CN116298291A - Application of RNA editing enzyme ADAR1 in predicting esophageal squamous carcinoma immunotherapy effect - Google Patents
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Abstract
The invention discloses application of RNA editing enzyme ADAR1 in predicting esophageal squamous carcinoma immunotherapy effect, and belongs to the technical field of immunotherapy. The invention aims to solve the technical problems that: how to predict the immune treatment effect of esophageal squamous carcinoma. The invention provides application of a biomarker or a substance for detecting the biomarker in predicting or assisting in predicting the curative effect of an immune single drug for treating esophageal squamous cell carcinoma or preparing a product for predicting or assisting in predicting the curative effect of the immune single drug for treating esophageal squamous cell carcinoma; the biomarker is ADAR1 protein. Experiments prove that ADAR1 possibly has the potential of predicting the curative effect of single immunity drug treatment of esophageal squamous cell carcinoma.
Description
Technical Field
The invention belongs to the technical field of immunotherapy, and particularly relates to application of RNA editing enzyme ADAR1 in predicting esophageal squamous cell carcinoma immunotherapy effect.
Background
Esophageal squamous carcinoma is the most important pathological type of patients suffering from esophageal carcinoma in China. Because most esophageal squamous carcinoma patients are diagnosed at an advanced stage, the treatment means are limited, and the death rate is high. Patient survival rates and survival treatments are urgently improved. In recent years, immune checkpoint inhibitor therapy (Immune checkpoint inhibitors, ICIs) has become a new breakthrough in esophageal squamous carcinoma therapy, for example, monoclonal antibodies targeting PD-1 or PD-L1 can release T cell immunosuppressive signals and exert antitumor effects. Clinical trials and real world studies have shown that adjuvant or neoadjuvant immunotherapy can bring long-term survival benefits to esophageal squamous carcinoma patients, but only a fraction of patients are sensitive to the immunotherapy response. So reliable marker screening of people suitable for immunotherapy is urgently needed at present.
Research shows that the curative effect of immunotherapy of esophageal cancer and CD8 in tumor immune microenvironment + The number of T cells and the expression level of PD-L1 on the surface of tumor cells are related. In a large amount of CD8 + Tumor immunity characterized by T cell infiltration and high expression of PD-L1 is environment-related to better immunotherapy efficacy. There are a number of popular markers currently emerging to predict the efficacy of immunotherapy, such as PD-L1 at protein levels associated with tumor inflammatory microenvironment, representing tumor mutational burden at DNA levels of the newly added antigen level (Tumor mutation burden, TMB), but there are still shortcomings. PD-L1 expression levels are one predictive marker uniquely approved by the U.S. FDA. However, PD-L1 sensitivity and specificity are limited, and the measurement of PD-L1 expression level is affected by various factors, the variety of antibodies and the inconsistency of cut off values lead to some inaccuracy in the quantification of PD-L1, so that the single use of this index cannot fully reflect the immune microenvironment. At the gene level, TMB can reflect the neoantigen and tumor immunogenicity produced by somatic cells to a certain extent, so that the reactivity of patients to immunotherapy is predicted, but the processes of antigen production, presentation and immune response excitation cannot be completely characterized by only using TMB, and people sensitive to treatment and insensitive to treatment cannot be distinguished by using TMB alone.
ADAR (Adenosine deaminase action RNA) is an enzyme involved in the adenosine-inosine RNA editing (A-to-I RNA editing) and in vertebrates the ADAR family consists of three members ADAR (ADAR 1), ADAR1 (ADAR 2) and ADAR2 (ADAR 3). Two subtypes p150 and p110 of ADAR1 are produced by using separate promoters and alternate splicing. ADAR1-p150 is located predominantly in the cytoplasm, while ADAR1-p110 is located predominantly in the nucleus. ADAR1p150 modulates mitochondrial antiviral signaling protein (MAVS), melanoma differentiation associated protein 5 (MDA 5), and interferon signaling (MDA 5-MAVS-ifn signaling) mediated dsRNA sensing mechanisms.
Disclosure of Invention
The invention aims to solve the technical problems that: how to predict the immune treatment effect of esophageal squamous carcinoma.
