STAT3-CDK-pRb通路在延胡索酸堆积促进PD-L1介导肾癌免疫逃逸中的机制研究

FH缺陷型肾癌往往具有很强的侵袭性和早期扩散倾向，但目前关于其发病及进展机制的研究较少。国内外文献和我们最近的研究结果发现，FH缺陷型肾癌存在PD-L1高表达，肿瘤组织具有显著免疫浸润特征（“热肿瘤”为主），临床上也提示该肿瘤对免疫治疗有效。为探寻FH缺陷型肾癌PD-L1高表达的调控机制，本课题前期通过气相色谱质谱联用检测、RNA-seq、生物信息学分析、RT-PCR、Western blot等实验发现：FH基因缺陷导致延胡索酸堆积，进而诱导PD-L1上调，可能是通过STAT3-CDK-pRb信号通路实现。本课题拟在此基础上，深入研究STAT3-CDK-pRb信号轴在FH缺陷型肾癌免疫逃逸中的具体作用，并阐明该信号通路介导PD-L1上调的具体分子机制，为改善FH缺陷型肾癌免疫疗效和预后提供新思路。

FH-deficient renal cell carcinoma (FH-deficient RCC) often presents as aggressive and tends to spread early. Unfortunately, research on its pathogenesis and progression is insuficient. With the basis of published studies and our previous results, we found FH-defiecient RCC was characterized as high PD-L1 expression profile, with highly immune cell infiltration (“warm tumor”) and sentitive to immuno-oncology (IO)-based treatment. In order to explore potential mechanism of high PD-L1 expression in FH-deficient RCC, we used Gas Chromatography-Mass Spectrometry, RNA-seq, bioinformatics analysis, RT-PCR, Western blot to demonstrated that PD-L1 mediated immune escape caused by fumaric acid accumulation may be realized through STAT3-CDK-pRB signaling pathway in FH-defiecient RCC. On this basis, we intends to further study the specific role of STAT3-CDK-PRB signal pathway in immune escape of FH-deficient RCC, and elucidate the specific molecular mechanism of PD-L1 upregulation mediated by this signal pathway, so as to provide insights to improve the immunotherapy efficacy and prognosis of FH-deficient RCC.