Cancer genomics & proteomics · 2026
IL1B-Expressing Exhausted CD4+ T Cells Are Associated With Disease Aggressiveness in Glioblastoma.
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Wang Jinshan, Zhu A O, Wang Jian, Hu Bin, Zahid Kashif Rafiq, Zeng Ailiang, Tan Yiheng, Yang Jia
Аннотация
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: 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.
CONCLUSION: 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.
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: 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.
CONCLUSION: 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.