Mu Luyan, Long Yu, Yang Changlin, Jin Linchun, Tao Haipeng, Ge Haitao, Chang Yifan E, Karachi Aida, Kubilis Paul S, De Leon Gabriel, Qi Jiping, Sayour Elias J, Mitchell Duane A, Lin Zhiguo, Huang Jianping
The Fourth Section of Department of Neurosurgery, The First Affiliated Hospital, Harbin Medical University, Harbin, China.
The First Section of Department of Neurosurgery, The Fourth Affiliated Hospital, Harbin Medical University, Harbin, China.
Front Mol Neurosci. 2018 Mar 28;11:82. doi: 10.3389/fnmol.2018.00082. eCollection 2018.
Malignant gliomas are heterogeneous brain tumors with the potential for aggressive disease progression, as influenced by suppressive immunoediting. Given the success and enhanced potential of immune-checkpoint inhibitors in immunotherapy, we focused on the connections between genetic alterations affected by IDH1 mutations and immunological landscape changes and PDL-1 expression in gliomas. Paired surgically resected tumors from lower-grade gliomas (LGGs) and glioblastomas (GBM) were investigated, and a genetic analysis of patients' primary tumor samples culled from TCGA datasets was performed. The results demonstrate that when compared with IDH1-mutant tumors, IDH1 wildtype tumors represent an immunosuppression landscape and elevated levels of PD-L1 expression. DNA hypo-methylation of the PD-L1 gene, as well as high gene and protein expressions, were observed in the wildtype tumors. We also found that quantitative levels of IDH1 mutant proteins were positively associated with recurrence-free survival (RFS). A key product of the IDH1 mutation (2-hydroxyglutarate) was found to transiently increase DNA methylation and suppress PD-L1 expression. IDH1 mutations impact the immune landscape of gliomas by affecting immune infiltrations and manipulating checkpoint ligand PD-L1 expression. Applications of immune checkpoint inhibitors may be beneficial for chemoradiation-insensitive IDH1-wildtype gliomas.
恶性胶质瘤是一种异质性脑肿瘤，受免疫抑制性免疫编辑的影响，具有侵袭性疾病进展的潜力。鉴于免疫检查点抑制剂在免疫治疗中的成功应用及其增强的潜力，我们重点研究了IDH1突变影响的基因改变与胶质瘤免疫格局变化以及PDL-1表达之间的联系。我们对来自低级别胶质瘤（LGG）和成胶质细胞瘤（GBM）的配对手术切除肿瘤进行了研究，并对从TCGA数据集中筛选出的患者原发性肿瘤样本进行了基因分析。结果表明，与IDH1突变型肿瘤相比，IDH1野生型肿瘤呈现出免疫抑制格局且PD-L1表达水平升高。在野生型肿瘤中观察到PD-L1基因的DNA低甲基化以及高基因和蛋白表达。我们还发现IDH1突变蛋白的定量水平与无复发生存期（RFS）呈正相关。发现IDH1突变的一个关键产物（2-羟基戊二酸）可短暂增加DNA甲基化并抑制PD-L1表达。IDH1突变通过影响免疫浸润和调控检查点配体PD-L1表达来影响胶质瘤的免疫格局。免疫检查点抑制剂的应用可能对放化疗不敏感的IDH1野生型胶质瘤有益。
