Roche) for visualization. Cells were counterstained with hematoxylin and bluing reagent (Roche) and digitalized. [515] MUM-1 expression was assessed by ICC. After antigen retrieval with CC1 (Roche), cells were incubated with rabbit anti-human MUM-1 antibody (clone EP190, Roche, 0.6 ug/ml), followed by omniMap anti-rabbit HRP (Roche) for detection and DAB was used (Roche) for visualization. Cells were counterstained with hematoxylin and bluing reagent (Roche) and digitalized. Results [516] FIG.8A shows quantification of the expression of A_2AR on sorted tonsillar B cell subsets. [517] FIG.8B shows quantification of the expression of MUM1 on sorted tonsillar B cell subsets. [518] A_2AR is shown to be expressed primarily on antibody-secreting cells and antibody-secreting cells are enriched for MUM-1 expression. B. Second Analysis: Methods [519] Human tonsil tissue samples were purchased from Discovery Life Science and obtained from adult patients who had tonsillectomies due to inflammation. Tonsillar mononuclear cells (TMNC) were obtained after mechanical dissociation followed by Lymphoprep gradient centrifugation and frozen in liquid nitrogen until further use. [520] Human ascites was obtained from a cancer patient. Ascites fluid underwent to three rounds of centrifugation respectively at 500g for 15 min, followed by two at 300g for 8 min before red blood cell lysis. Ascites cells were frozen in liquid nitrogen until further use. Thawed ascites cells were enriched for B cells using the EasySep™ Human Pan-B Cell Enrichment Kit (StemCell, Cat 19554) according to the manufacture’s instruction. [521] Thawed TMNC and ascites B cells were stained with an antibody mix and naïve B cells (CD45+CD19+IgD+CD27-), memory B cells (CD45+CD19+IgD-CD27+without CD38++CD27++ cells), and antibody-secreting cells, including plasma blasts (CD45+CD19+IgD-CD38++CD27++HLADR+), and plasma cells (CD45+CD19+IgD- CD38++CD27++HLADR-), were sorted (3000-200000 cells) on a FACS Aria III cell sorter. Summary of reagents for cell sorting for A_2AR staining by immunocytochemistry:

[522] Formalin-fixed cells coated on poly-L-lysine slides were prepared after sorting the populations of interest. [523] A_2AR expression was assessed by ICC on poly-L-lysin slides. After antigen retrieval with RiboCC (Roche) and a blocking step with the Antibody block reagent (Roche), cells were incubated with mouse anti-human A_2AR antibody (clone 7F6G5A2, Novus Biologicals, lot E, 0.4 ug/ml final), followed by anti-mouse HQ (Roche) and anti-HQ-HRP (Roche) for detection and DAB was used (Roche) for visualization. Cells were counterstained with hematoxylin and bluing reagent (Roche) and digitalized. Results [524] FIG. 8C shows quantification of the expression of A_2AR on sorted tonsillar B cell subsets. Sorted B cell subsets from TMNCs were analyzed by ICC for A_2AR expression. Frequency of A_2AR+ cells on sorted B cell subsets from human TMNCs (n=3) is shown in FIG.8C. Data are shown as mean ± SEM. ASCs = antibody secreting cells; PB = plasma blasts; PC = plasma cells. [525] FIG.8D shows quantification of the expression of A_2AR on sorted ascites B cell subsets. Sorted B cell subsets from ascites cells were analyzed by ICC for A_2AR expression. Frequency of A_2AR+ cells on sorted B cell subsets from human ascites (n=1) is shown in FIG.8D. Data are shown as mean ± SEM. ASCs = antibody secreting cells; PB = plasma blasts; PC = plasma cells. [526] Representative ICC image of A2AR staining on memory B cells and plasma cells of a TMNC donor is shown in FIG.8E and FIG.8F. [527] A_2AR is shown to be expressed primarily on ASCs. Example 11: Expression of adenosine pathway markers and AMP-generating ectoenzymes in ASCs in clinical samples collected A. Expression of adenosine pathway markers Methods [528] Thawed TMNC, ascites and dissociated tumor cells (DTC) were stained with an antibody mix and analyzed by flow cytometry in a Cytek Aurora with panel C or panel D. TMNC and ascites were obtained as described in the methods section of Example 10, Section 2): “A_2AR and/or MUM 1 immunocytochemistry of sorted tonsillar and ascites B cell subsets”. Summary of flow cytometry reagents for FIG.9B below:

