免疫检查点分子在子宫内膜癌中的表达及临床意义

Expression of Immune Checkpoint Molecules in Endometrial Carcinoma and Its Clinical Significance

目的:免疫检查点抑制剂在多种实体肿瘤中疗效显著,但是在子宫内膜癌中尚未大规模应用。研究表明程序性死亡蛋白1(programmed death protein-1, PD-1)/程序性死亡蛋白配体1 (programmed death protein-ligand 1, PD-L1)在POLE突变型、微卫星不稳定型(microsatellite instability,MSI)子宫内膜癌中表达升高,而其他免疫检查点分子的表达情况并不清楚。本研究旨在全面分析多种免疫检查点分子在子宫内膜癌中的表达及临床意义。方法:通过分析TCGA数据库中最新子宫内膜癌数据,比较多种免疫检查点分子与病理类型、分子亚型、患者预后的关系。结果:采用外显子及RNA测序数据对子宫内膜癌进行分子分型,分型结果与以往研究一致性较高。免疫抑制分子PD-1/PD-L1、CTLA-4/CD80和LAG-3在POLE突变型、MSI型子宫内膜癌中高表达。FGL1作为LAG-3配体,在MSI型和无特异性分子变异(NSMP)亚型中高表达。受体分子PD-1、CTLA-4、TIM-3、LAG-3高表达与患者总生存期延长相关。FGL1高表达与总生存及无复发生存延长显著相关,其他配体分子与预后相关性无统计学意义。FGL1在子宫内膜样癌中显著高表达,而在浆液性/混合型癌中表达较低。FGL1与多种淋巴细胞、巨噬细胞丰度无显著相关性,提示该基因可能主要表达于癌细胞。此外,FGL1高表达肿瘤中肿瘤突变负荷显著升高。结论:除PD-1/PD-L1外,其他免疫检查点分子(如LAG-3/FGL1)也在子宫内膜癌中异常表达,这为该类疾病的免疫治疗提供了新思路。

Objective: Immune checkpoint inhibitor treatment is effective in several solid tumors, but they have not been widely used in endometrial carcinoma ( EC). Previous studies have shown that programmed death protein-1 ( PD-1)/programmed death protein-ligand 1 ( PD-L1) is significantly elevated in POLE mutant EC and EC with MSI, while the expression of other immune checkpoint molecules is not yet clearly known. The purpose of this study is to comprehensively analyze the expression of various immune checkpoint molecules in EC and its clinical significance. Methods: By analyzing the EC data in TCGA database, this study investigated the relationship between various immune checkpoint molecules and EC molecular subtypes, pathological types and prognosis of patients. Results: First, we used exon sequencing and RNA sequencing data to classify molecular subtypes of EC. The classification results were consistent with previous studies. We found that the immune checkpoint molecules, PD-1 /PD-L1, CTLA-4 /CD80 and LAG-3 /FGL1, were highly expressed in POLE mutant EC and EC with MSI. FGL1 was highly expressed in MSI and no specific molecular profile subtypes. High expression of PD-1, CTLA-4, TIM-3 and LAG-3 was associated with prolonged overall survival. High-expression of FGL1 was significantly associated with prolonged overall survival and relapse-free survival, while other ligands were not significantly associated with prognosis. FGL1 was highly expressed in endometrioid carcinomas, and the expression of FGL1 was relatively low in serous or mixed tumors. FGL1 was not significantly correlated with the abundance of various lymphocytes and macrophages, suggesting that FGL1 may be expressed by cancer cells. In addition, the tumor mutation burden was significantly higher in FGL1-high tumors than in FGL1-low tumors. Conclusion: In addition to PD-1 /PDL1, other immunosuppressive pathways ( especially LAG-3 /FGL1) are dysregulated in EC, which suggests novel potential strategies for EC immunotherapy.