To solve the above technical problem, in a first aspect, the present invention provides the use of a biomarker or a substance detecting said biomarker in P1) or P2):
p1), predicting or assisting in predicting the curative effect of the immune single drug for treating esophageal squamous cell carcinoma;
p2), preparing a product for predicting or assisting in predicting the curative effect of the immune single drug on esophageal squamous cell carcinoma;
the biomarker is ADAR1 protein.
Further, in the application, the ADAR1 protein comprises an ADAR1-p150 subtype.
Further, in the application, the substance for detecting the biomarker is an agent for detecting the expression level or/and content of the ADAR1 protein or ADAR1-p150 subtype.
Specifically, the protein expression level refers to detecting the abundance of a protein encoded by a gene at the translational level.
In the above application, the substance for detecting the biomarker comprises a reagent for detecting the biomarker by reverse transcription-polymerase chain reaction, real-time fluorescent quantitative PCR, transcriptome sequencing technology, northern blot, in situ hybridization technology, gene chip technology, nanopore sequencing technology, pacBio sequencing technology, immunoblotting, immunohistochemistry, immunofluorescence, radioimmunoassay, co-immunoprecipitation, enzyme-linked immunosorbent assay, enzyme immunoassay, flow cytometry, high performance liquid chromatography, capillary gel electrophoresis, near infrared spectroscopy, mass spectrometry, immunochemiluminescence, colloidal gold immunoassay, fluorescent immunochromatography, surface plasmon resonance technology, immuno-PCR technology or biotin-avidin technology.
In embodiments of the invention, detecting the level of expression of the ADAR1 protein or ADAR1-p150 subtype specifically employs immunohistochemistry to detect the level of ADAR1 or ADAR1-p150 subtype in tumor tissue.
Further, in the application, the substance for detecting the biomarker is an antibody capable of specifically binding to ADAR1 or/and ADAR1-p150 subtype.
Further, in the application, the substance for detecting the biomarker is ADAR1 antibody or/and ADAR1-p150 antibody.
Further, in the application, the evaluation of the predicted or auxiliary predicted curative effect of the immune single drug for treating esophageal squamous carcinoma comprises any one or more of the following:
a1 Detecting the microenvironment of tumors before and after esophageal squamous carcinoma treatment by using an immune single drug;
a2 Efficacy evaluation index after esophageal squamous carcinoma treatment with immune single drug;
a3 Progression free survival and/or progression free survival after treatment of esophageal squamous carcinoma with an immune unit.
Further, in the application, A1) the tumor microenvironment detection comprises:
a1-1), immune single medicine for treating CD8 in tumor tissue/cell after esophageal squamous carcinoma + Percent T cell infiltration;
a1-2), the expression level of PD-L1 in tumor tissues/cells after treatment of esophageal squamous carcinoma with an immune single drug.
Further, in the application, the immune single drug treatment is treatment with a PD-1 inhibitor.
Further, in the application, the immune single drug treatment is to treat with PD-1 inhibitor as the only drug, and no other drug treatment is adopted.
Further, in said application, P2) said product is a diagnostic or/and prognostic or/and predictive or/and pharmacodynamic agent or kit.
The kit can be a protein immunoassay kit; the protein immunoassay kit comprises ADAR1 or/and ADAR1-p150 protein specific antibodies.
Further, in the application, the biomarker is used for diagnosis or/and prognosis or/and prediction or/and drug effect evaluation.
In the invention, ADAR1 is RNA specific adenosine deaminase 1, and the Genbank number of the amino acid sequence of the ADAR1 is NP 001102.3.
The ADAR1-p150 is a subtype of ADAR1, and the Genbank number of the amino acid sequence of the ADAR1 is NP 001020278.1.
In such applications, the product may include a kit, a gene chip, a protein chip, immunochromatographic diagnostic test paper, a high-throughput sequencing platform, or a biosensor.
In the above application, the test sample of the product may be a tumor tissue/cell sample.
Further, in the above application, the tumor tissue may be fresh or frozen tissue or formalin-fixed paraffin embedded (FFPE) pathological tissue sections.
In the present invention, the ADAR1 antibody is purchased from Abcam under the trade designation ab88574.