Summary of flow cytometry reagents for FIG.9C below

Results [529] FIG.9A-9C show frequency of CD39+ cells (FIG.9A) and MFI of CD39 (FIG. 9B-9C) on naïve B cells (CD45+CD19+IgD+CD27-), memory B cells CD45+CD19+IgD- CD27+without CD38++CD27++ cells), and antibody-secreting cells, including plasma blasts (CD45+CD19+IgD-CD38++CD27++HLADR+) and plasma cells (CD45+CD19+IgD- CD38++CD27++HLADR-), from tonsils. Graph shows the mean ± SEM. [530] ASC were preferentially shown to express the adenosine pathway marker CD39. B. Expression of AMP-generating ectoenzymes Methods [531] Thawed or fresh TMNC, fresh dissociated tumor cells (DTC) and fresh cancer peripheral blood mononuclear cells (PBMCs) were stained with an antibody mix and analyzed by flow cytometry in a Cytek Aurora. TMNCs were obtained as described in the methods section of Example 9, Section 2): “A_2AR and/or MUM1 immunocytochemistry of sorted tonsillar and ascites B cell subsets”. [532] DTCs were isolated from cancer patients (lung, ovarian) by mechanical and enzymatic dissociation. Tumor Dissociation (Miltenyi Biotech, Cat 130-095-929) was used according to the manufacture’s instruction. [533] Cancer PBMCs were obtained from blood of cancer patients (lung, ovarian, kidney) by Lymphoprep gradient centrifugation. [534] Summary of flow cytometry reagents:

Results [535] FIG.13A-13F showed frequency (FIG.13A-13C) and median fluorescence intensity (MdFI, FIG.13D-13F) of CD39 (FIG.13A and 13D), CD73 (FIG.13B and 13E) and CD38 (FIG.13C and 13F) on B cell subsets from cancer PBMCs (n=4), healthy donor tonsillar mononuclear cells (TMNCs) (n=5) and dissociated tumor cells (DTCs) (n=3). MdFI is calculated on total cells. Graph shows the mean ± SEM. PB = plasma blast; PC = plasma cell. [536] ASCs are shown to express high levels of AMP-generating ectoenzymes, and in particular ASCs are the major expressors of CD39 and CD38 in tumor and tonsil compared to other B cell subsets. Example 12: Plasma cell maturation in presence of A_2AR agonist with or without Inupadenant [537] Two similar analyses were done as follows: A. First Analysis: Method [538] Freshly purified B cells isolated from healthy donor PBMC (B cell isolation kit II, Miltenyi Biotech #130-091-151) were cultured for 7 days in 5%HS-xVivo medium containing human CD40-Ligand Multimer, anti-BCR (AffiniPure F(ab)2 Fragment), Il-21 and Il-2. Then, cells were incubated with or without an A_2AR agonist (CGS-21680) 5 uM and with or without inupadenant 300 nM for 3 days. [539] Monitoring of the different B cells subtypes generation was assessed by flow cytometry along the culture and the assay. Summary of cell culture reagents:

Summary of flow cytometry reagents for B cell culture:

Results [540] Purified B cells were cultured for 10 days in the presence of CGS (A_2AR agonist) with or without inupadenant. FIG.10A showed percentage difference of the plasma cells (PC; CD45+CD19+IgD-CD38++CD27++HLADR-) within CD19+ cells at the end of the culture, normalized on the untreated condition for each donor. Each line represents a B cell donor. FIG.10B shows percentage of the viability of the plasma cells at the end of the culture. [541] The A_2AR agonist CGS-21680 inhibited the maturation of healthy peripheral blood B cells into plasma cells in vitro, a process which could be fully restored by inupadenant. CGS-21680 did not affect B cell or plasma cell viability, indicating that the effect of A_2AR signaling on plasma cell differentiation was not due to preferential plasma cell death in culture. B. Second analysis: Method [542] Freshly purified B cells isolated from healthy donor PBMC (B cell isolation kit II, Miltenyi Biotech #130-091-151) were cultured for 6 days in 5%HS-xVivo medium containing human CD40-Ligand Multimer, anti-BCR (AffiniPure F(ab)2 Fragment), Il-21 and Il-2. Then, cells were incubated with or without an A2AR agonist (CGS-21680) 5 uM and with or without inupadenant 300 nM for 3 days. [543] Cells were analyzed by flow cytometry. Monitoring of the different B cells subtypes generation was assessed by flow cytometry along the culture and the assay. The following gating strategy was used to identify different B cell subsets: plasma blasts (CD45⁺CD19⁺IgD-CD38⁺⁺CD27⁺⁺HLADR⁺) and plasma cells (CD45⁺CD19⁺IgD- CD38⁺⁺CD27⁺⁺HLADR-). Summary of cell culture reagents:

