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

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.

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.

We identified 2088 protein-coding genes associated with disease aggressiveness in GBM. Among 1070 upregulated genes, 432 were risk-associated and enriched for immune-inflammatory pathways. Network analysis identified IL1B and CD4 as top hub genes, both of which were independently prognostic for poor overall survival. scRNA-seq analysis attributed CD4 expression to tumor-infiltrating T cells, more than half of which also co-expressed IL1B. CIBERSORTx deconvolution suggested progressive accumulation and exhaustion of CD4⁺ T memory resting cells and Tregs along disease aggressiveness. CCL5 is preferentially expressed by tumor cells, whereas CCR1 and CCR5 by CD4⁺ T cells, supporting a CCL5-CCR1/CCR5-associated recruitment pattern. IL1B correlates with accumulation of exhausted CD4⁺ 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.

CD4⁺ T cells are recruited to GBM tumors preferentially via 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.