Institute of Neurology, Medical University of Vienna, Vienna, Austria; Department of Medicine I, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Neurosurgery, Medical University of Vienna, Vienna, Austria; Department of Genome Science, The John Curtin School of Medical Research, The Australian National University, Canberra, Australia; Laboratory of Brain Tumor Biology and Genetics, Service of Neurosurgery & Neuroscience Research Center, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
Neuro Oncol. 2017 Oct 19;19(11):1460-1468. doi: 10.1093/neuonc/nox054.
BACKGROUND: Tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) are targets of immune checkpoint inhibitors. METHODS: Forty-three World Health Organization (WHO) grade II/III gliomas (39 IDH-mutant [mut], 4 IDH-wildtype [wt]) and 14 IDH-mut glioblastomas (GBM) were analyzed for TIL (CD3+; PD1+) infiltration and PD-L1 expression. Results were compared with the data of a previously published series of 117 IDH-wt glioblastomas. PD-L1 gene expression levels were evaluated in 677 diffuse gliomas grades II-IV from The Cancer Genome Atlas (TCGA) database. RESULTS: TIL and PD-L1 expression were observed in approximately half of WHO grade II/III gliomas. IDH-wt status was associated with significantly higher TIL infiltration and PD-L1 expression among all (grades II-IV) cases (n = 174, P < 0.001) and within the cohort of glioblastomas (n = 131, P < 0.001). In low-grade glioma (LGG) and glioblastoma cohorts of TCGA, significantly higher PD-L1 gene expression levels were evident in IDH-wt compared with IDH-mut samples (LGG: N = 516; P = 1.933e-11, GBM: N = 161; P < 0.009). Lower PD-L1 gene expression was associated with increased promoter methylation (Spearman correlation coefficient -0.36; P < 0.01) in the LGG cohort of TCGA. IDH-mut gliomas had higher PD-L1 gene promoter methylation levels than IDH-wt gliomas (P < 0.01). CONCLUSIONS: The immunological tumor microenvironment of diffuse gliomas differs in association with IDH mutation status. IDH-wt gliomas display a more prominent TIL infiltration and higher PD-L1 expression than IDH-mut cases. Mechanistically this may be at least in part due to differential PD-L1 gene promoter methylation levels. Our findings may be relevant for immune modulatory treatment strategies in glioma patients.
背景：肿瘤浸润淋巴细胞（TILs）和程序性死亡配体 1（PD-L1）是免疫检查点抑制剂的靶点。
方法：分析了 43 例世界卫生组织（WHO）二级/三级胶质瘤（39 例 IDH 突变[mut]，4 例 IDH 野生型[wt]）和 14 例 IDH 突变的胶质母细胞瘤（GBM）的 TIL（CD3+；PD1+）浸润和 PD-L1 表达情况。结果与之前发表的 117 例 IDHwt 胶质母细胞瘤系列的结果进行了比较。评估了癌症基因组图谱（TCGA）数据库中 677 例弥漫性胶质瘤 II-IV 级的 PD-L1 基因表达水平。
结果：约一半的 WHO 二级/三级胶质瘤观察到 TIL 和 PD-L1 表达。在所有（II-IV 级）病例（n=174，P<0.001）和胶质母细胞瘤队列（n=131，P<0.001）中，IDHwt 状态与 TIL 浸润和 PD-L1 表达显著相关。在 TCGA 的低级别胶质瘤（LGG）和胶质母细胞瘤队列中，与 IDHmut 样本相比，IDHwt 样本的 PD-L1 基因表达水平明显更高（LGG：N=516；P=1.933e-11，GBM：N=161；P<0.009）。在 TCGA 的 LGG 队列中，较低的 PD-L1 基因表达与启动子甲基化呈负相关（Spearman 相关系数-0.36；P<0.01）。IDHmut 胶质瘤的 PD-L1 基因启动子甲基化水平高于 IDHwt 胶质瘤（P<0.01）。
结论：弥漫性胶质瘤的免疫肿瘤微环境与 IDH 突变状态有关。与 IDHmut 病例相比，IDHwt 胶质瘤显示出更明显的 TIL 浸润和更高的 PD-L1 表达。从机制上讲，这至少部分是由于 PD-L1 基因启动子甲基化水平的差异。我们的发现可能与胶质母细胞瘤患者的免疫调节治疗策略相关。
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