Summary of flow cytometry reagents for B cell culture:

Results [544] Purified B cells were cultured for 6 days, then cells were incubated in the presence of CGS-21680 (A_2AR agonist) with or without inupadenant for 3 additional days. FIG.10C- 10E showed percent difference in frequency of plasma blasts (PB) and plasma cells (PC) among CD19+ cells (FIG.10C), viability (FIG.10D) and Ki-67 expression (FIG.10E) among PBs and PCs, normalized on the untreated condition for each donor, after 9 days of culture (n=4). Data are shown as mean ± SEM. [545] A_2AR engagement reduces the frequency of PCs (FIG.10C) without affecting their viability (FIG.10D) or proliferation (FIG.10E). This effect is reverted by inupadenant (FIG.10C). Example 13: Clinical data confirming partial response to inupadenant in patient with highest infiltration of ASCs [546] A table (FIG.11A) illustrating tumor size measurements is provided where a potential partial response with inupadenant monotherapy in a patient with a high level of MUM1+ cells having an adenocarcinoma tumor of unknown origin is seen. High MUM1+ cell ( >2000 cells/mm² vs threshold of 35) are observed whereas all other patients to date are < 500 cells/mm². [547] The patient first had radiotherapy (left iliac zone), and was then administered carboplatin plus paclitaxel, and at best had stable disease (SD). The patient then progressed and was given spartalizumab (antiPD1) and at best had a partial response (PR). The patient then progressed and was given inupadenant 80 mg BID as a monotherapy, which is ongoing. [548] An IHC assay for MUM1+ cells and H&E (showing architecture) are also shown (FIG.11B (left) and FIG.11C (right)). [549] An additional table (FIG.11D) further illustrating tumor size measurements is provided where a confirmed partial response with inupadenant monotherapy in a patient with a high level of MUM1+ cells having an adenocarcinoma tumor of unknown origin is seen. High MUM1+ cells ( >2000 cells/mm² vs threshold of 35) are observed, whereas 95% of the patients tested to date are < ~600 cells/mm². [550] An additional IHC image for MUM1+ cells is also shown in FIG.11E. Example 14. Clinical Trial to Evaluate Inupadenant Hydrochloride in Patients With Metastatic Non-Small Cell Lung Cancer (mNSCLC) or Locally Advanced, Unresectable NSCLC [551] A pharmaceutical composition comprising inupadenant (e.g., a pharmaceutical composition comprising inupadenant hydrochloride) is evaluated in an interventional, multicenter, randomized, placebo-controlled, phase 2 study evaluating the efficacy of inupadenant in non-small cell lung cancer. NSCLC includes non-small cell carcinoma not otherwise specified (<5%), squamous cell carcinoma (25%-30%), and nonsquamous carcinoma (adenocarcinoma, large cell, and undifferentiated carcinoma; 70%-75%. [552] The clinical study evaluates the safety and efficacy of inupadenant in combination with carboplatin and pemetrexed as a second-line therapy in adult patients with metastatic non-small cell lung cancer (mNSCLC) or locally advanced, unresectable NSCLC of nonsquamous pathology, with two primary goals: [553] Assess the safety and tolerability of the combination of inupadenant HCl and carboplatin/pemetrexed in an open-label, safety run-in phase, and determine the appropriate combination dose to continue to the randomized portion of the study [554] Assess the efficacy and safety of inupadenant HCl combined with carboplatin/pemetrexed compared to a control arm receiving placebo and carboplatin/pemetrexed. [555] The clinical study design is set forth in FIG.14. [556] The dose-finding part (Part 1) evaluates safety with a starting dose of inupadenant HCl at 40 mg twice daily (BID) combined with the standard approved doses of platinum chemotherapy (carboplatin area under the curve 5 mg/ml per min [AUC5] and pemetrexed 500 mg/m2 every 3 weeks [Q3W] for 4 cycles, followed by pemetrexed maintenance therapy). Each cycle covers 3 weeks. This dose is tested in a modified (3+3) escalation with a minimum of 6 evaluable participants, allowing for the enrollment of additional backup participants in case of non-evaluability of any participants in the starting cohort. Two additional dose cohorts (e.g., 80 mg BID and 160 mg BID) may be considered in the dose escalation if the starting dose is well tolerated. In addition, a 20 mg BID dose may be considered based on the available safety and PK data. [557] In Part 2, 150 patients are randomized 1:1 to inupadenant or placebo, both in combination with carboplatin and pemetrexed. Tumor response is determined according to RECIST 1.1 criteria and safety findings are reviewed by a Safety Review Committee (for Part 1) and a Data Monitoring Committee (for Part 2). [558] Key eligibility criteria include 1) Metastatic NSCLC (Stage IV) or locally advanced, unresectable (Stage III) NSCLC of nonsquamous pathology that has relapsed or progressed after prior anti-programmed death (PD)-ligand (L)1 therapy, 2) Stage IV patients should have received only 1 line of anti-PD-(L)1 therapy in the metastatic setting, without concomitant chemotherapy (immuno-oncology/immuno-oncology combination therapy is allowed); Stage III patients should have received single-agent durvalumab therapy post- chemoradiation), 3) have measurable disease as defined by RECIST 1.1 criteria and 4) Eastern Cooperative Oncology Group status ≤1. The primary endpoints are recommended Phase 2 dose to be used in combination with carboplatin and pemetrexed in Part 2 of the study (for Part 1) and progression-free survival between the active arm (inupadenant and carboplatin and pemetrexed) and the control arm (placebo and carboplatin and pemetrexed) (for Part 2). Secondary endpoints include change in tumor size, objective response rate, overall survival, and adverse events. Correlative aims include assessing blood and tissue biomarkers for association with clinical benefit. Example biomarkers include ASC markers, and the correlative aims include evaluating ASC infiltration for association with clinical benefit and evaluating potential patient enrichment/ selection strategy based on ASC infiltration.

