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Abstract：
Despite the successful application of programmed cell death ligand 1 (PD-L1)-blocking strategies in some types of cancers and well-established prognostic indicators in pancreatic ductal adenocarcinoma (PDAC), the biological and clinical implications of the methylation status of PD-L1/PD-L2 in PDAC remain largely unknown. Therefore, this study aimed to explore the biological role of PD-L1/PD-L2 methylation and its association with clinicopathological features, clinical outcomes, and the immune microenvironment by analyzing the data on PD-L1/PD-L2 methylation and mRNA expression in PDAC cohorts obtained from the Cancer Genome Atlas and International Cancer Genome Consortium. The correlation between PD-L1 promoter methylation and PD-L1 expression and survival was further validated in an independent validation cohort (Peking Union Medical College Hospital [PUMCH] cohort) using pyrosequencing and immunohistochemistry. These results demonstrated that hypomethylation of the PD-L1 promoter was strongly associated with upregulated PD-L1 expression and shorter overall survival in PDAC. Multivariate Cox regression analyses revealed that the PD-L1 promoter methylation was an independent prognostic factor. PD-L1 promoter hypomethylation and high expression were related to aggressive clinical phenotypes. Moreover, both PD-L1 and PD-L2 methylation correlated with immune cell infiltration and the expression of immune checkpoint genes. PD-L1 promoter methylation status was further validated as an independent prognostic biomarker in patients with PDAC using the PUMCH cohort. The prognostic significance of PD-L1 promoter methylation was more discriminative in tumors with perineural/lymphovascular invasion and distant metastasis than in those without perineural/lymphovascular invasion and distant metastasis. In summary, the methylation status of the PD-L1 promoter is a promising biomarker for survival outcomes, immune infiltration, and the potential immune benefits of immunotherapy in PDAC.
摘要：
尽管在某些类型的癌症中成功应用了程序性细胞死亡配体1（PD-L1）阻断策略，并在胰腺导管腺癌（PDAC）中建立了完善的预后指标，PDAC中PD-L1/PD-L2甲基化状态的生物学和临床意义仍不清楚.因此,本研究旨在探讨PD-L1/PD-L2甲基化的生物学作用及其与临床病理特征,临床结果，和免疫微环境，通过分析从癌症基因组图谱和国际癌症基因组联盟获得的PDAC队列中PD-L1/PD-L2甲基化和mRNA表达的数据。在独立验证队列（北京协和医院[PUMCH]队列）中，使用焦磷酸测序和免疫组织化学进一步验证了PD-L1启动子甲基化与PD-L1表达和生存之间的相关性。这些结果表明PD-L1启动子的低甲基化与PDAC中上调的PD-L1表达和较短的总生存期密切相关。多因素Cox回归分析显示PD-L1启动子甲基化是独立的预后因素。PD-L1启动子低甲基化和高表达与侵袭性临床表型有关。此外，PD-L1和PD-L2甲基化均与免疫细胞浸润和免疫检查点基因表达相关。使用PUMCH队列进一步验证PD-L1启动子甲基化状态作为PDAC患者的独立预后生物标志物。PD-L1启动子甲基化在有神经周/淋巴血管浸润和远处转移的肿瘤中的预后意义比没有神经周/淋巴血管浸润和远处转移的肿瘤更具区别性。总之,PD-L1启动子的甲基化状态是一个有希望的生存结果的生物标志物，免疫浸润，以及免疫疗法在PDAC中的潜在免疫益处。
