TRMT61A and application of TRMT61A inhibitor tetramethylthiuram disulfide in tumor immunotherapy

Abstract

The invention provides application of TRMT61A and its inhibitor tetramethylthiuram disulfide in tumor immunotherapy, and relates to the technical field of biological medicine, clinical research proves that RNA m1A methyltransferase TRMT61A is highly expressed in tumor tissues and is related to poor prognosis of tumor patients, and can be used as one of tumor therapy targets. Meanwhile, high expression of the TRMT61A is related to poor prognosis of a tumor patient receiving anti-PD-1 immunotherapy, and after anti-PD-1 antibody immunotherapy is carried out on the patient with low TRMT61A expression level in the tumor of the patient, pathological complete relief is easier. Tetramethylthiuram disulfide inhibits TRMT61A, inhibits m1A modification regulation of TRMT61A on PD-L1 mRNA, increases PD-L1 protein expression, and is combined with a PD-1 antibody drug to significantly enhance the immunotherapy effect of the anti-PD-1 immune checkpoint drug in treating malignant tumors.

Description

TECHNICAL FIELD

[0001] The application relates to the field of biological medicine, in particular to application of TRMT61A and a dithiotetramethyldithiuram inhibitor thereof in tumor immunotherapy. BACKGROUND

[0002] In recent years, immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) / programmed cell death ligand 1 (PD-L1) have brought breakthrough progress in the treatment of malignant tumors, and have shown sustained clinical benefits in various advanced solid tumors and hematologic malignancies, and have become the first-line treatment for advanced non-small cell lung cancer, metastatic colon cancer, melanoma and the like.

[0003] Despite the remarkable achievements of PD-1 immunotherapy, there are still several bottleneck problems. Primary or secondary drug resistance is the primary challenge. About 70% of malignant tumor patients are initially unresponsive or have disease progression after response to immune checkpoint inhibitors. For example, PD-1 / PD-L1 inhibitors have shown significant efficacy in microsatellite instability / high mismatch repair deficiency colorectal cancer, and the 2-year progression-free survival rate can reach 72%, and some patients even achieve long-term survival. However, only about 15% of colorectal cancer patients have microsatellite instability / high mismatch repair deficiency, and the dominant mismatch repair complete / microsatellite stable patients have almost no response to PD-1 / PD-L1 immunotherapy. In addition, PD-1 / PD-L1 immunotherapy still has problems such as large individual differences in efficacy and drug resistance. Therefore, how to improve the response of PD-1 / PD-L1 immunotherapy is the key to improve the prognosis of tumor patients.

[0004] Thiram is one of the drugs approved by the US Food and Drug Administration (FDA), which is mainly used for treating seeds and soil to prevent and control powdery mildew, smut, rice seedling damping-off of cereal crops, and can also be used for some fruit trees, vegetable diseases. The name of Thiram includes tetramethyl dithiuram disulfide, tetramethyl dithiuram disulfide, thiram, bisulfamide formyl (east fungicide), thiram (siran), bisulfamide formyl, selan, accelerator TMTD-Ⅱ, etc.

[0005] Therefore, the application is proposed. SUMMARY

[0006] One of the purposes of the present application is to provide TRMT61A as a target in evaluating the efficacy of anti-PD-1 or / and PD-L1 immunotherapy for tumor patients, so as to solve the technical problems of large individual differences in efficacy and drug resistance in the prior art.

[0007] The second purpose of the present application is to provide the use of a TRMT61A inhibitor in the preparation of a drug for up-regulating the level of PD-L1 or enhancing the efficacy of tumor immunotherapy.

[0008] The third purpose of the present application is to provide the use of a TRMT61A inhibitor in combination with an anti-PD-1 or / and anti-PD-L1 immunotherapy antibody or drug in the preparation of a tumor immunotherapy drug.

[0009] The fourth purpose of the present application is to provide a combined drug composition for tumor immunotherapy.

