IL1B-Expressing Exhausted CD4 ⁺ T Cells Are Associated With Disease Aggressiveness in Glioblastoma

BACKGROUND/AIM: Glioblastomas (GBMs) are aggressive primary brain tumors characterized by immune evasion and therapeutic resistance. Here, we aimed to decipher the transcriptional landscape of disease aggressiveness in GBM by employing a multi-layered transcriptomic approach. MATERIALS AND METHODS: We performed transcriptome-wide differential expression analysis using TCGA IDH-wildtype GBM data after stratifying the tumors based on epithelial-mesenchymal transition (EMT) signature scores. Functional and pathway enrichment analyses, STRING-based protein-protein interaction (PPI) network assisted with centrality and random-walk analyses, univariate and multivariate Cox survival analyses, Gene Set Enrichment Analysis (GSEA), single-cell RNA (scRNA) sequencing analysis, CIBERSORTx immune deconvolution, and T cell exhaustion profiling were performed. Key findings were validated in independent datasets. RESULTS: T memory cells and aligns with enrichment of disease aggressiveness and inflammatory signatures. IL1R1/NF-κB-related transcriptional targets downstream are coordinately upregulated in tumors having high EMT scores and high IL1B expression. CONCLUSION: the CCL5-CCR1/CCR5 axis, where their exhaustion-related IL1B upregulation along disease progression aligns with mesenchymal reprogramming that hallmarks disease aggressiveness in IDH-wildtype GBM.