CN116271050B - Application of CSNK2B gene target in preparation of medicines for preventing immune cell depletion in tumor treatment, inhibitor and combination - Google Patents
Application of CSNK2B gene target in preparation of medicines for preventing immune cell depletion in tumor treatment, inhibitor and combination Download PDFInfo
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The application belongs to the field of biological medicine, and relates to application of a CSNK2B gene target in preparing medicines, inhibitors and combinations for preventing immune cell depletion in tumor treatment. The application provides application of CSNK2B gene targets in preparing medicines for preventing immune cells from being exhausted in tumor treatment, inhibitors and combinations, and CSNK2B is used as a target of a novel tumor immunotherapy medicine, and can effectively reverse and inhibit the exhaustion of effector T cells, recover the functions of the effector T cells and enhance the curative effect of immunotherapy.
Description
Technical Field
The application belongs to the field of biological medicine, and relates to application of a CSNK2B gene target in preparing medicines, inhibitors and combinations for preventing immune cell depletion in tumor treatment.
Background
Malignant tumor is a progressive disease in which normal cells proliferate and differentiate abnormally and are uncontrolled. In the process of tumor development, various cytokines supporting the growth of tumor cells can be released by an autocrine or paracrine mode, and simultaneously forms an immunosuppressive tumor microenvironment together with suppressive immune cells, fibroblasts, endothelial cells and the like. Immune cells play an important role in the tumor microenvironment, for example, treg cells and tumor-associated macrophages can promote tumor cells to evade killing of effector cells. While effector T lymphocytes, also called Cytotoxic T Lymphocytes (CTLs), act as the principal force for killing tumor cells, and are continually stimulated by the tumor environment in the tumor microenvironment, resulting in inhibition of immune cell functional activity and progressive manifestation of a functional depletion phenotype, thereby resulting in a decrease in the ability of CTLs to kill tumors, and even promoting growth of tumor cells.
Protein Kinase CK2, also known as Casein Kinase 2 (Casein Kinase ii), is a ubiquitous protein Kinase that regulates metabolic pathways, signal transduction, transcription, translation and replication. The enzyme is a tetramer consisting of three subunits, α, α' and β. The alpha and alpha' subunits have a catalytic effect and the beta subunit has a regulatory effect. Each subunit in the CK2 tetramer is encoded by separate genes CSKN2A1 (CK 2 a), CSKN2A2 (CK 2 a') and CSNK2B (CK 2 β), and each subunit can function independently of its binding in the tetramer. Currently, a large number of CK2 substrates are involved in the basic pathway of carcinogenesis (e.g., PI3K/AKT, NFKB, JAK/STAT3, WNT, etc.), and significant increases in CK2 expression levels are observed in various malignant cells, with increased expression levels being closely related to poor prognosis. In addition, the expression of CK2 in immune cells was found to be involved in CD4 + Differentiation of T cells, CK2 alpha deficiency results in differentiation of a Th2/Th17 subpopulation to a population of Treg cells. In addition, there is literature that CK2 alpha participates in CD8 at the time of infection + Inflammatory response of T cells. However, the targets and directions of the existing research are focused on CK2 alpha, and the effect of CK2 beta, namely CSNK2B gene, is not involved.
Disclosure of Invention
The application mainly aims to provide a novel application of regulating and controlling a CSNK2B gene to realize the purpose of regulating tumor immunotherapy and inhibiting the CSNK2B gene to reverse immune cell depletion and CSNK2B siRNA in tumor immunotherapy.
In order to achieve the above object, according to one aspect of the present application, there is provided the use of CSNK2B gene targets for the preparation of a medicament for preventing immune cell depletion in tumor therapy.
The application also provides an inhibitor for preventing immune cell depletion in tumor treatment, wherein the inhibitor comprises a CSNK2B gene target.
The inhibitor comprises siRNA of CSNK2B gene target, shRNA, a vector for expressing siRNA or a vector for expressing shRNA.
The immune cell provided by the application is CD8 + T cells, including CAR-T, CTL, TIL, CIK, immune cell-based effector cell populations.
The application also provides a combination for preventing immune cell depletion in tumor treatment, which comprises an anti-PD-1 antibody and an inhibitor of a CSNK2B gene target.
The beneficial effects of the application are as follows:
the application provides application of CSNK2B gene targets in preparing medicines for preventing immune cells from being exhausted in tumor treatment, inhibitors and combinations, and CSNK2B is used as a target of a novel tumor immunotherapy medicine, and can effectively reverse and inhibit the exhaustion of effector T cells, recover the functions of the effector T cells and enhance the curative effect of immunotherapy.
Drawings
The accompanying drawings, which are included to provide a further understanding of the application and are incorporated in and constitute a part of this specification, illustrate embodiments of the application and together with the description serve to explain the application. In the drawings:
FIG. 1 is a 200X fold image and a 400X fold image of immunohistochemical double staining CD8+T and CSNK2B.
