A Radiosensitivity Gene Signature and PD-L1 Status Predict Clinical Outcome of Patients With Lower Grade Glioma in the Cancer Genome Atlas Dataset

Abstract

A radiosensitivity gene signature that included 31 genes was identified using microarray data from NCI-60 cancer cells. This study was aimed to validate 31 genes signature in lower grade glioma (LGG) data set and also investigate the relationship between this gene signature, programmed cell death ligand 1 (PD-L1) status, and clinical outcome in order to identify a group of patients that would be beneficial for radiotherapy (RT) combined with anti-PD1/PD-L1 therapy. We validated the 31-gene signature related to radiosensitivity and evaluated the PD-L1 status of lower grade glioma in The Cancer Genome Atlas (TCGA) dataset. First, we downloaded TCGA lower grade glioma (LGG) gene expression datasets from 516 samples that were analyzed with the RNA Sequencing platform (IlluminaHiSeq RNASeqV2). To validate the gene signature, 516 samples were divided into two clusters using a consensus clustering algorithm based on expression profile of gene signature. According to their prognosis, two clusters were designated as their radiosensitive (RS) or radioresistant (RR). Patients were also stratified as PD-L1-high or PD-L1-low based on the median value of CD274 mRNA expression level as surrogates of PD-L1. Survival outcomes were compared between RR with PD-L1-high (PD-L1-high-RR) versus the others using log-rank test and Cox proportional hazard models. Patents assigned to the RS group had better 5-year overall survival (OS) rate than patients in the RR group by univariate analysis (63% vs. 52%, P=0.019) only when patients were treated with primary RT. The RR group was independently associated with the PD-L1-high group, and PD-L1 mRNA expression was significantly higher in the RR group (P<0.001) compared to that of the RS group. ESTIMATE immune score, representing the immunogenicity of tumors, was positively correlated with PD-L1 mRNA expression level (Pearson’s correlation=0.46. P=<0.001). PD-L1-high-RR group had worse 5-year OS rate compared to the others (50% vs. 60%, P=0.010). Cox multivariate analysis demonstrated that IDH-wild type and RR signature with high PD-L1 expression demonstrated detrimental effect on overall survival (HR =1.68, 95% CI=1.00-2.81, P=0.048). Gene enrichment analysis showed that differentially expressed genes in the PD-L1-high-RR group were involved in immune and inflammatory response. KEGG pathway analysis revealed that these genes were mapped into T-cell receptor signaling pathway as well. We first validated the predictive value of the radiosensitivity gene signature and PD-L1 in the TCGA dataset for the LGG. The patients having RR signature with high PD-L1 expression demonstrated worse outcome and association with T-cell receptor signaling suggesting that PD-L1-high-RR group could be benefited from anti-PD1/PD-L1 therapy combined with RT.