COX通路对肝癌组织中PD-L1表达模式的影响及机制

The expression of PD-L1 in tumor tissue could induce tumor immune escape and disease progression; also it could be a biomarker for immunotherapy. We recently found that PD-L1 was expressed on tumor cell (TC) or/and macrophage (Mφ) in the tumor tissue of hepatocellular carcinoma (HCC) patients; however, the different expression patterns of PD-L1 were correlated with opposite outcomes of HCC patients. Whole-genome microarray analysis revealed that COX pathway was associated with PD-L1 expression patterns and the inhibitor of COX pathway could reduce PD-L1 expression in vitro. Based on these observations, we will combine clinical sample analysis and experimental studies to: 1) Examine the correlation and clinical value of COX pathway and PD-L1 expression patterns in HCC; 2) Compare the role of COX pathway in TC and Mφ, and also in the interaction between two cell types; 3) Define the key molecules/markers that influence COX pathway and its mechanism in regualting PD-L1 expression. 4) Explore the potential impact of inhibiting COX pathway in anti-PD-1/PD-L1 therpay and the clinic application of combination therapy. The prospective results would not only help to unveil the novel mechanisms of PD-L1 regulation in HCC, but would also contribute to the alternative rationale and effective strategy for immunotherapy.

PD-L1在肿瘤组织中的表达既可诱导免疫逃逸与疾病进展，又是反映个体对免疫治疗应答的重要指标。我们新近发现，PD-L1在肝癌中可表达在肿瘤细胞（TC）或/和巨噬细胞（Mφ）上，但这两类不同的PD-L1表达模式却对临床预后呈现完全相反的作用。我们经全基因组芯片分析已筛选到COX通路与PD-L1的不同表达模式相关；而COX通路抑制剂能在体外抑制PD-L1的表达。以此为基础，本项目拟结合临床样本与实验模型：1）进一步明确肝癌组织中COX通路及分子与PD-L1表达模式的相关性和临床意义；2）比较COX通路在TC和Mφ及两类细胞相互作用过程中对PD-L1表达的影响。3）阐明肝癌组织中COX通路紊乱及其对PD-L1表达调控的机制与关键调控分子。4）探讨COX通路对抗PD-L1/PD-1治疗的影响及相关联合治疗的潜在临床应用。所得结果将揭示肝癌中PD-L1表达调控的新机制，为有效的免疫治疗提供新思路。

肿瘤组织中PD-L1分子的表达是影响抗PD-1/PD-L1治疗的重要因素，但目前对其在组织中的表达调控机制尚不完全清楚。本研究以肝癌临床样本为基础，结合表达谱芯片及体外实验模型，阐述了PD-L1在肝癌癌巢中的不同表达模式和临床意义，提示Mo/Mφ表达PD-L1可能可以作为筛选适合anti-PD1/PD-L1治疗患者的潜在指标。机制研究揭示了Aspirin可部分通过COXs的抑制活性以及抑制STAT1通路磷酸化来调控PD-L1的表达；同时发现了表观遗传修饰分子EZH2可通过上调PD-L1及其转录因子IRF-1基因启动子上H3K27me3的水平从而抑制IFNγ诱导的PD-L1表达。这些结果揭示了肝癌微环境中PD-L1表达的意义和新的调控机制，有望为临床开发更有效的抗肿瘤联合治疗方案提供新的思路。