In the present invention, the ADAR1-p150 antibody is purchased from Abcam under the trade designation ab126745
In the present invention, the immunotherapy may be a PD-1 immunosuppressant or PD-L1 immunosuppressant therapy. The PD-1 immunosuppressant may be a PD-1 antibody. The PD-1 antibody is selected from the group consisting of: nal Wu Liyou mab, palbociclizumab, singal Li Shan mab, carlizumab or terlipressin Li Shan mab. In the invention, the efficacy evaluation index of the immune single drug after treating esophageal squamous carcinoma is evaluated according to the efficacy evaluation of patients during treatment according to the efficacy evaluation standard 1.1 version (Response Evaluation Criteria in Solid Tumors, RECIST version 1.1) of solid tumors. Efficacy evaluation criteria included complete remission (complete response, CR), partial Remission (PR), stable Disease (SD), and disease progression (progressive disease, PD).
In the present invention, the progression-free survival refers to the time from random to first occurrence of disease progression or death of any cause.
In the present invention, the progression-free survival refers to the time from random to first occurrence of disease progression or death of any cause.
The present study uses immunohistochemical methods to detect the expression levels of ADAR1 and ADAR1-p150 subtypes from tumor tissue of esophageal squamous carcinoma patients, and found that the expression levels of ADAR1 and ADAR1-p150 subtypes are significantly correlated with progression-free survival (PFS) of esophageal squamous carcinoma patients receiving ICIs treatment. We used ADAR1 and its mediated A-to-I RNA editing as markers for predicting the effects of immunotherapy to make up for the shortcomings of current markers.
In the invention, the immune single drug treatment effect of the esophageal squamous carcinoma patient to be detected is predicted or assisted by detecting the expression amounts of ADAR1 and ADAR1-p150 in the tumor tissue of the esophageal squamous carcinoma patient to be detected, and the judgment standard is as follows:
the immune single drug treatment effect of the patient to be detected in the ADAR1 or ADAR1-p150 low expression group is better than that of the patient to be detected in the ADAR1 high expression group;
the curative effect of the immune single drug treatment is expressed in the progression-free survival rate or progression-free survival time; the non-progressive survival rate of the patients tested in the high expression group was lower than that of the patients tested in the low expression group at the same follow-up time.
The experiment proves that ADAR1 has the potential of predicting the curative effect of single esophageal squamous carcinoma immune drug therapy, and the knocking down of ADAR1 and ADAR1-p150 subtype or the inhibition of ADAR1 and ADAR1-p150 subtype expression can possibly enhance the anti-tumor effect of immune therapy by relieving the immune inhibition state of the organism.
Drawings
FIG. 1 shows that ADAR1 expression is correlated with the effect of immunotherapy of esophageal squamous carcinoma, wherein A in FIG. 1 is the ADAR1 expression level in PR, SD, PD patients; FIG. 1B is a graph showing the progression-free survival analysis of ADAR1 expression levels versus patients with esophageal squamous carcinoma that received immunotherapy; FIG. 1C shows ADAR1 high and low expression sets and CD8 + Percent T cell infiltration; d in fig. 1 is the PD-L1 level of the ADAR1 high and low expression group, (×indicates that the difference reaches significant level (p < 0.05), ×indicates that the difference reaches significant level (p < 0.0001));
FIG. 2 shows ADAR1-p150 subtype expression and esophageal squamous cell carcinoma immunityTherapeutic effect is relevant, wherein a in fig. 2 is the ADAR1 expression level of PR, SD, PD patients; FIG. 2B is a graph showing the progression-free survival analysis of ADAR1 expression levels versus patients with esophageal squamous carcinoma that received immunotherapy; FIG. 2C shows ADAR1 high and low expression sets and CD8 + Percent T cell infiltration; d in FIG. 2 is the PD-L1 level of ADAR1 high and low expression sets. (indicating that the difference reaches a significant level (p < 0.05), -indicating that the difference reaches a significant level (p < 0.01), -indicating that the difference reaches a significant level (p < 0.001));
FIG. 3 shows that ADAR1 protein expression level is related to tumor microenvironment of esophageal squamous carcinoma, and FIG. 3A shows that ADAR1 low-expression group patient CD8 + The T cell infiltration positive proportion is obviously higher, the positive proportion of PD-L1 is obviously higher in FIG. 3, and the proportion of the adaptive immune tolerance type is obviously higher in FIG. 3.
