免疫检查点抑制剂在多种肿瘤中获得了令人振奋的疗效，但胃癌患者对免疫检查点抑制剂治疗的客观反应率只有15%左右，因此厘清胃癌患者免疫调节机制、扩大免疫治疗获益人群是目前晚期胃癌临床治疗所面临的重大挑战。申请人前期研究发现，胃癌组织中的CXCL8+肿瘤相关巨噬细胞可通过调控髓系细胞功能表型变化促进免疫逃逸（Gut 2019, Br J Surg 2017）。进一步分析发现，CXCL8+肿瘤相关巨噬细胞可促进CD4+T细胞向CXCL13+Tfh细胞亚群分化，抑制效应性T细胞功能活化。本项目拟在前期研究发现的基础上，阐述CXCL8+肿瘤相关巨噬细胞调控肿瘤浸润CD4+T细胞功能表型转化并介导免疫逃逸的细胞及分子机制，建立CXCL13+Tfh细胞参与CXCL8+肿瘤相关巨噬细胞介导胃癌免疫逃逸的分子调控机制和靶向干预模型，为认识胃癌免疫调节机制、寻找新的治疗靶点从而提高免疫治疗疗效奠定理论基础。

Checkpoint inhibitors have achieved exciting efficacy in a variety of tumors, but the objective response rate of patients with gastric cancer to checkpoint inhibitors is only about 15%. Therefore, it is a major challenge to clarify the immune regulatory mechanism of patients with gastric cancer and expand the population benefiting from immunotherapy. We previously demonstrated that CXCL8+tumor-associated macrophages could promote immune escape by regulating the functional phenotype of myeloid cells in gastric cancer (Gut 2019, Br J Surg 2017). Further analyses revealed that CXCL8+ tumor-associated macrophages can promote CD4+T cells to differentiate into CXCL13+Tfh cell subsets and inhibit the functional activation of effector T cells. On the basis of preliminary results, the project proposal is designed to demonstrate cellular and molecular mechanisms of tumor immune evasion induced by that CXCL8+ tumor-associated macrophages regulating tumor infiltrating CD4+ T cells functional phenotypes. We plan to establish a molecular regulation and intervention model for CXCL13+Tfh cells participating in CXCL8+ tumor-associated macrophages-mediated immune escape in gastric cancer that will establish the theoretical basis for understanding immune regulating mechanism and finding new therapeutic targets to improve immune treatment.