A Radiosensitivity Gene Signature and PD-L1 Status Predict Clinical Outcome of Patients with Glioblastoma: Integrative Analyses of Transcriptome and Methylome

Abstract

Combination of radiation therapy and immune checkpoint blockade such as programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) blockade is being actively tested in clinical trial settings. Here, we tried to identify a subset of patients that could potentially benefit from this strategy using The Cancer Genome Atlas (TCGA) dataset for glioblastoma (GBM). Total 399 patients from TCGA GBM data set were clustered into radiosensitive (RS) versus radioresistant (RR) groups using 30 genes alleged to radiosensitivity. According to median value of CD274 mRNA expression, patients were stratified as PD-L1-High versus PD-L1-Low groups. Differentially expressed genes were identified, and enrichment analysis was performed as well. Differentially methylated regions were analyzed, and integrated into differentially expressed genes. A computational cell composition characterization tool was used for enumeration of various immune repertoire from transcriptome profile. We identified a subset of GBM, “PD-L1 high-RR group” which showed worse clinical outcome compared to the other groups. In this group, differentially expressed genes were highly enriched for immune response and mapped into activation of PI3K-AKT and MAPK signaling pathways. Integration of differentially expressed genes and differentially methylated region identified that MAP3K8 involved in T cell receptor signaling was upregulated and BA1, a factor which inhibits angiogenesis, was silenced. CIBERSORT showed that higher infiltration of immune repertoire contributed to immunosuppressive tumor microenvironment such as M2 macrophage and regulatory T cells. We validated the predictive value of a radiosensitivity gene signature and identified a subset, “PD-L1-High-RR group” which showed worse outcome following current standard therapy. The results of integrative analyses suggest that this group could potentially benefit from radiation therapy combined with PD-L1 blockade and angiogenesis inhibitor.