Immune checkpoint expression and therapeutic implications in IDH1-mutant and wild-type glioblastomas

Abstract

Programmed cell death protein 1 (PDCD1) and cluster of differentiation 274 (CD274) expression is implicated in escaping tumors from immune surveillance. Immune checkpoint inhibitors show promise in cancer therapy, yet their efficacy in glioblastomas, particularly with IDH1 mutations, remains unclear. This study analyzed two independent NGS datasets (n = 577 and n = 153) from TCGA to investigate the expression of PDCD1 and CD274 in glioblastomas and their relationship with IDH1 mutations. We used cBioPortal for mutation analysis, RNA seq for expression analysis, miRDB and miRabel for differential expression of miRNAs, and Kaplan-Meier for survival prediction. We found that 5.4% of glioblastomas harbored IDH1 mutations, correlating with improved overall survival (OS) (p = 2.196e-3). Different glioblastoma cohorts showed a diverse IDH1 mutational prevalence (4-31%). Despite this, IDH1^Mu was consistently associated with better OS (p = 8.235e-5). Notably, PDCD1 and CD274 were statistically significantly highly expressed in both IDH1^Wt (p < 0.0001) and IDH1^Mu tumors (p < 0.0001), with higher expression linked to poorer survival outcomes (PDCD1: p = 0.009; CD274: p = 0.02). Differential co-expression analyses revealed distinct gene and miRNA profiles for IDH1^Wt and IDH1^Mu glioblastomas, with specific upregulation of PTEN and downregulation of MUC16 in IDH1^Wt, and upregulation of PIK3R1 in IDH1^Mu. Additionally, PIK3R1 and ITGB2 emerged as critical druggable targets. Our findings indicate that PDCD1 and CD274 are highly expressed irrespective of IDH1 mutation statuses, suggesting that glioblastomas could benefit from immunotherapy. Moreover, IDH1^Mu glioblastomas may require a combination of PI3K/AKT/mTOR inhibitors and immunotherapy due to PIK3R1 overexpression.

Keywords: AKT; CD274; Drug target; Glioblastomas; Glioma; IDH1; Immunotherapy; Mutation; PD-1; PD-L1; PDCD1; PI3K; PIK3R1; mTOR.