Drug target for improving sensitivity of tumor cells to immunotherapy and application of drug target

Abstract

The invention belongs to the technical field of biology, and relates to a drug target for improving sensitivity of tumor cells to immunotherapy and application of the drug target. On one hand, the invention discloses application of sterol O-acyltransferase 1 and / or 2 as a target spot in preparation of drugs for inhibiting tumor cell immune escape, a new direction is provided for tumor immunotherapy drugs, and a new platform is provided for screening of the tumor immunotherapy drugs. On the other hand, the invention provides a method for predicting the postoperative recurrence rate and / or lifetime of the tumor, and the method has a wide application prospect in the field of tumor treatment.

Description

Technical Field

[0001] The present invention belongs to the field of biotechnology, and in particular relates to a drug target for improving the sensitivity of tumor cells to immunotherapy and an application thereof. Background Art

[0002] Sterol O-acyltransferase 1 (SOAT1), also known as acyl-CoA, cholesterol acyltransferase 1 (acetyl-CoA acetyltransferase 1, ACAT1), is a crucial enzyme in the cholesterol esterification pathway, which can convert cholesterol in the endoplasmic reticulum into cholesterol esters, which are then stored in lipid droplets to maintain the balance of intracellular lipid metabolism. Studies have found that the expression level of SOAT1 is significantly correlated with the overall survival time of patients with liver cancer, and multivariate analysis shows that SOAT1 is an independent prognostic factor for patients with early liver cancer (Jiang, Ying et al. "Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma." Nature vol. 567, 7747 (2019): 257-261. doi: 10.1038 / s41586-019-0987-8).

[0003] Cancer cells often evade immune destruction and resist treatment by hijacking inherent or altering metabolic pathways, thereby promoting recurrence. Metabolic disorders are the main drivers of tumor progression and recurrence. Nonalcoholic fatty liver disease (NAFLD) and obesity-related metabolic dysfunction have become key factors in the development and recurrence of liver cancer. Although immunotherapy (such as immune checkpoint inhibitors) has revolutionized cancer treatment and achieved remarkable success in many cancer types, the response rate of hepatocellular carcinoma remains disappointingly low. This highlights the urgent need to identify liver cancer-specific drivers and mechanisms of immune evasion and recurrence so that more effective treatments can be found to prevent recurrence and manage recurrent tumors. Previous studies have found that in melanoma or lung cancer, ACAT1 inhibitors can enhance or promote CD8 T cell function, and ACAT1 can provide a new target for immunotherapy drugs (CN201610115227.2). However, in the case where tumor cells are insensitive to immune cells, even if immune cell function is enhanced, the expected therapeutic effect cannot be achieved. Summary of the invention

[0004] The present invention discloses an application of SOAT1 / 2 as a target in preparing a drug for inhibiting tumor cell immune escape.

[0005] The drug is an immunotherapy drug that inhibits the immune escape of tumor cells.

[0006] The tumor cells include but are not limited to liver cancer cells, breast cancer cells or pancreatic cancer cells.

[0007] The immune escape refers to immune escape of T cells and / or macrophages.

[0008] The T cells are further CD8 T cells.

[0009] The inhibition is the ability to inhibit oxidative stress and / or endoplasmic reticulum stress in tumor cells.

[0010] Another aspect of the present invention discloses the use of SOAT1 / 2 as a drug target for preparing a drug for increasing the sensitivity of tumor cells to immune cells.

[0011] The cancer includes but is not limited to liver cancer, breast cancer or pancreatic cancer.

[0012] The immune cells are T cells and / or macrophages.

[0013] The T cells are further CD8 T cells.

[0014] The aforementioned drug targets are used for the preparation of in vitro screening drugs.

[0015] On the other hand, the present invention discloses a method for predicting tumor recurrence rate and / or survival period, characterized in that the method comprises: determining the level of SOAT1 / 2 in the sample obtained from the patient, and diagnosing whether the patient has a tumor recurrence rate or predicting the patient's survival period (survival time) based on the level.