Claims

CLAIMS We claim: 1. A method of treating cancer characterized by increased IRF4/MUM-1 expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist.

2. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist, wherein the subject has previously been identified as having increased IRF4/MUM-1 expression.

3. The method of claim 2, wherein the subject has been the subject has previously been identified as having increased IRF4/MUM-1 expression as a result of infiltration of immune cells.

4. The method of any of claims 1-3, wherein the cancer is not a lymphoma.

5. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist, wherein the subject has previously been identified as having increased IRF4/MUM-1 expression.

6. A method of treating cancer in a patient in need thereof, comprising selecting a patient with cancer having a diagnosis of increased level of IRF4/MUM-1 expression; and treating the patient with an adenosine receptor antagonist.

7. A method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising detecting the level of IRF4/MUM-1 expression in a sample from the subject; comparing the level of IRF4/MUM-1 expression with a reference level or infiltration; selecting the subject for treatment with an adenosine receptor antagonist based on the comparison at the previous step.

8. The method of claim 7, wherein the subject is selected for treatment when IRF4 expression is increased.

9. The method of claim 7or 8, wherein the sample is a tumor tissue sample.

10. An adenosine receptor antagonist for use in the treatment of cancer in a patient in need thereof, wherein the cancer is characterized by increased IRF4/MUM-1 expression.

11. The method of any one of claims 1-9, or the adenosine receptor antagonist for use according to claim 10, wherein IRF4/MUM-1 expression is increased by comparison to a reference level or infiltration determined in a sample from a subject not affected and/or diagnosed with cancer.

12. The method of any one of claims 1-9, or the adenosine receptor antagonist for use according to claim 10, wherein the level of IRF4/MUM-1 expression is increased by comparison to a reference level or infiltration determined in a non-cancerous sample from the same subject.

13. The method of any one of claims 11 or 12, wherein the subject is treatment naïve.

14. The method of any one of claims 11 or 12, wherein the subject has previously received treatment for cancer.

15. The method or adenosine receptor antagonist for use according to any one of claims 1-14, wherein the level of IRF4 expression is measured using gene expression profiling.