FIG. 2 is a graph showing the progression free survival of immunohistochemical double-stained CD8+ T and CSNK2B, high being the CSNK2B high expressing group and low being the CSNK2B low expressing group.
FIG. 3 shows the in vitro heterodimer induced CD8 of the present application + Flow cytometry of T cell depletion.
FIG. 4 is a PD-1 of the present application + Tim-3 + Flow cytometry for CSNK2B high expression in terminal depleted cell populations.
FIG. 5 shows the inhibition of CD8 by siCSNK2B of the application + Flow cytometry of T cell depletion.
FIG. 6 is a SiCSN of the applicationReverse CD8 of K2B + Flow cytometry of T cell depletion.
FIG. 7 is a SiCSNK2B reverse CD8 of the application + Statistical graphs of relative expression of T cell depleted mRNA.
FIG. 8 shows the siCSNK2B enhanced CD8 of the present application + Flow cytometry map of T cell function.
FIG. 9 is a comparative graph of cell lysis in which siCSNK2B knockdown of the present application enhances the killing function of CIK cells.
FIG. 10 is a graph showing the prognostic effect of CSNK2B expression in patients with lung cancer on anti-PD-1 treatment according to the present application, wherein 200X and 400X represent 200X-fold and 400X-fold images, respectively.
FIG. 11 shows CD8 in MPR group (major pathology remission, active tumor ratio less than 10%) in lung cancer patients treated with anti-PD-1 drugs according to the present application + CSNK2B expression in T cells was significantly lower than in the Non-MPR group (without major pathological relief) control.
Detailed Description
The application is described in further detail below with reference to the drawings and examples. It is to be understood that the specific embodiments described herein are merely illustrative of the application and are not limiting thereof. It should be further noted that, for convenience of description, only some, but not all experimental results related to the present application are shown in the drawings.
Example 1 immunohistochemical staining:
(1) Paraffin-embedded lung adenocarcinoma patient tissue sections were placed in a oven at a constant temperature of 70 ℃ for 1 h or overnight baked.
(2) The slices were sequentially passed through cylinders for dewaxing in the following order, xylene I, xylene II, xylene III, absolute ethanol I, absolute ethanol II, 95% ethanol, 85% ethanol, 75% ethanol, respectively.
(3) The dewaxed tissue slices are hydrated, and the hydrated slices are placed in an autoclave at 130 ℃ for antigen retrieval for 2 and a half minutes.
(4) After the sections were returned to room temperature, they were blocked with 5% goat serum and 3% hydrogen peroxide, and the blocked sections were left at 4 ℃ overnight for antibody incubation.
And (3) performing secondary antibody incubation on the sections after antibody incubation according to the operating protocol of the China fir Jin Qiaoshuang staining kit, and counterstaining with hematoxylin.
(5) And (3) carrying out blue-turning, red-turning and dehydration on the counterstained slices, and finally sealing the slices by using neutral resin.
Results:
as shown in fig. 1: immunohistochemistry for CSNK2B and CD8 + T double staining (dark spots), CD8 found in tumor tissue + The high expression CSNK2B group on T cells possessed a poor Progression Free Survival (PFS), as shown in figure 2. This suggests CD8 + High expression of CSNK2B and CD8 on T cells + The function of T cells is closely related to the anti-tumor effect.
Example 2 in vitro CD8 + Construction of a T cell depletion model:
1. peripheral blood mononuclear cell extraction:
(1) Peripheral blood of healthy volunteers was added to a 15 mL centrifuge tube, diluted with PBS, and diluted in equal volume;
(2) Ficoll: the diluent is slowly added into Ficoll along the pipe wall to form a dividing surface which cannot be uniformly mixed, wherein the diluent is 1:1 or 1:2;
(3) Centrifuging at 1800rpm for 18min, quickly rising and slowly falling, and reducing the speed to zero;
(4) Aspirating the buffy coat (PBMC layer) (between the yellow serum layer and Ficoll liquid) with a sterile pipette;
(5) Centrifuging the sucked white membrane layer, discarding the supernatant, and washing with PBS once to obtain PBMC;
2.CD8 + construction of a T cell depletion model:
(1) Separation of CD8 from PBMC Using magnetic beads + T cells and activation of CD8 using a STEM CELL T cell activator at 25. Mu.L/mL stimulation + T cells, containing IL-2 (10 ng/mL) in the medium; after 3 days of culture, continued amplification with IL-2 until day 7;
(2) Preparing a heterodimer, (mixing the antibodies of the ratanti-human CD3 and the goat anti-ratIgG according to a molar ratio of 2:1);
(3) Adding the prepared heterodimer into a culture medium (containing 10 ng/mL IL-2) to induce CD8 + T cells were depleted for two days to obtain CD8 + T cells.
