Upregulated Immunogenic Cell-Death-Associated Gene Signature Predicts Reduced Responsiveness to Immune-Checkpoint-Blockade Therapy and Poor Prognosis in High-Grade Gliomas

Background: Immunogenic cell death (ICD) has emerged as a potential mechanism mediating adaptive immune response and tumor immunity in anti-cancer treatment. However, the signature of ICD in high-grade gliomas (HGGs) remains largely unknown, and its relevance to immunotherapies is still undetermined. The purpose of this study is to identify ICD-associated genotypes in order to explore their relevance to tumor immunity, patient prognosis and therapeutic efficacy of immune checkpoint blockade (ICB) therapy in HGGs. Methods: Bulk RNA-seq data and clinical information on 169 and 297 patients were obtained from the Cancer Genome Atlas (TCGA) and China Glioma Genome Atlas (CGGA), respectively. The functional enrichment and characterization of ICD genotyping were detected, and the ICD prognostic signature prediction model was constructed using least absolute shrinkage and selection operator (LASSO) regression. The responsiveness to immunotherapy was predicted according to the scoring of the ICD prognostic signature. Results: The HGG patients with high ICD gene signature (C1) showed poor outcomes, increased activity of immune modulation and immune escape, high levels of immune-checkpoint markers, and HLA-related genes, which may explain their reduced response to ICB immunotherapy. A gene set of the ICD signature, composing FOXP3, IL6 LY96, MYD88 and PDIA3, showed an independent prognostic value in both the TCGA and the CGGA HGG cohort. Conclusions: Our in silico analyses identified the ICD gene signature in HGGs with potential implications for predicting the responsiveness to ICB immune therapy and patient outcomes.