Pik3ip1-Serpinb2结合调控肿瘤免疫微环境T细胞耗竭的机制研究

T细胞免疫检查点抑制剂可逆转肿瘤微环境T细胞耗竭状态，是肿瘤免疫治疗的重要手段，但总体有效率仍较低，亟需深入探究其机制。申请人前期研究显示Pik3ip1可发挥免疫检查点样功能，可能介导T细胞耗竭，并鉴定出其在免疫微环境中的配体蛋白Serpinb2，体外实验显示Pik3ip1-Serpinb2结合可抑制T细胞功能，因此提出假说：Pik3ip1-Serpinb2结合调控肿瘤免疫T细胞耗竭。本研究拟进一步利用口腔鳞癌等实体瘤临床队列、Pik3ip1和Serpinb2重组蛋白、阻断性单抗及基因敲除鼠，OT-1TCR转基因鼠,构建4NQO口腔诱癌、EG7/B16-OVA皮下成瘤模型，评估免疫微环境中Serpinb2表达与临床预后相关性，探究Pik3ip1-Serpinb2结合对抗原特异性T细胞抗肿瘤反应及肿瘤生长的影响，其调控T细胞耗竭的机制及其阻断抗体逆转T细胞耗竭行肿瘤免疫治疗的潜能和机制。

Immune checkpoint inhibitors can reverse the exhaustion state of T cells in tumor microenvironment, which is an important method of tumor immunotherapy, but the overall efficacy is still low, thus it is urgent to explore the mechanism. According to the applicants' previous studies, Pik3ip1 may act as an immune checkpoint in mediating T cell exhaustion, and we have identified its ligand on the immune cells, Serpinb2. Previous in vitro experiments showed that Pik3ip1-Serpinb2 binding inhibited T cell response, thus the hypothesis is proposed: Pik3ip1-Serpinb2 binding regulates T cell exhaustion in antitumor immunity. This study plans to further evaluate the correlation between clinical prognosis and SERPINB2 expression in immune microenvironment, explore the effect of Pik3ip1-SerpinB2 binding on antitumor response of antigen-specific T cells and tumor growth, the mechanism of mediating T cell exhaustion and the potential and mechanism of its blockade antibodies to reverse the T cell exhaustion in tumor immunotherapy by using the clinical cohort of solid tumor such as oral squamous cell carcinoma, Pik3ip1 and Serpinb2 recombinant protein, blocking monoclonal antibodies, and constructing 4NQO-induced oral cancer model and EG7/ B16-OVA subcutaneous tumor model with Pik3ip1/Serpinb2 knockout mice and OT-1 and OT-2 TCR transgenic mice.