mGluR4通过调节肿瘤相关巨噬细胞功能促进结肠癌免疫逃逸的机制

肿瘤相关巨噬细胞（TAM）从抑肿瘤M1型逐渐转变为促肿瘤M2型，在结肠癌发展中发挥重要的作用，但其转变机制不明确。结肠癌病人生存率率与mGluR4（代谢型谷氨酸受体4）表达水平呈负相关。我们前期工作发现mGluR4主要表达在TAM中；其促进免疫抑制因子Arginase1、TGFβ表达，抑制CD8+T细胞增殖和功能；mGluR4显著地促进小鼠结肠癌的生长。因此，我们推测mGluR4通过上调TAM的免疫抑制作用，促进肿瘤免疫逃逸。本项目拟利用结肠癌模型①分析mGluR4对肿瘤免疫微环境的调节；②探究mGluR4对TAM功能的调节机制；③探究mGluR4通过TAM调节CD8+T细胞的增殖和功能的机制；④评价mGluR4对人巨噬细胞的调节作用。这一研究有助于深层次认识肿瘤微环境中mGluR4对巨噬细胞的调节作用及mGluR4介导的肿瘤免疫逃逸机制，为探索新的免疫治疗靶点提供线索。

Tumor-associated macrophages (TAM) are gradually converted from tumor-suppressing M1 into tumor-promoting M2 TAM, which play an important role in tumor progression. TAM The expression of metabotropic glutamate receptor (mGluR4) is negatively associated with colon cancer patient survival. Our preliminary data showed that mGluR4 predominately expressed in TAM. mGluR4 promoted the expression of immunosuppressive factor TGFβ and arginase 1, while suppressed CD8+ T cell proliferation and function. mGluR4 significantly promoted mouse colon cancer growth. We hypothesize that mGluR4 promoted immune evasion of colon cancer through promoting the immune-suppressive function of TAM. This study will ① analyze the regulatory effect of mGluR4 on TME, ② investigate the mechanism of mGluR4 regulating TAM functions, ③ explore how mGluR4 regulates CD8+ T cell proliferation and function via TAM and ④ assess the effect of mGluR4 on human macrophages. This study will provide an insight into the mechanism of mGluR4 regulating TAM in tumor microenvironment and mGluR4-mediated immune evasion, and clues for exploring new immunotherapy targets.