FIG. 4 shows that ADAR1-p150 subtype protein expression level correlates with tumor microenvironment of esophageal squamous carcinoma, and FIG. 4A shows that ADAR1-p150 subtype low-expression group patient CD8 + The T cell infiltration positive proportion is obviously higher, the positive proportion of PD-L1 is obviously higher in FIG. 4, and the proportion of the adaptive immune tolerance type is obviously higher in FIG. 4.
Detailed Description
The following detailed description of the invention is provided in connection with the accompanying drawings that are presented to illustrate the invention and not to limit the scope thereof. The examples provided below are intended as guidelines for further modifications by one of ordinary skill in the art and are not to be construed as limiting the invention in any way.
The experimental methods in the following examples, unless otherwise specified, are conventional methods, and are carried out according to techniques or conditions described in the literature in the field or according to the product specifications. Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The experimental methods used in the following examples are conventional methods unless otherwise specified.
Materials, reagents and the like used in the examples described below are commercially available unless otherwise specified.
The following examples were run using SPSS19.0 statistical software and the experimental results were expressed as mean.+ -. Standard deviation using One-way ANOVA test, with P < 0.05 indicating significant differences, P < 0.01 indicating very significant differences, and P < 0.001 indicating very significant differences.
Example 1, application of ADAR1 in predicting efficacy of esophageal squamous carcinoma immune monotherapy
Case selection in examples: the study was a retrospective, non-interventional clinical study. The study was approved by the ethical committee of oncology hospitals at the national academy of medicine (approval number: 20/453-2649) following the principles of declaration of helsinki and informed consent was obtained for all subjects.
The study was mainly incorporated into patients with esophageal squamous carcinoma who received anti-PD-1 antibody treatment at the tumor hospital of the national academy of medical science from 5 in 2016 to 8 in 2019.
The group entering standard is as follows: 1) Clinically diagnosing patients with restricted advanced stage or advanced stage esophageal squamous carcinoma; 2) The first time an immunotherapy is received, but the number of treatment lines is not limited. Exclusion criteria were 1) esophageal adenocarcinoma, mediastinum tumor, and other types of breast tumors; 2) No baseline treatment specimens. Patients enrolled in the study were treated once every two/three weeks with one of the following anti-PD-1 antibodies (carlizumab 200 mg/time, once every two weeks). Usually, the treatment effect is evaluated by enhancing CT of neck, chest and abdomen every six weeks, and the improvement of the treatment effect by enhancing MRI of the skull if necessary is evaluated.
General conditions for incorporation of the study into patients include initial age, sex, ECOG PS score, smoking status, pathology type, and type of genetic mutation.
Patient efficacy assessment during treatment was assessed according to solid tumor efficacy assessment standard version 1.1 (Response Evaluation Criteria in Solid Tumors, RECIST version 1.1). Efficacy evaluation criteria included complete remission (complete response, CR), partial Remission (PR), stable Disease (SD), and disease progression (progressive disease, PD).
The data are obtained by inquiring the medical history of hospitalization and carrying out telephone follow-up. The last follow-up time for this study was 2022, 3 months and 14 days.
The operation tissue specimens before the immune single drug treatment of the patients are collected in the study, the specimens are immediately obtained according to the operation standard after being isolated, and wax block embedding is carried out. All surgical tissue specimens were obtained with pathological tissue sections to confirm esophageal squamous carcinoma. The specimen obtaining and operating process is approved by the ethical committee of tumor hospitals of the national academy of medical science. The provider of the specimen had informed consent.
The study was carried into 15 patients with esophageal squamous carcinoma immunotherapy, and the baseline data are shown in Table 1.
Table 1 shows baseline data for patients with esophageal squamous carcinoma immunotherapy
Remarks: the numbers in the second column in table 1 represent the number and the numbers in brackets represent the proportion.
1. Detection of ADAR1 protein expression level in tissues of 15 esophageal squamous carcinoma patients
Expression of ADAR1 protein in FFPE samples of surgical tissues of 15 esophageal squamous carcinoma patients was detected by the Human anti-ADAR1 monoclonal antibody (Abcam Co., product, cat#ab 88574) using Immunohistochemical (IHC) technique, wherein ADAR1 antibody was used at a concentration of 1:200, and the expression level was expressed as an ADAR1 staining score, and the expression level was high as a score.