[0010] In order to achieve the above-mentioned purposes of the present application, the following technical solutions are adopted: In a first aspect, the present application provides the use of TRMT61A as a target in evaluating the efficacy of anti-PD-1 or / and PD-L1 immunotherapy for tumor patients.

[0011] In a second aspect, the present application provides the use of a TRMT61A inhibitor in the preparation of a drug for up-regulating the level of PD-L1 or enhancing the efficacy of tumor immunotherapy.

[0012] In a third aspect, the present application provides the use of a TRMT61A inhibitor in combination with an anti-PD-1 or / and anti-PD-L1 immunotherapy antibody or drug in the preparation of a tumor immunotherapy drug.

[0013] Further, the TRMT61A inhibitor is dithiotetramethylthiuram or / and a pharmaceutically acceptable salt thereof.

[0014] Further, the tumor is a solid tumor; Preferably, the solid tumor includes one or more of breast cancer, cholangiocarcinoma, colon cancer, esophageal cancer, glioma, head and neck squamous cell carcinoma, renal chromophobe carcinoma, liver cancer, lung adenocarcinoma, lung squamous cell carcinoma, pheochromocytoma, prostate cancer, rectal adenocarcinoma, gastric cancer, thyroid cancer, endometrial cancer, bladder cancer, melanoma, and urothelial carcinoma.

[0015] In a fourth aspect, the present application provides a combined drug composition for tumor immunotherapy, which includes a TRMT61A inhibitor in combination with an anti-PD-1 or / and anti-PD-L1 immunotherapy antibody or drug.

[0016] Further, the TRMT61A inhibitor is thiram or / and pharmaceutically acceptable salts thereof.

[0017] Further, the combination drug composition is a combination of two separate preparations, simultaneous administration of two separate preparations or sequential administration of two separate preparations. Preferably, the preparation is any one of the pharmaceutically acceptable dosage forms.

[0018] Further, the dosage of thiram ranges from 0.1 to 5 mg / kg body weight / time.

[0019] Further, the combination drug composition further comprises pharmaceutically acceptable pharmaceutical adjuvants. Preferably, the pharmaceutical adjuvants comprise any one or a combination of at least two of carriers, binders, diluents, emulsifiers, wetting agents, disintegrants, co-solvents, solubilizers, surfactants, osmotic pressure regulators, coloring agents, coating materials, buffers, bacteriostatic agents, antioxidants or pH regulators.

[0020] The present application provides the application of TRMT61A and its inhibitor thiram in tumor immunotherapy. Through clinical research, it is confirmed that RNA m 1 A methyltransferase TRMT61A is highly expressed in tumor tissues and is associated with poor prognosis of tumor patients, and can be used as one of the targets for tumor treatment. At the same time, high expression of TRMT61A is associated with poor prognosis of tumor patients receiving anti-PD-1 immunotherapy, and patients with low TRMT61A expression in tumor are more likely to achieve pathological complete remission after anti-PD-1 antibody immunotherapy. Thiram inhibits TRMT61A, releases its m 1 A modification, increases the expression of PD-L1 protein, and further combines with PD-1 antibody drugs, significantly enhances the immunotherapy effect of anti-PD-1 immune checkpoint drugs for treating malignant tumors. It provides a new feasible solution for clinical tumor immunotherapy sensitization. BRIEF DESCRIPTION OF DRAWINGS

[0021] In order to more clearly illustrate the specific embodiments of the present application or the technical solutions in the prior art, the drawings needed in the specific embodiments or prior art description will be briefly introduced below. Obviously, the drawings in the following description are some embodiments of the present application, and those skilled in the art can also obtain other drawings according to these drawings without creative labor.