[0016] The tumor includes but is not limited to liver cancer, breast cancer or pancreatic cancer.

[0017] The patients mentioned here are those who have undergone liver cancer transplantation treatment.

[0018] The patient is a liver cancer patient with a body mass index (BMI) greater than or equal to 28.

[0019] Another aspect of the present invention discloses an in vitro screening method for enhancing the sensitivity of tumor cells to immunotherapy drugs, comprising: taking SOAT1 / 2 as the drug action target, and selecting SOAT1 / 2 inhibitors as candidate primary screening drugs for enhancing the sensitivity of tumor cells to immunotherapy drugs.

[0020] The SOAT1 / 2 inhibitor refers to a compound that has an inhibitory effect on SOAT1 / 2.

[0021] The inhibitory effect on SOAT1 / 2 includes but is not limited to: inhibiting the activity of SOAT1 / 2, or inhibiting the gene transcription or expression of SOAT1 / 2.

[0022] The tumor cells include but are not limited to liver cancer cells, breast cancer cells or pancreatic cancer cells.

[0023] The determination of whether a drug can inhibit the activity of SOAT1 / 2 can be carried out using existing technologies, including: isotope-labeled sterol assay, fluorescent-labeled sterol assay and cholesterol oxidase assay.

[0024] The determination of whether the drug can inhibit the gene transcription or expression of SOAT1 / 2 can also be performed using existing technologies. For example, cells that normally express SOAT1 / 2 are provided, the cells are cultured in the presence of the drug to be tested or a vector carrying the drug to be tested, and whether the transcription or expression level of SOAT1 / 2 changes.

[0025] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 SOAT1 is a key driver of liver cancer immune evasion and recurrence after liver transplantation

[0027] A and B are the results of tumor cell viability after 48 hours of co-culture of tumor cells Hepa-OVA-Cas9 and OT-I CD8+T cells at a ratio of 2:1 (effector to target, E:T). The results of the control group and SOAT1 knockout in SOAT1 mutation complementation (A) and wild-type SOAT1 complementation (B), respectively.

[0028] C and D are tumor growth curves of immunodeficient Rag2- / - mice (control group n=5; SOAT1 knockout n=8) (C) and immunocompetent C57BL / 6 mice (control group and SOAT1 knockout, n=10 / 10) (D) subcutaneously inoculated with Hepa1-6 tumor cells.

[0029] Figure 2 SOAT1 expression is associated with increased recurrence and decreased overall survival in liver cancer

[0030] A. Representative immunofluorescence images (left) and quantification of SOAT1 expression (right) in primary HCC tissues of relapsed (Recur, n=21) and non-relapsed (Non-recur, n=76) after liver transplantation.

[0031] BC. The prognostic significance of SOAT1 expression in tumor cells on recurrence (B) and overall survival (C) in liver transplant patients was evaluated by dividing the patients into SOAT1 high group (n=30) and SOAT1 low group (n=101). Compared with the SOAT1 low group, the SOAT1 high group had a significantly higher recurrence rate (B) and a worse overall survival rate (C).

[0032] D. The effect of SOAT1 expression around tumor cells on the prognosis of patients with HCC undergoing liver transplantation was evaluated by dividing the patients into two groups: those with high SOAT1 expression around tumor cells (n=50) and those with low SOAT1 expression around tumor cells (n=81).

[0033] EG. The patients were divided into two groups: BMI ≥ 28 (obesity, n = 16) and BMI < 28 (normal, n = 16), and the relationship between obesity and HCC recurrence (E) and overall survival (F) was analyzed. The SOAT1 expression levels in obese HCC patients (obesity) and patients with normal BMI (normal) were compared (G).

[0034] Figure 3 SOAT1 knockout or inhibition can make liver cancer cells sensitive to T cell-mediated killing in vivo and in vitro. Tumor cell growth curve of mice subcutaneously inoculated with Hepa-OVA-Cas9 tumor cells after immunotherapy.