ADAR1 expression was scored according to the following principle: staining score (ADAR 1 staining score) =staining intensity x percent positive tumor cells x 100. Wherein, the staining intensity score is: no color development was 0 (negative), pale yellow was 1 (weak positive), yellow was 2 (medium positive), brown yellow was 3 (strong positive); the percentage of positive tumor cells was determined by examining ten randomly selected fields under a high power microscope (x 400), calculating the percentage of stained positive tumor cells (weak positive + medium positive + strong positive) in the field to all tumor cells in the field, and using the average of the percentages of ten field positive tumor cells as the percentage of positive tumor cells.
The results are shown in fig. 1 and table 2, where the ADAR1 expression was significantly higher in the patients of the disease progression group (a in fig. 1).
Table 2 shows staining scores and progression-free survival of ADAR1 in 15 esophageal squamous carcinoma patient tissues
| Patient numbering | Evaluation of efficacy | State of progress | Progression free survival time (month) | Staining scoring of ADAR1 |
| Pt-1 | |
0 | 54.30 | 6 |
| Pt-2 | |
1 | 42.87 | 3 |
| Pt-3 | |
1 | 3.93 | 6 |
| Pt-4 | |
1 | 8.33 | 4 |
| Pt-5 | |
1 | 9.37 | 6 |
| Pt-6 | |
1 | 0.67 | 9 |
| Pt-7 | |
1 | 23.17 | 2 |
| Pt-8 | |
1 | 1.83 | 12 |
| Pt-9 | |
1 | 4.20 | 4 |
| Pt-10 | |
1 | 0.87 | 9 |
| Pt-11 | |
1 | 7.70 | 8 |
| Pt-12 | |
1 | 0.97 | 12 |
| Pt-13 | |
0 | 13.57 | 6 |
| Pt-14 | |
0 | 26.83 | 2 |
| Pt-15 | |
0 | 38.50 | 4 |
In the table above, 1 in the progression status in column 3 indicates recurrence during the 4 th column follow-up time, and 0 indicates no recurrence or no follow-up during the 4 th column follow-up time.
2. Survival curve
Based on the optimal cutoff (ADAR 1 staining score of 6), the group-in patients were divided into a high baseline ADAR1 expression level group (higher than 6) and a low baseline ADAR1 expression level group (lower than or equal to 6).
The survival curves are plotted according to the progression state and the progression-free survival time, the results are shown as B in figure 1, and the analysis results show that: the survival without progression of the low group of ADAR1 expression levels was significantly increased (p < 0.001) at the same follow-up time.
3. Relationship between ADAR1 expression and tumor immune microenvironment
CD8 of low group of baseline ADAR1 expression levels + T cell infiltration ratio (CD 8 (ZA-0508)) and PD-L1 (CST, # 13684) were expressed at higher levels (C in FIG. 1 and D in FIG. 1).
Therefore, the immune single drug treatment effect of the esophageal squamous carcinoma patient to be detected can be predicted or assisted by detecting the expression quantity of ADAR1 in the tumor tissue of the esophageal squamous carcinoma patient to be detected, and the judgment standard is as follows:
the immune single drug treatment effect of the patient to be detected in the ADAR1 low expression group is better than or the candidate is better than that of the patient to be detected in the ADAR1 high expression group;
the curative effect of the immune single drug treatment is expressed in the progression-free survival rate or progression-free survival time; at the same follow-up time, the non-progressive survival rate of the test patients in the high expression group is less than or the candidate is less than the test patients in the low expression group.
The expression level of ADAR1 in the tumor tissue was expressed by a staining score.
Example 2 application of ADAR1-p150 in predicting efficacy of esophageal squamous carcinoma immune monotherapy
1. Detection of ADAR1-p150 protein expression level in tissues of 15 esophageal squamous carcinoma patients
The expression of ADAR1-p150 protein in FFPE samples of surgical tissues of 15 esophageal squamous carcinoma patients was detected by the Human anti-ADAR1-p150 monoclonal antibody (Abcam company product, cat#ab 126745) using an Immunohistochemical (IHC) technique, wherein the ADAR1-p150 antibody was used at a concentration of 1:200, the expression level was expressed by staining with ADAR1-p150, and the expression level was high.