[0022] Figure 1 The result graph of the pan-cancer analysis of TRMT61A expression level in cancer and paracancer tissues provided for Example 1 of the present application is shown in the following figure: Figure 2 The result figure of detecting the expression of TRMT61A in human colon cancer and corresponding paracancer normal colon paraffin tissues provided for the embodiment 2 of the present application, wherein a is a representative picture of TRMT61A immunohistochemical staining; b is the TMR6T1A immunohistochemical score of colon cancer and paracancer tissues; c is the Kaplan-Meier survival curve of colon cancer patients in TMR6T1A high / low expression group; Figure 3 The result figure of analyzing the relationship between the expression level of TRMT61A and the prognosis or efficacy of PD-1 immunotherapy provided for the embodiment 3 of the present application, wherein a is the Kaplan-Meier survival curve of tumor patients receiving PD-1 immunotherapy in TRMT61A high / low expression group; b is the result figure of human colon cancer 10x single cell data set GSE205506; Figure 4 The result figure of detecting the RNA m 1 A level and PD-L1 protein level provided for the embodiment 4 of the present application, wherein a is the result figure of HCT116 cells; b is the result figure of CT26 cells; Figure 5 The result figure of evaluating the in vivo biological safety of gradient Thiram provided for the embodiment 5 of the present application. a is the body weight change of mice before and after treatment, wherein b is the H&E staining result of main organs of mice after treatment; Figure 6 The result figure of evaluating the growth of subcutaneous transplanted tumor of mice treated with gradient Thiram and the PD-L1 protein expression of subcutaneous tumor tissue provided for the embodiment 6 of the present application, wherein a is the white light figure of subcutaneous transplanted tumor of mice after treatment with gradient Thiram; b is the PD-L1 protein expression of subcutaneous tumor tissue of mice after treatment with gradient Thiram; Figure 7 The result figure of verifying the efficacy of subcutaneous transplanted tumor of mice treated with Thiram combined with anti-PD-1 provided for the embodiment 7 of the present application, wherein a is the white light figure of subcutaneous transplanted tumor of mice after treatment; b is the H&E staining result of main organs of mice after treatment. DETAILED DESCRIPTION

[0023] Unless otherwise defined herein, scientific and technical terms used in connection with the present application shall have the meanings that are commonly understood by those of ordinary skill in the art. Clear dictates, however, that the definitions of commonly- understood terms follow the dictates of the commonly- understood meanings. In case of any latent ambiguity, definitions provided herein prevail over any dictionary or extrinsic definition. In this application, the use of "or" means "and / or" unless otherwise stated. Moreover, the use of the "including" and other forms of the word "comprising" is intended to be non-limiting.

[0024] Generally, the nomenclature used in connection with, and the techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics and protein and nucleic acid chemistry and hybridization described herein are those well-known and commonly used in the art. The methods and techniques of the present application are generally performed according to conventional methods in the art, unless otherwise indicated, and such methods and techniques are explained fully in the literature in the field of the application. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as described herein. The nomenclature used in connection with, and the techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art.

[0025] The technical solutions of the present application will be described clearly and completely below in conjunction with the embodiments. Obviously, the described embodiments are part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor are within the scope of protection of the present application.

[0026] The present application is confirmed by clinical research that RNA m 1 A methyltransferase TRMT61A is highly expressed in tumor tissues and is associated with poor prognosis of tumor patients, and can be used as one of the targets for tumor treatment. At the same time, high expression of TRMT61A is associated with poor prognosis of tumor patients receiving anti-PD-1 immunotherapy, and patients with low TRMT61A expression in tumor are more likely to achieve pathological complete remission after anti-PD-1 antibody immunotherapy. In addition, preclinical experiments have confirmed that knocking down TRMT61A or inhibiting TRMT61 by drugs can effectively increase the efficacy of anti-PD-1 immunotherapy for tumors.

[0027] In one aspect, the present application provides the use of TRMT61A as a target in evaluating the efficacy of anti-PD-1 or / and anti-PD-L1 immunotherapy for tumor patients.

