Abstract
Background: 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.Methods: 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.Results: 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.Conclusions: 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.
Highlights
PD-1 and its ligands, programmed death-ligand 1 (PD-L1) (Dong et al, 1999) and PD-L2 (Latchman et al, 2001), were shown to be part of an important family of molecules involved in tumor immunosuppression (Freeman et al, 2000; Brahmer et al, 2012)
We provide more evidence to support the finding that the regulation of PD-L1 known as cluster of differentiation 274 (CD274) glioma expression is directly associated with tumor isocitrate dehydrogenase 1 (IDH1) mutation status
Paired samples were derived from patients with three categories of tumor recurrence; LGG recurred to LGG (LGG-LGG), LGG recurred to GBM (LGG-GBM), and GBM recurred to GBM (GBM-GBM) were evaluated (Mu et al, 2017)
Summary
PD-1 and its ligands, programmed death-ligand 1 (PD-L1) (Dong et al, 1999) and PD-L2 (Latchman et al, 2001), were shown to be part of an important family of molecules involved in tumor immunosuppression (Freeman et al, 2000; Brahmer et al, 2012). Patients with IDH1 wildtype LGGs suffer from the most aggressive form of the disease and have overall survival (OS) that are strikingly similar to those of patients with GBMs, with a median overall survival of ∼1 year; treatment options are confined to surgery and chemo/radiation with dismal efficacy in these patients (EckelPassow et al, 2015; Suzuki et al, 2015; Ceccarelli et al, 2016) As a result, this population of patients is in desperate need of novel treatment approaches, such as the use of immune-checkpoint inhibitors or combinations featuring other treatment modalities. 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
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