Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
Department of Dermatology, Yale School of Medicine, New Haven, Connecticut.
Pigment Cell Melanoma Res. 2019 May;32(3):435-440. doi: 10.1111/pcmr.12745. Epub 2018 Nov 22.
The aim of this study is to determine the significance of programmed death ligand 1 (PD-L1 or CD274) methylation in relation to PD-L1 expression and survival in melanoma. Despite the clinical importance of therapies targeting the PD-1/PD-L1 immune checkpoint in melanoma, factors regulating PD-L1 expression, including epigenetic mechanisms, are not completely understood. In this study, we examined PD-L1 promoter methylation in relation to PD-L1 expression and overall survival in melanoma patients. Our results suggest that DNA methylation regulates PD-L1 expression in melanoma, and we identify the key methylated CpG loci in the PD-L1 promoter, establish PD-L1 methylation as an independent survival prognostic factor, provide proof of concept for altering PD-L1 expression by hypomethylating agents, and uncover that PD-L1 methylation is associated with an interferon signaling transcriptional phenotype. Based on our findings, measuring and altering PD-L1 promoter DNA methylation may have potential prognostic and therapeutic applications in melanoma.
本研究旨在确定程序性死亡配体 1 (PD-L1 或 CD274) 甲基化与黑色素瘤中 PD-L1 表达和生存的关系。尽管针对 PD-1/PD-L1 免疫检查点的治疗在黑色素瘤中具有重要的临床意义，但包括表观遗传机制在内的调节 PD-L1 表达的因素尚不完全清楚。在这项研究中，我们研究了 PD-L1 启动子甲基化与黑色素瘤患者 PD-L1 表达和总生存的关系。我们的结果表明，DNA 甲基化调节黑色素瘤中的 PD-L1 表达，我们确定了 PD-L1 启动子中关键的甲基化 CpG 位点，将 PD-L1 甲基化确立为独立的生存预后因素，提供了通过低甲基化剂改变 PD-L1 表达的概念验证，并揭示了 PD-L1 甲基化与干扰素信号转导转录表型相关。基于我们的发现，测量和改变 PD-L1 启动子 DNA 甲基化可能在黑色素瘤中具有潜在的预后和治疗应用。