[0028] By inhibiting TRMT61A, the m 1 A modification regulation to increase the expression of PD-L1 protein, combined with PD-1 antibody drugs, significantly enhances the immunotherapy effect of anti-PD-1 immune checkpoint drugs for malignant tumors. According to another aspect of the present application, the use of TRMT61A inhibitors in the preparation of drugs for up-regulating PD-L1 levels or enhancing the efficacy of tumor immunotherapy is also provided.

[0029] According to another aspect of the present application, the use of TRMT61A inhibitors in combination with anti-PD-1 or / and anti-PD-L1 immunotherapy antibodies or drugs in the preparation of tumor immunotherapy drugs is also provided.

[0030] In some embodiments, the TRMT61A inhibitor is tetramethylthiuram disulfide or / and pharmaceutically acceptable salts thereof.

[0031] Low-dose tetramethylthiuram disulfide (Thiram) can be used as a TRMT61A small molecule inhibitor, which can effectively enhance the anti-PD-1 immunotherapy of tumors; low-dose Thiram can inhibit the function of TRMT61A and show good anti-PD-1 immunotherapy sensitization effect in preclinical experiments.

[0032] In some embodiments, the tumor is a solid tumor; in some embodiments, the solid tumor includes one or more of breast cancer, cholangiocarcinoma, colon cancer, esophageal cancer, glioma, head and neck squamous cell carcinoma, renal chromophobe carcinoma, liver cancer, lung adenocarcinoma, lung squamous cell carcinoma, pheochromocytoma, prostate cancer, rectal adenocarcinoma, gastric cancer, thyroid cancer, endometrial cancer, bladder cancer, melanoma, urothelial carcinoma.

[0033] According to another aspect of the present application, a combined pharmaceutical composition for tumor immunotherapy is also provided, which includes a TRMT61A inhibitor and an anti-PD-1 or / and anti-PD-L1 immunotherapy antibody or drug.

[0034] The combination of TRMT61A inhibitor and anti-PD-1 or / and anti-PD-L1 immunotherapy antibody or drug can significantly improve T cell activation and tumor inhibition rate, significantly enhance the immunotherapy effect of anti-PD-1 immune checkpoint drug for treating malignant tumors, and reverse the tolerance and resistance of malignant tumors to anti-PD-1 immunotherapy; animal experiments show that low-dose Thiram has good biological safety and significant anti-tumor effect; and the present application provides a new and feasible solution for clinical tumor immunotherapy sensitization.

[0035] In some embodiments, the TRMT61A inhibitor is tetramethylthiuram disulfide or / and pharmaceutically acceptable salts thereof.

[0036] In some embodiments, the administration dose of tetramethylthiuram disulfide is 0.1-5 mg / kg body weight / time.

[0037] In some embodiments, the combination pharmaceutical composition is a combination of two separate formulations, the two separate formulations are administered simultaneously, or the two separate formulations are administered sequentially. In some embodiments, the method of preparing the combination of two separate formulations comprises mixing a pharmaceutical comprising thiram or / and pharmaceutically acceptable salts thereof with an anti-PD-1 and / or anti-PD-L1 immunotherapy antibody or drug. Or, in some embodiments, the method of administering the two separate formulations simultaneously or sequentially comprises administering thiram to a patient with a malignant tumor; and simultaneously or sequentially administering an anti-PD-1 and / or anti-PD-L1 immunotherapy antibody or drug. The combination of the two drugs can improve the response rate of the patient to PD-1 immunotherapy and inhibit tumor growth.

[0038] In some embodiments, the anti-PD-1 and anti-PD-L1 immunotherapy antibody or drug is administered at a dose and frequency according to the drug instructions or clinical practice.

[0039] In some embodiments, the formulation is any pharmaceutically acceptable dosage form.

[0040] In some embodiments, the combination pharmaceutical composition further comprises a pharmaceutically acceptable pharmaceutical excipient.

