C5aR1调控肿瘤相关巨噬细胞重编程促进胃癌免疫逃逸的作用和机制研究

目前免疫治疗药物PD-1/PD-L1抗体仅对不足20%胃癌患者有效，解析肿瘤微环境导致免疫逃逸的机制，是开发新的免疫治疗药物的重要基础。项目申请人研究发现，肿瘤微环境信号通过促进肿瘤相关巨噬细胞亚群分化调控杀伤性T细胞功能活化参与胃癌免疫逃逸（Gut 2019、Br J Cancer 2020、Eur J Cancer 2020、Int J Cancer 2021、Ann Surg 2021）。本项目预实验中，申请人发现胃癌中C5aR1+肿瘤相关巨噬细胞浸润与患者不良预后及瘤内杀伤性T细胞功能抑制密切相关，进一步发现C5aR1诱导肿瘤相关巨噬细胞分泌IL-23并抑制杀伤性T细胞活化。本项目拟在前期发现基础上，研究C5aR1调控肿瘤相关巨噬细胞重编程介导胃癌免疫逃逸的作用及其机制，探索靶向干预C5aR1在胃癌免疫治疗中的意义，为认识胃癌免疫逃逸机制、开发新的胃癌免疫治疗药物提供理论依据。

Currently, immunotherapy drugs PD-1/PD-L1 antibodies are only effective in less than 20% of gastric cancer patients. Understanding the mechanism of immune evasion caused by tumor microenvironment is the important basis for the development of new immunotherapy drugs. Previous studies of the project applicants have shown that tumor-associated macrophages can differentiate into specific subsets under the regulation of complex microenvironmental signals, and further suppress the activation of effector immune cells through different functional molecules to promote immune evasion of gastric cancer (Gut 2019, Br J Cancer 2020, Eur J Cancer 2020, Int J Cancer 2021, Ann Surg 2021). In the preliminary experiments of this project, we found that C5aR1+ tumor associated macrophage infiltration was correlated with poor prognosis and dysfunction of intratumoral cytotoxicity T cells in gastric cancer, further study showed that C5aR1 can facilitate immunosuppression phenotype differentiation and IL-23 secretion by tumor associated macrophages, thereby inhibiting cytotoxicity T cell activation. Based on preliminary results, our current project was intended to further study the role and mechanism of C5aR1 in regulating tumor-associated macrophage reprogramming to mediate gastric cancer immune evasion, and explore the clinical significance of C5aR1 blockade in gastric cancer immunotherapy. This project will be of great significance to further understand the regulatory mechanism of tumor immune evasion and lay foundation for the development of new immunotherapy drugs for gastric cancer.