以免疫检查点抑制剂为代表的肿瘤免疫治疗在部分晚期胃癌患者中取得显著疗效，但由于肿瘤免疫逃逸引发的治疗抵抗，大部分患者并不能从中获益。项目申请人前期研究发现，胃癌微环境中特定亚群的肿瘤相关巨噬细胞（TAM）通过分泌不同的调节性细胞因子，调控CD4+T细胞的分化及功能表型转换，抑制杀伤性T细胞、γδT细胞等效应免疫细胞的功能活化，参与胃癌免疫调控（Oncoimmunology 2017；Cancer Immunol Immunother 2018；Ann Oncol 2019；Eur J Cancer 2020）。本申请项目拟在前期发现基础上，研究DC-SIGN+TAM通过诱导CD4+T细胞向RORγt+Treg亚群分化介导胃癌免疫逃逸的作用及其机制，探索靶向DC-SIGN+TAM重激活胃癌抗肿瘤免疫反应的免疫治疗策略，为认识胃癌免疫调控的细胞与分子机制及开发新的胃癌免疫治疗药物奠定理论基础。

Tumor immunotherapy represented by immune checkpoint inhibitors can significantly improve the survival of some advanced gastric cancer patients, while most patients cannot benefit from immunotherapy due to therapeutic resistance resulted from tumor immune evasion. In previous researches we revealed that certain tumor associated macrophages (TAM) in gastric cancer microenvironment can mediate the differentiation and transdifferentiation of CD4+T cells via secretions of various regulatory cytokines, inhibit functions of effector immune cells such as cytotoxic T cells, γδT cells, etc. and finally participate in the immune regulation of gastric cancer (Oncoimmunology 2017; Cancer Immunol Immunother 2018; Ann Oncol 2019; Eur J Cancer 2020). Based on these findings, we plan to investigate the molecular mechanisms of DC-SIGN+TAM inducing the differentiation of RORγt+ Treg devived from CD4+T cells and mediating gastric cancer immune evasion and explore immunotherapeutic strategies of reactivating anti-tumor immune responses in gastric cancer by targeting DC-SIGN+TAM. This will provide a theoretical foundation for understanding the cellular and molecular mechanisms of immune regulation and developing novel immunotherapeutic drugs for gastric cancer.