TP53INP1调控PD-1/PD-L1轴与肿瘤干细胞干性介导膀胱癌免疫逃逸的机制研究

免疫逃逸与膀胱癌的复发、进展密切相关。近期研究显示免疫检查点PD-1/PD-L1轴以及肿瘤干细胞是促进肿瘤免疫逃逸的重要因素。本项目组在前期研究中发现高表达TP53INP1的膀胱癌患者预后较好，敲低TP53INP1后膀胱癌细胞中PD-L1表达升高且肿瘤干细胞相关因子（CD44、Oct4、Sox2、Bim1、HMGA2、ALDH1A1）表达升高；金雀异黄酮可上调TP53INP1的表达并促进膀胱癌细胞凋亡。因此我们推测，TP53INP1可通过PD-1/PD-L1信号轴及肿瘤干细胞干性调控膀胱癌细胞的免疫逃逸。本项目中，我们拟通过细胞生物学、分子生物学、药理学和实验动物学等技术与方法，阐明TP53INP1对PD-1/PD-L1轴与肿瘤干细胞干性介导的免疫逃逸的作用与机制，探索以TP53INP1和PD-1/PD-L1轴为靶点的联合治疗效果，为膀胱癌的诊断、预后以及免疫治疗提供临床前实验依据。

Immune escape is closely related to the recurrence and progression of bladder cancer. Recent studies have shown that PD-1/PD-L1 axis and cancer stem cell (CSC) are important factors in promoting tumor immune escape. Our previous study demonstrated that patient with high expression of TP53INP1 got better prognosis in bladder cancer. After knocking down TP53INP1, the expression of PD-L1 increased in bladder cancer cells, and cancer stemness-regulating factors (CD44, Oct4, Sox2, Bim1, HMGA2, ALDH1A1) expression are elevated. And Genistein can up-regulate the expression of TP53INP1 and promote apoptosis of bladder cancer cells. Therefore, we hypothesized that TP53INP1 can regulate the immune escape of bladder cancer cells through PD-1/PD-L1 axis and cancer stemness. In this project, we intend to elucidate the regulatory effect and mechanism of TP53INP1 on PD-1/PD-L1 axis and cancer stemness mediated immune escape by techniques and methods such as cell biology, molecular biology, pharmacology and experimental zoology. And exploring the combined treatment effect of targeting TP53INP1 and blocking PD-1/PD-L1 axis in bladder cancer immunotherapy, and providing preclinical experimental basis for the diagnosis, prognosis and immunotherapy of bladder cancer.