[0041] In some embodiments, the pharmaceutical excipient comprises any one or a combination of at least two of a carrier, a binder, a diluent, an emulsifier, a wetting agent, a disintegrant, a co-solvent, a solubilizer, a surfactant, an osmotic pressure regulator, a coloring agent, a coating material, a buffer, a bacteriostatic agent, an antioxidant, or a pH regulator.

[0042] The present application is further illustrated by the following examples. Unless otherwise specified, the materials in the examples were prepared according to existing methods or purchased directly from the market.

[0043] Materials: Thiram: Thiram-d12, Catalog No. HY-132426S, MedKoo Anti-PD-1 antibody: InVivoMAb anti-mouse PD-1 (CD279), Catalog No. BE0146, Bioxcell (Bio X Cell, LLC).

[0044] Anti-PD-1 antibody: Example 1 Analysis of TRMT61A expression levels in various malignant tumors (pan-cancer) and their corresponding normal tissues Methods: The expression level of TRMT61A in TCGA RNA-seq data was analyzed by Timer 2.0 (http: / / timer.comp-genomics.org / ).

[0045] Results as shown in Figure 1 Figure 1, compared with adjacent normal tissues, the expression of TRMT61A was increased in breast cancer, cholangiocarcinoma, colon cancer, esophageal cancer, glioma, head and neck squamous cell carcinoma, renal chromophobe carcinoma, liver cancer, lung adenocarcinoma, lung squamous cell carcinoma, pheochromocytoma, prostate cancer, rectal adenocarcinoma, gastric cancer, thyroid cancer, endometrial cancer, and TRMT61A can be used as an intervention target for these tumors.

[0046] Example 2: Differential analysis of TRMT61A expression in human colon cancer tissue chip Materials: Human colon cancer tissue chip (94 patients, 46 males and 48 females, aged 64.2 ± 13.2 years) (Shanghai Xisuper Company, HCol-A180Su-21); TRMT61A antibody; HRP-labeled goat anti-rabbit antibody; diaminobenzidine; hematoxylin.

[0047] Methods: The colon cancer tissue and the paired normal colon tissue adjacent to the cancer were routinely deparaffinated and hydrated, and then placed in 1 mM EDTA (pH 8.0) buffer for antigen retrieval by high-pressure steam repair method. Then, cool to room temperature, block endogenous peroxidase with 3% H2O2 for 15 min. PBS buffer (2%) was washed for 3 times, 3 min each time. Then, add goat serum blocking solution, incubate at room temperature for 25 min. Then, add 50ul of the prepared anti-TRMT61A antibody (1:200), incubate at 4℃ overnight, wash with PBS buffer (2%) for 5 times, 5 min each time. Then, add 50ul of HRP-labeled goat anti-rabbit antibody (1:2000), incubate at room temperature for 45 min, wash with PBS buffer (2%) for 5 times, 5 min each time, develop with diaminobenzidine (DAB) for 1-3 min, hematoxylin counterstaining, routine dehydration and transparency, neutral resin sealing.

[0048] Microscopy scanning was performed on the sections, and the immunohistochemical staining pictures were analyzed and scored: according to the staining intensity, 0 points for no brownish yellow; 1 point for light brownish yellow; 2 points for brownish yellow; 3 points for brownish brown. The number of positive cells was observed under the same objective, and the number of positive cells ≤ 10% was 0 points (when this item is scored as zero, no matter how deep the staining is, it is not scored); the number of positive cells 11%~50% was 2 points; the number of positive cells 51%~80% was 3 points; the number of positive cells > 80% was 4 points; the scores of staining intensity and the percentage of positive cell number were added, which was the score of the expression level of GYSY-2 in this sample. The score of TRMT61A in colon cancer tissue was less than or equal to 6, indicating that TRMT61A was lowly expressed in colon cancer tissue (Low), and the other was highly expressed (High). Kaplan-Meier survival curve analysis was performed on the patients in the high / low expression group of TRMT61A.