Results:
as shown in fig. 3: PD-1 as the heterodimer concentration in the culture system increases + Tim-3 + CD8 + The proportion of T cells is also gradually increased, suggesting that the heterodimer can significantly promote CD8 + Depletion of T cells.
As shown in fig. 4: in PD-1 + Tim-3 + CSNK2B expression was significantly elevated in the final depleted cell population of T cells. This suggests that depletion of T cells correlates with CSNK2B expression.
As shown in fig. 5: under normal culture conditions, siCSNK2B against CD8 + The proportional effect of T cells is not apparent. While in the induction of depletion of CD8 + In a T cell model, the siCSNK2B can obviously inhibit PD-1 + Tim-3 + T cell ratio and promote PD-1 - Tim-3 - The ratio of T increases, p value<0.05 p value<0.01 p value<0.001 p value<0.0001. Suggesting that siCSNK2B can significantly inhibit CD8 + Depletion of T cells.
As shown in fig. 6: we induced T cells to depleted state and then knockdown CSNK2B, we found that in siCSNK2B group, the proportion of depleted T cells was significantly reduced, while PD-1 - Tim-3 - The proportion of cells is markedly increased. This result suggests that siCSNK2B can significantly reverse CD8 + Depletion of T cells. Also shown in FIG. 7 is the CD8 for knock down of CSNK2B + Expression of some of the mRNA associated with depletion in T cells was found to be significantly reduced by knock-down of CSNK2BEomes，TOX，DDIT3，XBP1Is expressed by the mRNA of (A). This result suggests that siCSNK2B can reverse CD8 + T cell function by inhibiting expression of depletion-associated mRNA. Inhibitors may of course include siRNA, shRNA, expression of CSNK2B gene targetsMultiple forms of siRNA vectors or vectors expressing shRNA.
As shown in fig. 8: except that knocking down CSNK2B expression in the final depleted cell population had no significant effect on granzyme B expression, whereas knocking down CSNK2B in the other cell populations would significantly promote GzmB expression, suggesting that inhibiting CSNK2B expression would be effective in promoting T cell function.
Example 3 knockdown of CSNK2B expression in CIK cells will enhance killing capacity of CIK cells.
PBMC were extracted as in example 2 and cultured for 14 days using various cytokine expansion, e.g., anti-CD3, IL-1a, IFN-g, IL-2, etc.
The CIK cells expanded for 14 days were placed in 6-well plates coated with recombinant human fibronectin for siRNA transfection.
The transfected CIK cells were co-cultured with A549 cells according to different target ratios 4 h. And detecting the OD value in the supernatant by using an enzyme-labeled instrument so as to obtain the lysis rate of the target cells.
Results:
as shown in fig. 9: CIK cells of the sicnk 2B group had a stronger capacity to lyse target cells (a 549 cells) than the control group. This result suggests that siCSNK2B can enhance the function of CIK cells and enhance the ability of the CIK cells to kill tumor cells.
As shown in fig. 11: CD8 in MPR group (major pathology remission, active tumor ratio less than 10%) in lung cancer patients after treatment with anti-PD-1 drugs + CSNK2B expression in T cells was significantly lower than in Non-MPR group (without major pathological remission). As shown in FIG. 10, CSNK2B and CD8 are performed in the prognostic effect of anti-PD-1 treatment of lung cancer patients + After T double staining (dark spots), this result was found to suggest that CSNK2B expression affects the effectiveness of immunotherapy, in particular anti-PD-1 therapy.
The disclosed embodiments of the application are described in detail herein using a number of examples, but are not to be construed as limiting the application. It should also be noted that although preferred embodiments have been described in detail herein, it should be emphasized that the present application is not limited to these specific embodiments. Indeed, any obvious modification, equivalent replacement or other improvement made by those skilled in the art without departing from the inventive concept shall fall within the scope of the present application.
Claims (1)
1. Preparation of inhibitors of CSNK2B Gene for preventing CD8 + Use of a T cell depleting agent, wherein said inhibitor is sicnk 2B.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101076341A (en) * | 2004-12-14 | 2007-11-21 | 明尼苏达大学董事会 | Casein kinase 2 antisense therapy |
| CN113015529A (en) * | 2018-10-19 | 2021-06-22 | 生华生物科技股份有限公司 | Immunomodulatory combinations for cancer treatment |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101076341A (en) * | 2004-12-14 | 2007-11-21 | 明尼苏达大学董事会 | Casein kinase 2 antisense therapy |
| CN113015529A (en) * | 2018-10-19 | 2021-06-22 | 生华生物科技股份有限公司 | Immunomodulatory combinations for cancer treatment |
Non-Patent Citations (1)
| Title |
|---|
| 蛋白激酶2β对肺腺癌细胞增殖的抑制作用;阮杰 等;中国肿瘤临床;第36卷(第12期);第701-706页 * |
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