TAMs通过外泌体源LncRNA H19/STAT3/PD-L1通路介导胃癌免疫抑制微环境的机制研究

肿瘤相关巨噬细胞(Tumor-associated macrophages, TAMs)是肿瘤微环境中重要的组成部分，与肿瘤的侵袭转移和免疫逃逸密切相关。然而，关于TAMs在胃癌免疫抑制微环境中的作用及具体调控机制仍不清楚。申请者前期预实验发现高表达FoxQ1胃癌细胞分泌的外泌体源LncRNA H19可能通过磷酸化STAT3促进TAMs M2极化和负向免疫调控；同时STAT3表达改变可能影响TAMs PD-L1表达改变。结合前期文章发表成果及预实验提出科学假说：胃癌免疫抑制微环境中存在“外泌体源LncRNA H19磷酸化STAT3从而促进TAMs M2极化和PD-L1转录”这样一个全新的分子机制，促进胃癌侵袭转移和免疫逃逸。本项目拟阐述该信号通路的上下游调控关系，明确通路维系胃癌免疫抑制微环境形成潜能，以期为逆转胃癌的恶性进展、提高肿瘤免疫治疗疗效提供潜在的靶点。

Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with immune escape and metastasis in human cancers. However, the role of TAMs in the immunosuppressive microenvironment of gastric cancer and its specific regulatory mechanisms remain unclear. Our previous study found that exosomal LncRNA H19 secreted by overexpressing FoxQ1 gastric cancer cells may promote TAMs M2 polarization and negative immune regulation through phosphorylation of STAT3; meanwhile, changes in STAT3 expression may affect PD-L1 expression in TAMs. Therefore, we put forward the existence of the “exosomal LncRNA H19/STAT3/PD-L1” axis in immunosuppressive microenvironment. The present study aims to systematically determine the existence of the axis, and validate the impact of the axis on the generation of immunosuppressive microenvironment, finally identifying the treatment target for reversing the malignant potential of gastric cancer and improving the efficacy of tumor immunotherapy.