[0035] A. Schematic diagram of Rag2- / - mice receiving immunotherapy (T cell therapy) (above). Rag2- / - mice were treated with PBS or OT-I CD8+T cells (T cells) on day 14 after tumor inoculation. Mice were divided into knockout control group (Hepa), Hepa+T cell treatment, SOAT1 knockout, SOAT1 knockout+T cell treatment, n=9 in each group.

[0036] B. Schematic diagram of C57BL / 6 mice receiving immunotherapy (anti-PD1 therapy, aPD1) (above). C57BL / 6 mice control group n=8, anti-PD1 immunotherapy group n=6; SOAT1 knockout (SOAT1-KO) group and SOAT1-KO + immunotherapy (anti-PD1) group n=10 each, treated with PBS or anti-PD1 from day 14, 3 times every 3 days.

[0037] C. Schematic diagram of C57BL / 6 mice receiving combined treatment (avasimibe (ava) and anti-PD1 (aPD1)) (top). Avasimibe was administered 8 times daily, and anti-PD1 was administered 3 times every 3 days, starting from day 10.

[0038] DE. In vitro proliferation of human hepatoma cell lines Huh7 (D) and HepG2 (E), SOAT1 knockout (Huh7-SOAT1-knockout, Hepg2-SOAT1 knockout) and control (Huh7-control, Hepg2-control) tumor cells was evaluated using CCK-8 assay (Huh7, n=6; HepH2, n=5).

[0039] FG. Liver cancer cell viability of SOAT1 knockout and control groups after co-culture with liver cancer cell Huh7, HepG2 and GPC3 specific CAR-T cells at an effector-target ratio of 1:1 for 48 h, n = 4 in each group.

[0040] H. Schematic diagram of CAR-T therapy combined with SOAT1 inhibition (top). Tumor growth curves of SOAT1-KO and control Huh7 tumors in NSG mice treated with PBS, CAR-T cells, injected once by tail vein on day 10, or avaimibe (Ava), once daily starting on day 10, and CAR-T cells in combination.

[0041] Control group: Huh7-Vector+PBS, n=7

[0042] Immunotherapy control group: Huh7-Vector+CAR-T, n=6

[0043] SOAT1 knockout control group: SOAT1-KO+PBS, n=12

[0044] SOAT1 knockout immunotherapy group: SOAT1-KO+CAR-T, n=12

[0045] Immunotherapy and SOAT1 inhibitor combination group: Vector+Ava+CAR T, n=6

[0046] I. Schematic diagram of in vivo CAR-T therapy (left). Growth curves of SOAT1-KO and control Huh7 tumors in immunodeficient NSG mice treated with PBS or GPC3 CAR-T cells on day 10 after tumor inoculation.

[0047] Control group: Ctrl, n=5

[0048] Immunotherapy control group: Ctrl+CAR-T, n=6

[0049] SOAT1 knockout control group: SOAT1-KO, n=6

[0050] SOAT1 knockout immunotherapy group: SOAT1-KO+CAR-T, n=5

[0051] Figure 4 A. Tumor cell viability after 48 h of co-culture of tumor cells (Hepa1-6) with or without SOAT1 knockout (SOAT1-KO, control group Vector) and immune cells (CD8 T cells) at a ratio (E:T) of 0.5:1, 1:1, or 2:1, n = 3.

[0052] Figure 4 B. Tumor cell viability after 48 h of co-culture of tumor cells (Hepa1-6-OVA) with or without SOAT1 knockout (knockout group, control group) and bone marrow-derived macrophages (BMDM), where the ratio of BMDM:Hepa-OVA-Cas9 was 1:1, or 48 h of co-culture of OT-II CD4+T cells and BMDM, where the ratio of CD4:BMDM:Hepa-OVA-Cas9 was 2:1:1, n=3 per group.

