Department of Otolaryngology, Head and Neck Surgery, University Hospital Bonn, Bonn, Germany.
Institute of Pathology, University Hospital Bonn, Bonn, Germany.
EBioMedicine. 2018 Feb;28:97-104. doi: 10.1016/j.ebiom.2018.01.016. Epub 2018 Jan 31.
Immune checkpoints are important targets for immunotherapies. However, knowledge on the epigenetic modification of immune checkpoint genes is sparse. In the present study, we investigated promoter methylation of CTLA4, PD-L1, PD-L2, and PD-1 in diffuse lower-grade gliomas (LGG) harboring isocitrate dehydrogenase (IDH) mutations with regard to mRNA expression levels, clinicopathological parameters, previously established methylation subtypes, immune cell infiltrates, and survival in a cohort of 419 patients with IDH-mutated LGG provided by The Cancer Genome Atlas. PD-L1, PD-L2, and CTLA-4 mRNA expression levels showed a significant inverse correlation with promoter methylation (PD-L1: p=0.005; PD-L2: p<0.001; CTLA-4: p<0.001). Furthermore, immune checkpoint methylation was significantly associated with age (PD-L2: p=0.003; PD-1: p=0.015), molecular alterations, i.e. MGMT methylation (PD-L1: p<0.001; PD-L2: p<0.001), ATRX mutations (PD-L2: p<0.001, PD-1: p=0.001), and TERT mutations (PD-L1: p=0.035, PD-L2: p<0.001, PD-1: p<0.001, CTLA4: p<0.001) as well as methylation subgroups and immune cell infiltrates. In multivariate Cox proportional hazard analysis, PD-1 methylation qualified as strong prognostic factor (HR=0.51 [0.34-0.76], p=0.001). Our findings suggest an epigenetic regulation of immune checkpoint genes via DNA methylation in LGG. PD-1 methylation may assist the identification of patients that might benefit from an alternative treatment, particularly in the context of emerging immunotherapies.
免疫检查点是免疫疗法的重要靶点。然而，关于免疫检查点基因的表观遗传修饰知之甚少。在本研究中，我们调查了 IDH 突变的弥漫性低级别胶质瘤（LGG）中 CTLA4、PD-L1、PD-L2 和 PD-1 的启动子甲基化情况，并结合来自癌症基因组图谱（TCGA）的 419 名 IDH 突变型 LGG 患者的 mRNA 表达水平、临床病理参数、先前建立的甲基化亚型、免疫细胞浸润和生存情况进行分析。PD-L1、PD-L2 和 CTLA-4 的 mRNA 表达水平与启动子甲基化呈显著负相关（PD-L1：p=0.005；PD-L2：p<0.001；CTLA-4：p<0.001）。此外，免疫检查点甲基化与年龄（PD-L2：p=0.003；PD-1：p=0.015）、分子改变（即 MGMT 甲基化（PD-L1：p<0.001；PD-L2：p<0.001）、ATRX 突变（PD-L2：p<0.001，PD-1：p=0.001）和 TERT 突变（PD-L1：p=0.035，PD-L2：p<0.001，PD-1：p<0.001，CTLA4：p<0.001）以及甲基化亚群和免疫细胞浸润显著相关。在多变量 Cox 比例风险分析中，PD-1 甲基化被确定为强预后因素（HR=0.51 [0.34-0.76]，p=0.001）。我们的研究结果表明，在 LGG 中，免疫检查点基因通过 DNA 甲基化实现表观遗传调控。PD-1 甲基化可能有助于识别可能受益于替代治疗的患者，特别是在新兴免疫疗法的背景下。