[0049] The results are shown in Figure 2 TRMT61A was significantly highly expressed in colon cancer compared with normal colon tissue. Compared with the low expression group, the survival time of colon cancer patients in the high expression TRMT61A group was significantly shortened.

[0050] Example 3 Correlation analysis between TRMT61A level in patient tumor and tumor anti-PD-1 immunotherapy responsiveness Methods: Kaplan-Meier survival curve analysis was performed on bladder cancer, esophageal cancer, glioblastoma, liver cancer, head and neck squamous cell carcinoma, melanoma, lung cancer, urothelial carcinoma and other tumor patients receiving PD-1 immunotherapy with high / low expression of TRMT61A in the tumor by the Kaplan Meier plotter (https: / / kmplot.com / analysis / ) platform.

[0051] Using 10x single-cell transcriptome sequencing data (GSE205506) containing 40 cancer and paracancer samples of 19 patients with colon cancer receiving PD-1 treatment, the expression of TRMT61A in malignant epithelial cells of patients with pathologic complete response (pCR) and non-pathologic complete response (non-pCR) was analyzed.

[0052] The results are shown in Figure 3As shown, in bladder cancer, esophageal cancer, glioblastoma, liver cancer, head and neck squamous cell carcinoma, melanoma, lung cancer, urothelial carcinoma, the prognosis of tumor patients receiving PD-1 immunotherapy was poorer, and the survival time was shorter in the tumor patients with high expression of TRMT61A than in the tumor patients with low expression of TRMT61A. In colon cancer, colon cancer patients with high expression of TRMT61A had higher non-pCR after anti-PD-1 immunotherapy, while colon cancer patients with low expression of TRMT61A had higher pCR after anti-PD-1 immunotherapy.

[0053] Example 4 In vitro cell experiment function analysis of Thiram Materials: HCT116, CT26 cell lines; Thiram; anti-PD-1 antibody.

[0054] Methods: HCT116 and CT26 cells were treated with different concentrations of Thiram for 24 hours, and Dot blot was used to detect the RNA m 1 A level, and Western blot was used to detect the expression of PD-L1 protein.

[0055] As shown in the results Figure 4 , 8 mM or 6 mM Thiram significantly reduced the RNA m 1 A modification level of HCT116 or CT26 cells and up-regulated the expression of PD-L1 protein.

[0056] Example 5 Safety evaluation of Thiram Materials: Balb / c mice; Thiram.

[0057] Methods: Thiram concentration gradient treatment groups (0, 0.2, 0.4, 0.8 mg / kg) were set up, and the administration method was intraperitoneal injection, with a frequency of once every 2 days, for a total of 20 days of treatment. The body weight changes of mice before and after treatment were monitored; the heart, liver, spleen, lung, and kidney tissues of mice after treatment were collected and stained with hematoxylin and eosin (H&E).

[0058] As shown in the results Figure 5 , there was no significant difference in body weight of mice in each group before and after treatment; the structure of organ tissues in each group was normal, and there was no obvious toxic pathological change.

[0059] Example 6 Thiram-treated mouse subcutaneous tumor transplantation model Materials: Balb / c mice; CT26 cells; Thiram.

[0060] Methods: CT26 cells were injected subcutaneously, and when the tumor volume reached about 100 mm3, the mice were grouped (0, 0.2, 0.4, 0.8 mg / kg), and Thiram was injected intraperitoneally every two days for a total of 20 days. Subcutaneous tumors were collected for photography, and part of the subcutaneous tumor tissue was taken for protein extraction and Western blot detection of PD-L1 protein expression.

[0061] Results as shown in Figure 6 Compared with the control group, 0.2, 0.4 mg / kg Thiram treatment did not affect the growth of subcutaneous tumors, and 0.8 mg / kg Thiram treatment slightly inhibited the growth of subcutaneous tumors. Thiram treatment increased the expression level of PD-L1 protein in tumor tissue, and reached a peak at 0.4 mg / kg.

