PBRM1通过TRAF6/EZH2通路抑制肾癌CD8+T细胞浸润及肾癌免疫治疗抵抗的机制

靶向PD-1/L1免疫治疗给转移性肾癌患者带来了新希望，但临床缓解率仅30%，机制不清楚。CD8+T细胞浸润是免疫治疗的关键因素。我们发现约75.9%肾癌存在PBRM1蛋白表达缺失，并伴随CD8+T细胞浸润减少，而PBRM1过表达通过E3泛素连接酶TRAF6促进EZH2蛋白降解，增加CXCL9/10的表达。因此我们推测，肾癌PBRM1表达缺失抑制TRAF6表达，导致EZH2蛋白稳定性增加，进而抑制CXCL9/10转录，最终引起CD8+T细胞浸润减少，产生PD-1/L1免疫治疗抵抗。本项目拟通过分子生物学手段，以肾癌小鼠模型和临床标本等为研究对象，明确PBRM1表达缺失是否为影响CD8+T细胞浸润及免疫治疗的关键因素及其分子机制，探讨EZH2抑制剂联合PD-L/L1抑制剂在PBRM1缺失转移性肾癌治疗中的应用价值。本项目有望解释肾癌PD-1/L1免疫治疗抵抗的原因，探索联合免疫治疗新策略。

PD-1/L1 inhibitor immunotherapy brings new hope to metastatic renal cell carcinoma (RCC) patients, however， the clinical response rate is only 30%, and the mechanism is unknown. CD8+T cell infiltration is a key factor in immunotherapy. We found that about 75.9% of RCC had a loss of expression tumor suppressor gene PBRM1 protein, and accompanied by CD8+T cell infiltration decreasing. PBRM1 low expression was accompanied by reducing CD8+T cell infiltration. We found that PBRM1 promoted the ubiquitination of EZH2 protein by regulating E3 ubiquitin ligase TRAF6, and EZH2 inhibited the transcription of chemokine CXCL9/10. Therefore, we speculate that loss of PBRM1 expression inhibits the expression of TRAF6, and leading to increase EZH2 protein stability, which in turn inhibits the transcription of CXCL9/10, and reducing the infiltration of CD8+T cell. Molecular biology experiments, mouse models and clinical specimens will be used to investigate the mechanism of PBRM1 regulating CD8+T cell infiltration, and the effect on immunotherapy in this project. Meanwhile, the potential of EZH2 inhibitors combined with PD-1/L1 inhibitors as a novel therapeutic strategy for the treatment of PBRM1 low expression metastatic RCC patients will be study in our project. We will to explore the reasons of PD-1/L1 immunotherapy resistance and provide new strategy for combined immunotherapy in RCC.