[0053] Figure 4 C. Tumor cell viability after HCC51-OVA tumor cells with or without SOAT1 knockout (control group, SOAT1 knockout) were co-cultured with immune cells (OT-I CD8+ T cells) at a ratio of 2:1 for 48 hours, n=6 in each group.

[0054] Figure 5 Relationship between SOAT1 and cellular metabolism. Heat maps showing the differential expression of genes related to cholesterol biosynthesis, fatty acid biosynthesis, lipid biosynthesis regulation, oxidative stress response, and ER stress response between SOAT1 knockout (SOAT1-KO) and control (Vector) in Hepa1-6 cells (A) and Huh7 cells (B).

[0055] Figure 6 .The phenotypic consistency of SOAT1 and its isoenzyme SOAT2 in the co-culture system. The viability of tumor cells after Hepa-OVA with or without SOAT1 or SOAT2 or double knockout of SOAT1 and SOAT2 and immune cells (OT-ICD8+T cells) at a ratio of 2:1 for 48 hours, n≥3 per group. DETAILED DESCRIPTION

[0056] the term

[0057] The terms used in the present invention have the meanings commonly understood by those of ordinary skill in the relevant art. However, in order to better understand the present invention, some definitions and explanations of related terms are as follows. It should be noted that the explanations of the terms are provided here only to enable those skilled in the art to better understand the present invention and are not intended to limit the present invention.

[0058] Oxidative stress is an important biological characteristic of tumor cells. Compared with normal cells, tumor cells often have higher levels of reactive oxygen species (ROS), which causes oxidative stress. A certain threshold of oxidative stress (oxidative eustress) can promote the occurrence and development of tumors by regulating multiple signaling pathways within cells, while excessive oxidative stress (oxidative distress) can lead to oxidative damage and even tumor cell death. Therefore, while tumor cells have high ROS levels, they also activate the intracellular antioxidant system to relieve oxidative stress, maintain intracellular redox homeostasis, and promote tumor cell survival. A large number of studies have shown that tumor cell metabolic reprogramming plays an important role in the generation of ROS, activation of the antioxidant system, and maintenance of redox homeostasis.

[0059] Endoplasmic Reticulum Stress (ER stress for short), the endoplasmic reticulum (ER) is a central organelle where secretory and transmembrane proteins are synthesized, folded, and modified. Although this process is precisely regulated, a variety of external factors and cell-intrinsic events can disrupt the protein folding capacity of this organelle and induce an ER stress state, which is characterized by the accumulation of misfolded or unfolded proteins. Multiple genetic, transcriptional, and metabolic abnormalities enriched in tumors produce an unfavorable microenvironment, leading to persistent ER stress in tumor cells, ultimately affecting their function, fate, and survival.

[0060] Unless otherwise stated, the experimental methods, detection methods, and preparation methods disclosed in the present invention all adopt conventional techniques in the field of molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology, and related fields.

[0061] Experimental methods

[0062] The present study found that targeted inhibition of SOAT1 / 2 can enhance the sensitivity of tumor cells themselves to immune cell killing, rather than by affecting the function of immune cells.

[0063] SOAT1 is a key driver of liver cancer immune evasion and recurrence

[0064] SOAT1 is a multi-transmembrane enzyme residing in the endoplasmic reticulum that catalyzes the esterification of cholesterol for storage. To investigate whether SOAT1 helps cancer evade immune cell (T cell)-mediated killing, we expressed wildtype SOAT1-rescued (mutSOAT1) and mutant (catalytic-inactive mutant SOAT1-rescued, H460N mutant, Science 359, 1361–1365 (2018)) in SOAT1 knockout (SOAT1-KO) Hepa-OVA-Cas9 cells and co-cultured them with antigen-specific OT-I CD8+T cells. The results showed that only wildtype SOAT1 restored the resistance of SOAT1-KO cells to T cell killing, indicating that SOAT1 plays an important role in evading immune cell killing in tumor cells ( Figure 1 A, 1B). We then subcutaneously inoculated Hepa1-6 tumor cells into immune-deficient Rag2- / - mice and immune-competent C57BL / 6 mice, and knocked out SOAT1 in some mice (SOAT1-KO). The results showed that SOAT1 knockout had little effect on tumor growth in Rag2- / - mice ( Figure 1 C), but tumor growth was reduced in immunocompetent C57BL / 6 mice ( Figure 1 D) These findings suggest that SOAT1 is a key driver of immune evasion in liver cancer.

