| BackgroundIn recent years,the emergence of new target molecules with clear function in T cell immunosuppression,that is,immunologic checkpoint molecules,v-domain immunoglobulin suppressor of T-cell activation(VISTA).Earlier animal experiments confirmed that if the VISTA target was closed,combined use of VISTA with other immunosuppressant inhibitors,such as PD-1(programmed death factor),can kill the tumor.CD8+T cells are the most important effector cells in tumor infiltrating lymphocytes(TILs),and the sustainability of CD8+T cells is highly expressed as the PD-1 suppressor receptor.VISTA and PD-1/PD-L1 have different signaling pathways to immunize T cells.What is the relationship between VISTA expression related to CD8+T cells?What is the correlation between the prognosis of liver cancer and the total survival time of the two?It is the focus of this study.In recent years,studies have found that VISTA may represent another compensatory inhibitory pathway in the anti PD-1 or anti CTLA-4 treatment of tumor.VISTA immunologic checkpoints are becoming a hot spot in the research of tumor immunosuppressive therapy,and related research in lung cancer,gastric cancer,melanoma,oral squamous cell carcinoma,prostate cancer and other cancers have been reported.But there is no report on the study of VISTA protein in hepatocellular carcinoma.A literature on the clinical trials of PD1 blocker nivolumab in advanced hepatocellular carcinoma(lancet)was published in April 2017.The safety and effectiveness of nivolumab as a first-line and second line drug are reported in the lancet,however,as a first-line drug,the objective remission rate was 23%,and 25%of the subjects had the side effects of treatment,and the acquired resistance was increasing.The combination of VISTA and PD-1/CTLA-4 block may be a promising new choice for the treatment of liver cancer.The correlation between the expression of VISTA and CD8 protein and the correlation with the clinicopathological features of primary liver cancer were investigated.Based on the expression status of VISTA/CD8,the immune microenvironment of liver cancer and the total survival time in immune microenvironment were constructed,so as to evaluate the VISTA blocking immunotherapy for hepatocellular carcinoma and its overall survival.It provides a reference for the research and development of immunotherapy for VISTA and other immunoassay points,and will also provide a new direction for future research on anti-tumor.MethodsA continuous microarray microarray(TMAs)was used as an experimental group in 183 patients with hepatocellular carcinoma.The expression of VISTA and CD8+protein in the tissues of 183 patients with primary liver cancer was analyzed by immunohistochemical method(IHC).The cancer gene(TCGA)database is used as a validation queue.VISTA and CD8 +mRNA(expression data)were extracted from 372 patients with primary liver cancer.The relationship between the expression of VISTA in tumor cells,immune cells and tumor microenvironment and pathological variables was analyzed,and the correlation with the prognosis of patients with hepatocellular carcinoma was also analyzed.The possible biological characteristics of VISTA protein in the tumor cells of patients with hepatocellular carcinoma were preliminarily investigated by MTT experiment,plate cloning experiment and flow cytometry.Based on the expression of VISTA/CD8,the immune microenvironment of liver cancer was classified and the correlation with the prognosis was analyzed.Results1.The expression of VISTA in primary liver cancer has significant correlation with pathological histological grading(P=0.038),cirrhosis(P=0.011)and high density CD8+ tumor infiltrating lymphocytes(P<0.001).The high expression of VISTA in tumor cells indicates a smaller tumor and a lower incidence of liver cirrhosis in the patients with liver cancer.2.based on the expression of VISTA/CD8,the immune microenvironment of primary liver cancer is divided into 4 subtypes of immune subtypes,each subtype in this group is as follows:VISTA+/CD8+(16.9%,31/183),VISTA+/CD8-(12.6%,23/183),VISTA-/CD8+(16.4%,30/183),VISTA-/CD8-(54.1%,99/183).Kaplan Meier curve showed that the total survival time of patients with positive expression of VISTA in tumor cells(not expression of VISTA in immune cells)was significantly longer than that in tumor cells with negative expression of VISTA(74months vs41months,P=0.037).The overall survival time of VISTA+/CD8+ double positive expression in liver cancer tissue was significantly longer than that of other immunophenotyping(74 months vs53 months vs35 months,P=0.023),indicating better survival prognosis.3.The high expression of VISTA in hepatoma cells inhibits the growth of tumor cells in vitro and inhibits the progress of cell cycle.Conclusions1.The expression of VISTA and CD8+TILs in primary liver cancer is positively correlated,and the expression of VISTA protein has a specific cell specificity.The types of cells expressed in VISTA showed different prognosis.2.The study in this group believes that:the expression of VISTA and CD8+TILs proteins can be used to reflect the immune microenvironment of cancer of the liver cancer.The double positive expression of VISTA+/CD8+ in the liver cancer tissues has a better survival prognosis for the patients with hepatocellular carcinoma.3.VISTA may play a role in the tumor suppressor gene in the hepatoma cells. |
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