IL1B-Expressing Exhausted CD4+ T Cells Linked to Glioblastoma Aggressiveness and Poor Survival

Glioblastoma (GBM), an aggressive primary brain tumor, is notoriously resistant to therapy and characterized by significant immune evasion. Current treatments often fail due to the tumor's profound heterogeneity and immunosuppressive microenvironment. Understanding the molecular drivers of disease aggressiveness and immune cell dynamics within the tumor is crucial for identifying novel prognostic markers and therapeutic targets. This study aimed to decipher the transcriptional landscape associated with GBM aggressiveness, focusing on immune-inflammatory pathways.

Researchers performed transcriptome-wide differential expression analysis using TCGA IDH-wildtype GBM data, stratifying tumors by epithelial-mesenchymal transition (EMT) signature scores. They conducted functional and pathway enrichment analyses, STRING-based protein-protein interaction (PPI) network analysis, univariate and multivariate Cox survival analyses, and Gene Set Enrichment Analysis (GSEA). Single-cell RNA (scRNA) sequencing analysis and CIBERSORTx immune deconvolution were used to profile tumor-infiltrating immune cells and T cell exhaustion. Key findings were validated in independent datasets.

The analysis identified 2088 protein-coding genes associated with GBM aggressiveness. Among 1070 upregulated genes, 432 were risk-associated and significantly enriched for immune-inflammatory pathways. Network analysis pinpointed IL1B and CD4 as top hub genes, both independently prognostic for poor overall survival. scRNA-seq analysis attributed CD4 expression primarily to tumor-infiltrating T cells.

More than half of these tumor-infiltrating CD4+ T cells also co-expressed IL1B. CIBERSORTx deconvolution revealed a progressive accumulation and exhaustion of CD4+ T memory resting cells and Tregs correlating with increased disease aggressiveness. CCL5 was preferentially expressed by tumor cells, while CCR1 and CCR5 were found on CD4+ T cells, suggesting a CCL5-CCR1/CCR5-associated recruitment pattern. IL1B expression correlated with the accumulation of exhausted CD4+ T memory cells and aligned with enrichment of disease aggressiveness and inflammatory signatures. Downstream IL1R1/NF-κB-related transcriptional targets were coordinately upregulated in tumors with high EMT scores and high IL1B expression.