ADAR1-p150 expression was scored according to the following principle: staining score (ADAR 1 staining score) =staining intensity x percent positive tumor cells x 100. Wherein, the staining intensity score is: no color development was 0 (negative), pale yellow was 1 (weak positive), yellow was 2 (medium positive), brown yellow was 3 (strong positive); the percentage of positive tumor cells was determined by examining ten randomly selected fields under a high power microscope (x 400), calculating the percentage of stained positive tumor cells (weak positive + medium positive + strong positive) in the field to all tumor cells in the field, and using the average of the percentages of ten field positive tumor cells as the percentage of positive tumor cells.
The results are shown in FIG. 2 and Table 3, where ADAR1-p150 expression was significantly higher in the disease progression group patients (FIG. 2A).
Table 3 shows staining scores and progression-free survival of ADAR1-p150 in 15 esophageal squamous carcinoma patient tissues
In the table above, 1 in the progression status in column 3 indicates recurrence during the 4 th column follow-up time, and 0 indicates no recurrence or no follow-up during the 4 th column follow-up time.
2. Survival curve
Based on the optimal cutoff (ADAR 1-p150 staining score of 6), the group-entered patients were divided into a high group (above 6) of baseline ADAR1-p150 expression levels and a low group (below or equal to 6) of baseline ADAR1-p150 expression levels.
Survival curves were plotted according to status of progression and time to progression free survival, and the results of the analysis are shown in FIG. 2B, and the results of the analysis suggest that the survival rate of progression free groups with low ADAR1-p150 expression levels is significantly increased (p < 0.001) at the same follow-up time.
3. Relationship between ADAR1-p150 expression and tumor immune microenvironment
Detection of CD8 of test sample by the method provided in example 1 + T cell infiltration ratio and PD-L1 expression level. The results show that: CD8 of low group of baseline ADAR1 expression levels + T cell infiltration ratio and PD-L1 expression level were higher (C in FIG. 2 and D in FIG. 2).
Therefore, the immune single drug treatment effect of the esophageal squamous carcinoma patient to be detected can be predicted or assisted predicted by detecting the expression quantity of ADAR1-p150 in the tumor tissue of the esophageal squamous carcinoma patient to be detected, and the judgment standard is as follows:
the immune single drug treatment effect of the patient to be detected in the ADAR1-p150 low expression group is better than that of the patient to be detected in the ADAR1-p150 high expression group;
the curative effect of the immune single drug treatment is expressed in the progression-free survival rate or progression-free survival time; the non-progressive survival rate of the patients tested in the high expression group was lower than that of the patients tested in the low expression group at the same follow-up time.
The expression level of ADAR1-p150 in the tumor tissue was expressed by a staining score.
Therefore, the immune single drug treatment efficacy of the esophageal squamous carcinoma patient to be detected can be predicted or assisted predicted by detecting the expression amounts of ADAR1 and ADAR1-p150 in the tumor tissue of the esophageal squamous carcinoma patient to be detected, and the judgment standard is as follows:
the immune single drug treatment effect of the patient to be detected in the ADAR1 or ADAR1-p150 low expression group is better than that of the patient to be detected in the ADAR1 high expression group;
the curative effect of the immune single drug treatment is expressed in the progression-free survival rate or progression-free survival time; the non-progressive survival rate of the patients tested in the high expression group was lower than that of the patients tested in the low expression group at the same follow-up time.
EXAMPLE 3 Effect of ADAR1 on esophageal squamous carcinoma immune microenvironment
Case selection in examples: the study was a retrospective, non-interventional clinical study. The study was approved by the ethical committee of oncology hospitals at the national academy of medicine (approval number: 20/453-2649) following the principles of declaration of helsinki and informed consent was obtained for all subjects.