[0065] SOAT1 expression is associated with increased recurrence and decreased overall survival in liver cancer

[0066] After confirming that SOAT1 is a key factor for tumor cells to evade immune cells (T cells), we explored the clinical significance of SOAT1 in the prognosis and recurrence of patients with hepatocellular carcinoma (HCC). We collected 97 patients who underwent liver transplantation for primary liver cancer. The pathological specimens were primary HCC tissues obtained during liver transplantation, and the recurrence outcomes of these patients were known through follow-up after liver transplantation. We analyzed the correlation between SOAT1 expression and post-transplant recurrence by detecting the SOAT1 level in primary HCC samples of patients with and without recurrence after liver transplantation. The analysis showed that the SOAT1 level of primary HCC in recurrent patients was significantly higher than that in patients without recurrence ( Figure 2 A).

[0067] To evaluate whether SOAT1 expression can serve as an independent prognostic marker, we divided HCC patients undergoing liver transplantation into two groups: SOAT1 high and SOAT1 low, using the mean intratumoral SOAT1 score as the threshold. SOAT1 expression was scored from 0 to 4 based on staining intensity using HALO software on human tissue microarrays (TMA): negative, weak, moderate, or strongly positive. SOAT1 intensity score (SOAT1 H-Score) = [1×% SOAT1 weak cells + 2×% SOAT1 moderate cells + 3×% SOAT1 strong cells].

[0068] We analyzed 37 patients who underwent liver transplantation due to HCC recurrence after liver resection. The pathological specimens were HCC tissues recurring after liver resection that were obtained during liver transplantation. The recurrence outcomes of these patients were also known through follow-up after liver transplantation. We called the HCC recurrence after liver transplantation in these patients second recur (2nd Recur). We detected the SOAT1 level in the HCC samples recurring after liver resection and compared them. The results showed that the SOAT1 level in the samples of patients with second recurrence after liver transplantation was significantly higher than that in the samples of patients without second recurrence ( Figure 2 B).

[0069] Four patients in the primary HCC cohort died of non-tumor causes during follow-up, and 10 patients in the post-liver resection HCC recurrence cohort died of non-tumor causes during follow-up. After excluding these patients, a subgroup analysis was performed on patients who received liver transplantation for primary HCC or post-liver resection HCC recurrence. It was unexpectedly found that high levels of SOAT1 in the tumor were associated with poor overall survival in both groups ( Figure 2 C). In addition, elevated SOAT1 levels in paracancerous tissues were also associated with significantly worse overall survival ( Figure 2 D) It was confirmed that high expression of SOAT1 in cells is a potential risk factor for HCC recurrence, especially after liver transplantation, and is associated with poor overall survival.

[0070] We further investigated the association between obesity and liver cancer immune evasion, and we investigated whether SOAT1 contributes to obesity-related HCC recurrence. Liver cancer patients undergoing liver transplantation were divided into a normal group (BMI < 28) and an obese group (BMI ≥ 28) according to their body mass index (BMI). The results showed that compared with liver cancer patients with normal BMI, obese liver cancer patients had a significantly higher recurrence rate and a worse overall survival rate ( Figure 2 E, 2F). Immunofluorescence staining confirmed that SOAT1 expression in obese liver cancer patients was significantly higher than that in liver cancer patients with normal BMI ( Figure 2G), further confirming that SOAT1 plays an important role in the recurrence of HCC in obese patients.

