Abstract
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.
Highlights
Gliomas are the most common primary brain tumors accounting for approximately 80% of all brain malignancies in the United States (Ostrom et al, 2016)
We found a significant inverse correlation between gene methylation and mRNA expression levels for PD-1 ligand 1 (PD-L1), PD-L2 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) (PD-L1: ρ = − 0.136, p = 0.005; PD-L2: ρ = −0.642, p b 0.001; CTLA-4: ρ = −0.249, p b 0.001), while no correlation was present for programmed cell death 1 receptor (PD-1) (ρ = 0.020, p = 0.68)
Immune checkpoint promoter methylation was significantly associated with patients' age (PD-L2: p = 0.003; PD-1: p = 0.015), O6-methylguanine DNA methyltransferase(MGMT) methylation (PD-L1: p b 0.001; PDL2: p b 0.001), ATRX mutations (PD-L2: p b 0.001, PD-1: p = 0.001), telomerase reverse transcriptase (TERT) mutations (PD-L1: p = 0.035, PD-L2: p b 0.001, PD-1: p b 0.001, CTLA4: p b 0.001), and methylation subgroups (LGm1, LGm2 and LGm3; PD-L1: p b 0.001, PD-L2: p b 0.001, PD-1: p = 0.001, CTLA4: p b 0.001)
Summary
Gliomas are the most common primary brain tumors accounting for approximately 80% of all brain malignancies in the United States (Ostrom et al, 2016). Diffuse lower-grade gliomas (LGG) often present with very variable clinical appearances and survival rates before fatally progressing to glioblastoma multiforme (Cancer Genome Atlas Research Network et al, 2015). Recent developments in genomic profiling have led to a paradigm shift in the classification of gliomas. The 2016 World Health Organization (WHO) classification includes the molecular characterization of primary brain tumors (e.g. isocitrate dehydrogenase (IDH) mutations and codeletions of. Recent evidence suggests that DNA methylation profiles might shed light on significantly differing outcomes. Unsupervised cluster analysis of 1122 grade II-III-IV gliomas from The Cancer Genome Atlas (TCGA) identified six methylation groups (LGm1–6) that were in part associated with IDH status and further discovered an epigenetic signature that segregated a subgroup of IDH-mutant diffuse lower-grade gliomas with unfavorable clinical outcome (Ceccarelli et al, 2016). As D-2HG inhibits key enzymes involved in histone- and DNA-demethylation, excess D-2HG results in DNA
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