p57不同结构域对肝细胞肝癌免疫检查点抑制剂敏感性的影响及机制研究

PD-L1表达率低是导致肝癌免疫检查点抑制剂PD-1单抗疗效不佳的重要原因，如何提升肝癌细胞PD-L1表达及具体机制有待阐明。我们前期在肝癌组织中发现超过50%的肝癌患者存在p57表达降低或缺失，并与肝癌的恶性生物学行为及不良预后相关，p57下调在促进肝癌生长和侵袭同时，还与肝癌细胞PD-L1低表达相关，提示p57可能参与调控肝癌PD-L1的表达。文献表明CDK和JNK通路活化可以导致PD-L1表达降低。我们预实验发现p57可以通过其不同结构域直接抑制下游CDK和JNK通路。因此推测，p57的不同结构域可以通过抑制CDK和JNK通路促进肝癌细胞PD-L1表达，进而提高PD-1单抗的敏感性。基于此，本课题拟在临床病理、动物模型、肝癌细胞三个层面解析p57不同结构域对PD-L1表达的作用方式和调控机制，阐明p57对肝癌免疫检查点抑制剂敏感性的影响及治疗作用，为p57低表达肝癌的防治提供新思路。

The low expression of PD-L1 is the key point that leads to poor efficacy of anti-PD-1 inhibitor in hepatocellular carcinoma (HCC). There is an urgent need to improve the expression of PD-L1 and elucidate specific mechanisms in HCC cells. Through previous work we found that p57 signifificantly decreased in more than 50% of HCC patients, which was related to the malignant biological behavior and poor prognosis. Down-regulation of p57 not only promoted the growth and invasion of HCC, but also reduced the expression of PD-L1 in HCC cells, suggesting that p57 may involved in the regulation of PD-L1 expression. The literature indicates that activation of the CDK and JNK pathways can lead to decreased PD-L1 expression. Our preliminary experiments found that p57 could directly inhibit the downstream CDK and JNK pathways through its different domains. Therefore, it is speculated that different domains of p57 can promote the expression of PD-L1 by inhibiting the CDK and JNK pathways, and ultimately increase the sensitivity of anti-PD-1 inhibitor in HCC cells . Based on previous study, this project intends to analyze the role and regulation mechanism of different p57 domains on PD-L1 expression at levels of clinical pathology, animal models, and cancer cells, and test the effect of p57 on the sensitivity of anti-PD-1 inhibitor in HCC. The completion of this study will provide new ideas for the prevention and treatment of p57 low-expressing HCC.