16. The method or adenosine receptor antagonist for use according to any of claims 1- 15, wherein the level of IRF4/MUM-1 expression is measured using an assay selected from the group consisting of Nanostring technology, immunohistochemistry (IHC), quantitative reverse transcription PCR (RT-qPCR), Western blot, flow cytometry, fluorescent IHC, and in situ hybridization.

17. The method or adenosine receptor antagonist for use according to claim 16, wherein a cutoff value is determined with ROC curve analysis.

18. The method or adenosine receptor antagonist for use according to claim 16, wherein the assay is Nanostring technology.

19. The method or adenosine receptor antagonist for use according to claim 16, wherein the assay is immunohistochemistry (IHC).

20. The method or adenosine receptor antagonist for use according to claim 19, wherein the infiltration of MUM-1+ cells in a tumor is higher than a cutoff value.

21. The method or adenosine receptor antagonist for use according to claim 19, wherein the level of MUM-1 expression is measured as density of MUM-1+ cells in cells/mm².

22. The method or adenosine receptor antagonist for use according to claim 21, wherein the density of MUM-1+ cells in a tumor is higher than a cutoff value.

23. The method or adenosine receptor antagonist for use according to claim 22, wherein the cutoff value is 30-40 MUM-1+ cells/mm².

24. The method or adenosine receptor antagonist for use according to claim 22, wherein the cutoff value is about 35 MUM-1+ cells/mm².

25. The method or adenosine receptor antagonist for use according to claim 16, wherein the assay is RT-qPCR.

26. The method or adenosine receptor antagonist for use according to claim 16, wherein the assay is Western blot.

27. The method or adenosine receptor antagonist for use according to claim 16, wherein the assay is flow cytometry.

28. The method or adenosine receptor antagonist for use according to claim 16, wherein the assay is fluorescent IHC.

29. The method or adenosine receptor antagonist for use according to claim 16, wherein the assay is in situ hybridization.

30. The method or adenosine receptor antagonist for use according to any of claims 1- 29, wherein the IRF4/MUM-1 expression level is greater than a cutoff value.

31. The method or adenosine receptor antagonist for use according to claim 30, wherein the reference value is determined by ROC analysis.

32. A method of treating cancer characterized by increased expression of at least one antibody-secreting cell marker in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist.

33. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist, wherein the subject has previously been identified as having increased expression of at least one antibody-secreting cell marker.

34. The method of claim 33, wherein the subject has previously been identified as having increased expression of at least one antibody-secreting cell marker as a result of infiltration of immune cells.

35. The method of any one of claims 32-34, wherein the cancer is not a lymphoma.

36. A method of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an adenosine receptor antagonist, wherein the subject has previously been identified as having increased expression of at least one antibody-secreting cell marker.

37. A method of treating cancer in a patient in need thereof, comprising selecting a patient with cancer having a diagnosis of increased level of expression of at least one antibody-secreting cell marker; and treating the patient with an adenosine receptor antagonist.

38. A method of selecting a subject with cancer for treatment with an adenosine receptor antagonist, comprising detecting the level of expression of at least one antibody-secreting cell marker in a sample from the subject; comparing the level of expression of the at least one antibody-secreting cell marker with a reference level or infiltration; selecting the subject for treatment with an adenosine receptor antagonist based on the comparison at the previous step.

39. The method of claim 38, wherein the subject is selected for treatment when expression of at least one antibody-secreting cell marker is increased.

40. The method of claim 38 or 39, wherein the sample is a tumor tissue sample.

41. The method of any one of claims 32-40, wherein the at least one antibody- secreting cell marker is chosen from MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A, and CD138.

42. An adenosine receptor antagonist for use in the treatment of cancer in a patient in need thereof, wherein the cancer is characterized by increased expression of at least one antibody-secreting cell marker.

43. The adenosine receptor antagonist for use according to claim 42, wherein the at least one antibody-secreting cell marker is chosen from MUM-1, CD38, TNFRSF17, SLAMF7, CD27, FAM30A, CD79A, and CD138.

44. The method of any one of claims 32-41, or the adenosine receptor antagonist for use according to claims 42-43, wherein expression of the at least one antibody- secreting cell marker is increased by comparison to a reference level or infiltration determined in a sample from a subject not affected and/or diagnosed with cancer.

45. The method of any one of claims 32-41, or the adenosine receptor antagonist for use according to claims 42-43, wherein the level of expression of the at least one antibody-secreting cell marker is increased by comparison to a reference level or infiltration determined in a non-cancerous sample from the same subject.