[0071] SOAT1 knockout or inhibition sensitizes hepatocellular carcinoma cells to T cell-mediated killing in vivo and in vitro

[0072] To determine whether SOAT1 knockout would make tumors sensitive to T cell killing in vivo, we transplanted SOAT1-KO and control groups (Hepa-1-6-OVA-Cas9 cells) into immunodeficient mice (Rag2- / - mice) to exclude the influence of immune cells. Then OT-I CD8+T cell therapy was performed. There are no immune cells in the mice themselves. The only variable in this experiment was whether SOAT1 was knocked out in the tumor cells. The results showed that the control group tumors were resistant to T cell therapy, but the SOAT1-KO tumor group showed a significant decrease in tumor growth after T cell therapy ( Figure 3 A). Next, we explored the role of SOAT1 in anti-programmed cell death 1 (PD1) immunotherapy by transplanting SOAT1-KO and control Hepa1-6 cells into C57BL / 6 mice followed by anti-PD1 treatment. Tumors in the SOAT1-KO group responded significantly to anti-PD1 treatment, whereas tumors in the control group did not ( Figure 3 B). In addition, treatment with the SOAT1 chemical inhibitor Avasimibe (Ava) significantly enhanced the sensitivity of Hepa1-6 tumors to anti-PD1 therapy, similar to the effect of SOAT1 knockout ( Figure 3 C). In summary, we unexpectedly discovered that targeted inhibition of SOAT1 can enhance the sensitivity of tumor cells themselves to immune cells, rather than achieving tumor immunotherapy (immune cells killing tumor cells) by enhancing the function of immune cells.

[0073] In addition, we investigated whether SOAT1 knockout would sensitize human hepatoma cells to T cell-mediated killing. The effect of SOAT1 knockout on tumor cell proliferation was confirmed in human hepatoma cell lines Huh7 and HepG2. CCK-8 assay showed that SOAT1 knockout had little effect on tumor cell proliferation ( Figure 3 D, 3E). We then generated Glypican-3 (GPC3) CAR-T cells to evaluate the effect of SOAT1 knockout tumor cells on the sensitivity of CAR-T therapy. In vitro co-culture experiments showed that SOAT1 knockout Huh7 and HepG2 cells were more sensitive to CAR-T cell-mediated killing ( Figure 3F, 3G). To confirm this in vivo, we transplanted 2x106 SOAT1-KO and control Huh7 cells into immunodeficient mice (NSG mice), followed by GPC3 CAR-T cell therapy 10 days later. SOAT1 knockout significantly increased the sensitivity of human liver cancer cells to CAR-T therapy without affecting the growth of immunodeficient NSG mice ( Figure 3 H, 3I). It is worth noting that treatment with the SOAT1 inhibitor Avasimibe (Ava) also enhanced the therapeutic effect of CAR-T on liver cancer ( Figure 3 H). These results suggest that SOAT1 knockout enhances the responsiveness of human tumor cells to immune cell (T cell) immunotherapy without significantly affecting tumor proliferation.

[0074] In the experiment, we did not perform any treatment or intervention on the immune cells in the tumor and immune cell co-culture system or in the experimental animals. We only knocked out the SOAT1 gene in the tumor cells themselves. We could clearly observe that the response of tumor cells to the same immune pressure changed. Figure 4 As shown in A: Knockout of SOAT1 significantly increased the vulnerability of Hepa1-6 cells to T cell-mediated killing.

[0075] In addition, SOAT1 knockout Hepa1-6 cells and vector Hepa1-6 cells were co-cultured with bone marrow-derived macrophages (BMDMs) and antigen-specific OT-II CD4+ T cells, respectively, indicating that SOAT1 knockout tumor cells were more susceptible to immune killing ( Figure 4 B). In addition, in the conventional mouse (C57BL / 6 mouse) homologous liver cancer cell line HCC51 (HCC51-OVA-Cas9), we observed that SOAT1 knockout did not affect proliferation in vitro, but significantly enhanced sensitivity to antigen-specific T cell killing ( Figure 4 C).