All human tissue samples collected were from the tumor hospital of the national academy of medical science. 84 esophageal squamous carcinoma patients receiving radical resection obtained ESCC tissue for the tissue array and adjacent non-tumor esophageal tissue. All esophageal squamous carcinoma cases were pathologically confirmed. Esophageal squamous carcinoma patients had not received anti-tumor therapy or had a history of other malignancies within three years of diagnosis. Clinical pathology of patients was collected by telephone interviews and routine laboratory studies performed prior to surgery. Tumors and adjacent normal tissues obtained during surgery were flash frozen in liquid nitrogen within 30 minutes after excision and stored at-80 ℃ until tissue arrays were made.
The study was carried into 84 esophageal squamous carcinoma patients, and the baseline data is shown in Table 4.
Table 4 shows baseline data for patients with esophageal squamous carcinoma immunotherapy
Table 5 shows staining scores and immune microenvironment index classifications for ADAR1 and ADAR1-p150 in tissues of 84 esophageal squamous carcinoma patients
In the above table, CD8 in column 2 + T cell infiltration 1 indicates positive, 0 indicates negative; column 3 PD-L1 status 1 indicates positive and 0 indicates negative. Column 4 immune microenvironment type 1 represents CD8 + T cell infiltration positive, PD-L1 positive (adaptive immune tolerance type); 2 represents CD8 + T-cell infiltration negative, PD-L1 negative (immune-disregard type); 3 represents CD8 + T cell infiltration negative, PD-L1 positive (endogenous immune-resistant); 4 represents CD8 + T cells infiltration positive, PD-L1 negative (immune tolerance type).
1. Detection of ADAR1 protein expression level in tissues of 84 esophageal squamous carcinoma patients
The expression of ADAR1 protein in FFPE samples of surgical tissues of 84 esophageal squamous carcinoma patients was detected by the method provided in example 1 using an Immunohistochemistry (IHC) technique by means of Human anti-ADAR1 monoclonal antibody (product of Abcam, cat#ab 88574), wherein the ADAR1 antibody was used at a concentration of 1:200, the expression level was expressed as an ADAR1 staining score, and the expression level was high.
ADAR1 expression was scored according to the following principle: staining score (ADAR 1 staining score) =staining intensity x percent positive tumor cells x 100. Wherein, the staining intensity score is: no color development was 0 (negative), pale yellow was 1 (weak positive), yellow was 2 (medium positive), brown yellow was 3 (strong positive); the percentage of positive tumor cells was determined by examining ten randomly selected fields under a high power microscope (x 400), calculating the percentage of stained positive tumor cells (weak positive + medium positive + strong positive) in the field to all tumor cells in the field, and using the average of the percentages of ten field positive tumor cells as the percentage of positive tumor cells.
CD8 was performed according to the method provided in example 1 + T cell infiltration assay, CD8 + T cell infiltration positive determination criteria were: CD8 in tumor parenchyma + When the proportion of T cells in the matrix exceeds 20%, CD8 is judged + T cells infiltration positive.
The PD-L1 positive assay was performed according to the method provided in example 1, with the PD-L1 positive determination criteria: PD-L1 staining (Tumor proportion score, TPS) >1 was considered positive for PD-L1.
The results are shown in FIG. 3 and Table 5, and CD8 of ADAR1 low-expression group patient + The T cell infiltration positive proportion is obviously higher (A in FIG. 3), the PD-L1 positive proportion is obviously higher (B in FIG. 3), and the proportion of the adaptive immune tolerance type is obviously higher (C in FIG. 3).
2. Detection of ADAR1-p150 protein expression level in tissues of 84 esophageal squamous carcinoma patients
The expression of ADAR1-p150 protein in the surgical tissue (baseline tumor tissue) of 84 esophageal squamous carcinoma patients was examined by the method provided in reference example 2 using Human anti-ADAR1-p150 monoclonal antibody (Abcam Co., product, cat#ab 126745) using Immunohistochemical (IHC) techniques, wherein the ADAR1-p150 antibody was used at a concentration of 1:200, the expression level was expressed by staining with ADAR1-p150, and the expression level was scored high.
ADAR1-p150 expression was scored according to the following principle: staining score (ADAR 1 staining score) =staining intensity x percent positive tumor cells x 100. Wherein, the staining intensity score is: no color development was 0 (negative), pale yellow was 1 (weak positive), yellow was 2 (medium positive), brown yellow was 3 (strong positive); the percentage of positive tumor cells was determined by examining ten randomly selected fields under a high power microscope (x 400), calculating the percentage of stained positive tumor cells (weak positive + medium positive + strong positive) in the field to all tumor cells in the field, and using the average of the percentages of ten field positive tumor cells as the percentage of positive tumor cells.