46. The method of any one of claims 44 or 45, wherein the subject is treatment naïve.

47. The method of any one of claims 44 or 45, wherein the subject has previously received treatment for cancer.

48. The method or adenosine receptor antagonist for use according to any one of claims 32-47, wherein the level of expression of the at least one antibody-secreting cell marker is measured using gene expression profiling.

49. The method or adenosine receptor antagonist for use according to any of claims 32- 48, wherein the level of expression of the at least one antibody-secreting cell marker is measured using at least one assay chosen from Nanostring technology, immunohistochemistry (IHC), quantitative reverse transcription PCR (RT-qPCR), Western blot, flow cytometry, fluorescent IHC, and in situ hybridization.

50. The method or adenosine receptor antagonist for use according to claim 49, wherein a cutoff value is determined with ROC curve analysis.

51. The method or adenosine receptor antagonist for use according to claim 49, wherein the assay is Nanostring technology.

52. The method or adenosine receptor antagonist for use according to claim 49, wherein the assay is immunohistochemistry (IHC).

53. The method or adenosine receptor antagonist for use according to claim 52, wherein the level of expression of the at least one antibody-secreting cell marker is measured as density of cells positive for the at least one antibody-secreting cell marker in cells/mm².

54. The method or adenosine receptor antagonist for use according to claim 49, wherein the assay is RT-qPCR.

55. The method or adenosine receptor antagonist for use according to claim 49, wherein the assay is Western blot.

56. The method or adenosine receptor antagonist for use according to claim 49, wherein the assay is flow cytometry.

57. The method or adenosine receptor antagonist for use according to claim 49, wherein the assay is fluorescent IHC.

58. The method or adenosine receptor antagonist for use according to claim 49, wherein the assay is in situ hybridization.

59. The method or adenosine receptor antagonist for use according to any of claims 1- 58, wherein the adenosine receptor antagonist is an A_2AR antagonist.

60. The method or adenosine receptor antagonist for use according to any of claims 1- 58, wherein the adenosine receptor antagonist is a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ represents 5- or 6-membered heteroaryl or 5- or 6-membered aryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from C1- C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro); preferably R¹ represents 5-membered heteroaryl; more preferably R¹ represents furyl; R² represents 6-membered aryl or 6-membered heteroaryl, wherein heteroaryl or aryl groups are optionally substituted by one or more substituent selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino and alkylsulfonealkyl; said substituents being optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl alkylsulfonyl and alkylsulfonealkyl; or the heteroaryl or aryl groups are optionally substituted with two substituents that form together with the atoms to which they are attached a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring; optionally substituted by one or more substituent selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

61. The method or adenosine receptor antagonist for use according to any of claims 1- 59, wherein the adenosine receptor antagonist is selected from the group consisting of (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; and (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1- yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one, or a pharmaceutically acceptable salt thereof.

62. The method or adenosine receptor antagonist for use according to any of claims 1- 61, further comprising administration of an additional therapeutic agent.

63. The method or adenosine receptor antagonist for use according to claim 62, wherein the adenosine receptor antagonist is administered prior to the additional therapeutic agent.

64. The method or adenosine receptor antagonist for use according to claim 62, wherein the adenosine receptor antagonist is administered simultaneously with the additional therapeutic agent.

65. The method or adenosine receptor antagonist for use according to claim 62, wherein the adenosine receptor antagonist is administered after the additional therapeutic agent.

66. The method or adenosine receptor antagonist for use according to any of claims 1- 65, wherein the subject has previously received treatment with an additional therapeutic agent.

67. The method or adenosine receptor antagonist for use according to any one of claims 1-66, wherein the cancer is selected from the group consisting of lung cancer, endometrial cancer, gastric cancer, melanoma, breast cancer, colorectal cancer, oral squamous cell carcinoma, multiple myeloma, prostate cancer, and a head/neck cancer.

68. The method or adenosine receptor antagonist for use according to any one of claims 1-66, wherein the cancer is non-small cell lung cancer.

69. An adenosine receptor antagonist for use in a method of treating cancer in a patient in need thereof, wherein the cancer is characterized by increased expression of at least one antibody-secreting cell marker.

70. An adenosine receptor antagonist for use in a method of treating cancer in a patient in need thereof, wherein the cancer is characterized by increased IRF4/MUM-1 expression.