[0076] In another experiment with mice and human cancer cells, we found that genes related to cholesterol synthesis, fatty acid synthesis, and reactive oxygen species (ROS) metabolism were downregulated, while genes involved in responding to oxidative stress and ER stress were upregulated in SOAT1 knockout cells ( Figure 5 A, 5B). These findings suggest that SOAT1 knockout increases the sensitivity of tumor cells to T cell killing.

[0077] SOAT2 has the same phenotype as SOAT1

[0078] In addition, we found that SOAT1 and its isoenzyme SOAT2 had consistent phenotypes in the co-culture system. Tumor Hepa-OVA cells with or without SOAT1 or SOAT2 or double knockout of SOAT1 and SOAT2 were co-cultured with immune cells (OT-I CD8+T cells) at a ratio of 2:1 for 48 hours, and the viability of tumor cells was detected (n≥3 per group). The results showed that SOAT2 and SOAT1 had consistent inhibitory functions, and the inhibitory effect was better in the group where both were knocked out ( Figure 6 ).

[0079] In summary, even when the immune function of immune cells is low, the sensitivity of tumor cells to immunotherapy can be increased by inhibiting the expression of SOAT1 / 2 in tumor cells themselves; at the same time, the expression of SOAT1 / 2 is also a target for cancer recurrence. The cancers include but are not limited to liver cancer, breast cancer or pancreatic cancer.

[0080] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

Claims

1. Use of sterol O-acyltransferase 1 and / or 2 as a target for preparing a drug target for inhibiting tumor cell immune escape and / or recurrence.

2. The use according to claim 1, characterized in that: For in vitro drug screening applications.

3. The use according to claim 1, characterized in that: The tumor cells are liver cancer cells, breast cancer cells and / or pancreatic cancer cells.

4. Use of sterol O-acyltransferase 1 and / or 2 as a drug target for preparing a drug that increases the sensitivity of tumor cells to immunotherapy.

5. The use according to claim 4, characterized in that: The immune cells are T cells and / or macrophages.

6. A method for predicting tumor recurrence rate and / or survival period, characterized in that: The method comprises: determining the level of sterol O-acyltransferase 1 and / or 2 in a sample obtained from the patient, and diagnosing whether the patient has a tumor recurrence rate or predicting the patient's survival period (survival time) based on the level.

7. The method for predicting tumor recurrence rate and / or survival period according to claim 6, characterized in that: The tumor is liver cancer, breast cancer and / or pancreatic cancer.

8. The method for predicting tumor recurrence rate and / or survival period according to claim 7, characterized in that: The patients mentioned here are patients who have received liver transplantation for liver cancer.

9. The method for predicting tumor recurrence rate and / or survival period according to claim 7, characterized in that: The patient is an obese liver cancer patient with a body mass index greater than or equal to 28.

10. A method for in vitro screening to enhance the sensitivity of tumor cells to immunotherapy drugs, comprising: Sterol O-acyltransferase 1 and / or 2 are used as drug targets, and inhibitors of sterol O-acyltransferase 1 and / or 2 are selected as candidate initial screening drugs for enhancing the sensitivity of tumor cells to immunotherapy drugs.

11. The method for in vitro screening to enhance the sensitivity of tumor cells to immunotherapy drugs according to claim 10, characterized in that: The sterol O-acyltransferase 1 and / or 2 inhibitor refers to a compound that has an inhibitory effect on sterol O-acyltransferase 1 and / or 2.

12. The method for in vitro screening to enhance the sensitivity of tumor cells to immunotherapy drugs according to claim 10, characterized in that: The tumor cells are liver cancer cells, breast cancer cells or pancreatic cancer cells.

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