[0062] Example 7 Thiram combined with anti-PD-1 treatment in mouse subcutaneous transplanted tumor model Materials: Balb / c mice; CT26 cells; Thiram; anti-PD-1 antibody.

[0063] Methods: CT26 cells were injected subcutaneously, and when the tumor volume reached about 100 mm3, the mice were grouped (control, PD-1 alone, Thiram alone, combination), 0.4 mg / kg Thiram was injected intraperitoneally every two days, and 10 mg / kg anti-PD-1 antibody was injected intraperitoneally every three days, for a total of 21 days.

[0064] Results as shown in Figure 7 The tumor volume and weight of the Thiram and anti-PD-1 antibody drug combination treatment group were significantly smaller than those of each single drug group (P<0.01); H&E staining showed no major organ toxicity.

[0065] Finally, it should be noted that: the above examples are only used to illustrate the technical solutions of the present application, and not to limit them; although the present application has been described in detail with reference to the foregoing examples, those skilled in the art should understand that they can still modify the technical solutions described in the foregoing examples, or make equivalent substitutions for part or all of the technical features; and these modifications or substitutions do not make the essence of the corresponding technical solutions deviate from the scope of the technical solutions of the embodiments of the present application.

Claims

1. Application of TRMT61A as a target in evaluating the efficacy of anti-PD-1 and / or anti-PD-L1 immunotherapy in cancer patients.

2. Application of TRMT61A inhibitors in the preparation of drugs that upregulate PD-L1 levels or enhance the efficacy of tumor immunotherapy.

3. Use of TRMT61A inhibitors in combination with anti-PD-1 and / or anti-PD-L1 immunotherapeutic antibodies or drugs in the preparation of drugs for tumor immunotherapy.

4. The use according to claim 2 or 3, characterized in that The TRMT61A inhibitor includes tetramethylthiuram disulfide and / or pharmaceutically acceptable salts thereof.

5. The use according to any one of claims 1 to 3, characterized in that The tumor is a solid tumor; Preferably, the solid tumor includes one or more of breast cancer, bile duct cancer, colon cancer, esophageal cancer, glioma, head and neck squamous cell carcinoma, renal chromophobe cell carcinoma, liver cancer, lung adenocarcinoma, lung squamous cell carcinoma, pheochromocytoma, prostate cancer, rectal adenocarcinoma, gastric cancer, thyroid cancer, endometrial cancer, bladder cancer, melanoma, and urothelial carcinoma.

6. A combined pharmaceutical composition for tumor immunotherapy, characterized in that: The combination pharmaceutical composition includes a TRMT61A inhibitor and an anti-PD-1 or / and anti-PD-L1 immunotherapeutic antibody or drug.

7. The combined pharmaceutical composition according to claim 6, characterized in that The TRMT61A inhibitor is tetramethylthiuram disulfide or / and its pharmaceutically acceptable salts.

8. The combined pharmaceutical composition according to claim 6, characterized in that The combination pharmaceutical composition is a combination of two separate preparations, two separate preparations are administered simultaneously, or two separate preparations are administered sequentially; Preferably, the preparation is in any pharmaceutically acceptable dosage form.

9. The combined pharmaceutical composition according to claim 7, characterized in that The dosage range of the tetramethylthiuram disulfide is 0.1 to 5 mg / kg body weight / time.

10. The combined pharmaceutical composition according to claim 6, characterized in that The combined pharmaceutical composition further comprises pharmaceutically acceptable excipients; Preferably, the pharmaceutical excipients include any one or a combination of at least two of a carrier, a binder, a diluent, an emulsifier, a wetting agent, a disintegrant, a solubilizer, a surfactant, an osmotic pressure regulator, a colorant, a coating material, a buffer, an antibacterial agent, an antioxidant or a pH regulator.

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