The Role And Mechanism Of Myeloid Derived Suppressor Cells (MDSC) In The Immune Escape Of Non-small Cell Lung Cancer

Lung cancer is the first malignant tumor with morbidity and mortality in the world.Non-small cell lung cancer(NSCLC)accounts for 80%of the total number of lung cancer.Most patients with NSCLC have been in the middle and late stage of the course of disease at the time of diagnosis and have lost the opportunity of surgical treatment.The biggest obstacle in the treatment of advanced NSCLC is the occurrence of tumor recurrence and metastasis.Failure to respond effectively to tumor antigens is a key factor in tumor recurrence and metastasis.In recent years,it has been found that a group of heterogeneous immature bone marrow cells,called myelogenous inhibitory cells(myeloid derived suppressor cells,MDSC),have been accumulated in tumor patients.The immune escape mediated by MDSC promotes the growth,differentiation and metastasis of tumor cells,and brings problems to anti-tumor immunotherapy.It is important to understand its mechanism in monitoring tumor development and seeking new immunotherapy targets.At present,the phenotypic characteristics of MDSC and the biological characteristics of immunosuppression in patients with NSCLC are not very clear.The aim of this study was to investigate the phenotype and immunosuppressive characteristics of MDSC in patients with NSCLC,and to explore the possible ways of T cell immunosuppressive effect of specific phenotypic MDSC.To elucidate the evidence and biological mechanism of MDSC involved in immune escape in oncogenesis.Based on the clinical data of patients with lung cancer,the relationship between MDSC level and malignant biological characteristics such as differentiation,metastasis and recurrence of non-small cell lung cancer was analyzed.To determine whether MDSC can be used as an immunological marker for monitoring and evaluating the efficacy of NSCLC.To identify the expression of CHOP/GADD153 protein on the surface of MDSC and its functional characteristics in peripheral blood of patients with NSCLC,and to provide a new idea for immunotherapy of NSCLC.PART 1:Phenotype and proportion of MDSC in peripheral blood and tumor tissues in patients with non-small cell lung cancer.Objective:To investigate the specific phenotype of MDSC and its proportion in peripheral blood and tumor tissues in patients with non-small cell lung cancer(NSCLC).Methods:A total of 77 cases of NSCLC diagnosed by pathology were collected from the respiratory department of Shandong Provincial Hospital,and the peripheral blood samples were collected.Forty-six cases of NSCLC patients who were clinically diagnosed and received surgical treatment in thoracic surgery department of Shandong Provincial Hospital were selected.The expression levels of HLA-DR,CD 14,CD 15,CD11 CD3,CD3,CD4 and CD34 in peripheral blood of patients with NSCLC and healthy controls were detected by flow cytometry,and the expression levels of these McAbs in cancer tissues and adjacent tissues were compared,aim ing to investigate the MDSC phenotype in patients with NSCLC.The relationship between the proportion of specific phenotype MDSC and the clinical data of patients with NSCLC was analyzed,and the patients with NSCLC were followed up for 4-6 cycles of chemotherapy.To investigate the correlation between the proportion of MDSC in peripheral blood and chemotherapeutic efficacy in patients with NSCLC.Results:The two groups of MDSC cells,CD 11b+/CD 14+ and CD11b+/CD 14-were significantly higher in the proportion of peripheral blood non-lymphoid monocytes in lung cancer patients than in healthy people.The number of CD11b+/CD14+ MDSC in peripheral blood of NSCLC patients was significantly correlated with age,sex,differentiation degree and PS score.The proportion of CDllb+/CD 14+ MDSC in peripheral blood of patients with stage IV and low differentiation was significantly increased.In addition,there was significant correlation between the proportion of CDllb+/CD14+ MDSC and the clinical efficacy after chemotherapy in patients with NSCLC(P<0.05).However,there was no significant correlation between the proportion of CD11b+/CD14-MDSC and the clinical data of patients with non-small cell lung cancer and the clinical effect after chemotherapy(P>0.05).Conclusion:The proportion of CDllb+/CD14+ and CDllb+/CD14-MDSC were significantly increased in the peripheral blood and cancer tissues of patients with NSCLC.The number of CD11b+/CD14+ MDSC in peripheral blood of patients with NSCLC was positively correlated with the severity of the disease.There was no significant correlation between the proportion of CD11b/CD14-MDSC and the severity of the disease and the effect of chemotherapy.PART 2:To investigate the inhibitory effect and pathway of MDSC on T cell proliferation in patients with non-small cell lung cancerObjective:To investigate the inhibitory effect of MDSC on T cell proliferation in patients with non-small cell lung cancer(NSCLC),and to determine the expression level and functional characteristics of MDSC surface CHOP/GADD153 protein in peripheral blood of NSCLC patients.Methods:CD11b+CD 14+and CDllb+CD 14-cells were isolated from peripheral blood and tumor single cell suspension of patients with NSCLC by magnetic bead sorting system.The inhibitory effect of two groups of MDSC cells on T cell proliferation was detected.The ARG1 content in MDSC cells of patients with NSCLC was detected.The expression of CHOP/GADD153 protein in NSCLC was detected by immunohistochemistry and the expression of CHOP/GADD153 protein in MDSC cells was detected by Western blot.After blocking CHOP/GADD153 protein of MDSC cells,the inhibitory effects of MDSC on T cell proliferation and ARG1 content in MDSC cells were compared before and after blocking.Results:CD 11 b+CD 14+MDSC in peripheral blood and tumor cell suspension of NSCLC patients significantly inhibited the proliferation of T cells,and the expression of ARG1 mRNA in MDSC cells of NSCLC patients was significantly higher than that of healthy control group.The expression of CHOP/GADD153 in cancer tissues and in MDSC cells was related to the degree of differentiation,and the expression of CHOP/GADD153 in moderately and poorly differentiated lung cancer tissues was significantly higher than that in highly differentiated lung cancer tissues.The inhibitory effect of CD 11 b+CD 14+MDSC on T cell proliferation was significantly decreased after blocking CHOP/GADD153 protein in MDSC cells.The Argl mRNA expression level of CD11b+CD14+MDSC cells was significantly decreased after blocking CD11b+CD14+MDSC cells by CHOP-GADD153.Conclusion:1.CDllb+CD14+MDSC can significantly inhibit the proliferation of CD8 T cells in peripheral blood and cancer tissues of patients with non-small cell lung cancer.It is a characteristic MDSC phenotype with immunosuppressive activity in NSCLC.2.CD11b+CD14+MDSC overexpresses CHOP/GADD153 protein in patients with NSCLC.The expression of CHOP is related to the immunosuppressive activity of MDSC.Interfering with CHOP/GADD1453 signaling pathway may be a new way of immunotherapy for NSCLC.