酪氨酸磷酸酶Shp2调控肿瘤相关巨噬细胞功能促进肿瘤免疫逃逸的机制研究

肿瘤相关巨噬细胞(TAM)是介导肿瘤免疫逃逸的关键因素，其功能主要受肿瘤微环境影响，寻找调控TAM功能的分子靶点对于肿瘤免疫治疗具有重要意义。酪氨酸磷酸酶Shp2作为一种癌基因，是当前肿瘤靶向药物研发的新热点，我们以往的研究表明Shp2与巨噬细胞的可塑性密切相关，但其在肿瘤免疫中的作用尚不清晰。本研究经预实验发现，巨噬细胞中Shp2的缺失显著抑制了肿瘤生长，初步分析Shp2可能通过上调TAM中免疫抑制分子PD-L1的表达，抑制了CD8+ T细胞介导的抗肿瘤应答，导致肿瘤的免疫逃逸。基于此，本项目拟利用已构建的巨噬细胞Shp2敲除小鼠作为研究工具，明确Shp2在PD-L1介导的肿瘤免疫逃逸中的作用，及其通过调控TAM功能对CD8+ T细胞增殖、活化的影响，同时进一步明晰Shp2调节TAM磷酸化信号传导的方式。本课题预期为靶向Shp2的肿瘤干预新策略从免疫学角度提供理论基础与实验依据。

Tumor-associated macrophages (TAMs) play critical roles in mediating tumor immune evasion, elucidating the molecular targets responsible for shaping the function of TAMs in tumor microenvironment is pivotal for improving the efficacy of tumor immunotherapy. As an oncogene, phosphatase Shp2 is recently reported to have the potential to become novel anti-tumor agent. However, whether Shp2 participate in the modulation of TAM functions is poorly understood. We have previously indicated the involvement of Shp2 in regulating macrophage plasticity, and in our present project, we observed that Shp2 deficiency in macrophages significantly inhibited tumor growth, further investigations suggested that Shp2 might hamper CD8+ T cell-mediated anti-tumor immune response by upregulating the expression of immunoinhibitory molecule PD-L1 on TAMs. Based on these findings, we plan to further explore the effect of Shp2 on PD-L1-mediated tumor immune evasion as well as the improper proliferation or activation of CD8+ T cells, by regulating TAM functions. We will also investigate the mechanisms by which Shp2 affects the signaling transduction events in TAMs. Our project will help to provide theoretical and experimental clues for Shp2-based tumor intervention strategy from an immune perspective .