口腔鳞癌微环境中PA28γ通过BCLAF1调控CTLA-4促进免疫逃逸的机制与意义

以免疫检查点抑制剂（ICI）为靶向的肿瘤免疫治疗近年备受关注（Cell,2017），但在多种肿瘤中响应不佳，机制不清。申请人前期发现口腔鳞癌（OSCC）肿瘤细胞中PA28γ可经外泌体传输至T细胞并与BCLAF1互作，靶向调控免疫检查点分子CTLA-4的表达。因此假定：OSCC微环境中PA28γ可通过BCLAF1调控CTLA-4促进肿瘤免疫逃逸。为验证此假说，首先采用基因改造细胞模型验证PA28γ参与肿瘤细胞和T细胞互作；其次蛋白修饰分析PA28γ调控BCLAF1的精细机制，同时转录修饰分析BCLAF1调控CTLA-4表达的路径；然后在临床队列中采用组织微环境景观分析PA28γ、BCLAF1和CTLA-4等表达规律及意义；最后采用转基因动物模型干预PA28γ/BCLAF1后行ICI治疗，评估PA28γ作为ICI治疗标志物的潜力，为寻求新的基于CTLA-4靶标的ICI治疗策略提供理论依据。

Tumor immunotherapy, represented by immune checkpoint inhibitor (ICI), has attracted great attention in recent years (Cell, 2017), but the response is poor in various tumor types, and the mechanism is unclear. The applicant found that PA28γ in tumor cells of oral squamous cell carcinoma could be transmitted to T cells by exosomes, and then interact with BCLAF1, thereby regulating the expression of CTLA-4. Therefore, it was assumed that PA28γ in OSCC microenvironment regulated CTLA-4 by BCLAF1 to promote tumor immune escape. To verify this hypothesis, firstly, we will use the genetically modified cell model to verify the mechanism and involvement of PA28γ in the interaction between tumor cells and T cells. Secondly, we will analyze the molecular mechanism of PA28γ regulating BCLAF1 by protein modification regulation. Thirdly, we will explore the mechanism of BCLAF1 regulating CTLA-4 expression by transcriptional regulation. Then, the expression patterns and significance of PA28γ, BCLAF1 and CTLA-4 proteins in cohort study will be analyzed through the microenvironmental landscape，. Finally, we will employ transgenic animal models to intervene PA28γ/BCLAF1, followed by ICI treatment, and evaluating the feasibility of PA28γ as a marker of ICI treatment. Moreover, it can provide an important theoretical basis to find out a new strategy for ICI treatment based on CTLA-4 target.