CD8 was performed according to the method provided in example 1 + T cell infiltration assay, CD8 + T cell infiltration positive determination criteria were: CD8 in tumor parenchyma + When the proportion of T cells in the matrix exceeds 20%, CD8 is judged + T cells infiltration positive.
The PD-L1 positive assay was performed according to the method provided in example 1, with the PD-L1 positive determination criteria: PD-L1 staining (Tumor proportion score, TPS) >1 was considered positive for PD-L1.
The results are shown in FIG. 4 and Table 5, and CD8 of ADAR1-p150 low expression group patient + The T cell infiltration positive proportion is obviously higher (A in FIG. 4), the PD-L1 positive proportion is obviously higher (B in FIG. 4), and the proportion of the adaptive immune tolerance type is obviously higher (C in FIG. 4).
Therefore, the immune single drug treatment effect of the esophageal squamous carcinoma patient to be detected can be predicted or assisted predicted by detecting the expression quantity of ADAR1-p150 in the tumor tissue of the esophageal squamous carcinoma patient to be detected, and the judgment standard is as follows:
the immune single drug treatment effect of the patient to be detected in the ADAR1-p150 low expression group is better than that of the patient to be detected in the ADAR1-p150 high expression group;
the curative effect of the immune single medicine treatment is reflected in the immune microenvironment of the esophageal squamous carcinoma; at the same follow-up time, the proportion of the adaptive immune tolerance type of the patients to be tested in the high expression group is obviously higher than that of the patients to be tested in the low expression group.
The present invention is described in detail above. It will be apparent to those skilled in the art that the present invention can be practiced in a wide range of equivalent parameters, concentrations, and conditions without departing from the spirit and scope of the invention and without undue experimentation. While the invention has been described with respect to specific embodiments, it will be appreciated that the invention may be further modified. In general, this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains.
Claims (9)
1. Use of a biomarker or a substance that detects said biomarker in P1) or P2):
p1), and application in predicting or assisting in predicting curative effect of immune single drug for treating esophageal squamous cell carcinoma;
p2), and the application of the product in the preparation of the product for predicting or assisting in predicting the curative effect of the immune single drug for treating esophageal squamous cell carcinoma;
the biomarker is ADAR1 protein.
2. The use according to claim 1, characterized in that: the ADAR1 protein includes ADAR1-p150 subtype.
3. Use according to claim 1 or 2, characterized in that: the substance for detecting the biomarker is a reagent for detecting the expression quantity or/and content of the ADAR1 protein or ADAR1-p150 subtype.
4. A use according to any one of claims 1-3, characterized in that: the substance for detecting the biomarker is an antibody capable of specifically binding to ADAR1 or/and ADAR1-p150 subtype.
5. The use according to any one of claims 1-4, characterized in that: the substance for detecting the biomarker is ADAR1 antibody or/and ADAR1-p150 antibody.
6. The use according to any one of claims 1-5, characterized in that: the evaluation of the predicted or auxiliary predicted curative effect of the immune single drug for treating esophageal squamous carcinoma comprises any one or more of the following:
a1 Detecting the microenvironment of tumors before and after esophageal squamous carcinoma treatment by using an immune single drug;
a2 Efficacy evaluation index after esophageal squamous carcinoma treatment with immune single drug;
a3 Progression free survival and/or progression free survival after treatment of esophageal squamous carcinoma with an immune unit.
7. The use according to any one of claims 1-6, characterized in that: a1 The tumor microenvironment detection comprises:
a1-1), immune single medicine for treating CD8 in tumor tissue/cell after esophageal squamous carcinoma + Percent T cell infiltration;
a1-2), the expression level of PD-L1 in tumor tissues/cells after treatment of esophageal squamous carcinoma with an immune single drug.
8. The use according to any one of claims 1-7, characterized in that: the immune single drug treatment is treatment by adopting PD-1 inhibitor.
9. The use according to any one of claims 1-8, characterized in that: p2) the product is a diagnostic or/and prognostic or/and predictive or/and pharmacodynamic reagent or kit.
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