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Updated: Jul 16, 2025
Isolation and Flow Cytometric Analysis of Glioma-infiltrating Peripheral Blood Mononuclear Cells
Published on: November 28, 2015
Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T effector cell infiltration
Jin-Min Sun1,2, Hong-Ye Fan3, Yan Zhu1,3
1Research Center for Biochemistry and Molecular Biology, Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical University, Xuzhou, China.
Abstract:
MAP4K1 has been identified as a cancer immunotherapy target. Whether and how cancer cell-intrinsic MAP4K1 contributes to glioblastoma multiforme (GBM) progression remains unclear. We found that MAP4K1 was highly expressed in the glioma cells of human GBM specimens. High levels of MAP4K1 mRNA were prevalent in IDH-WT and 1p/19q non-codeletion gliomas and correlated with poor prognosis of patients. MAP4K1 silencing inhibited GBM cell proliferation and glioma growth. Transcriptome analysis of GBM cells and patient samples showed that MAP4K1 modulated cytokine‒cytokine receptor interactions and chemokine signaling pathway, including IL-18R and IL-6R Importantly, MAP4K1 loss down-regulated membrane-bound IL-18R/IL-6R by inhibiting the PI3K-AKT pathway, whereas MAP4K1 restoration rescued this phenotype and therefore GBM cell proliferation. MAP4K1 deficiency abolished GBM cell pro-proliferation responses to IL-18, suggesting an oncogenic role of MAP4K1 via the intrinsic IL-18/IL-18R pathway. In addition, GBM cell-derived MAP4K1 impaired T-cell migration and reduced CD8+ T-cell infiltration in mouse glioma models. Together, our findings provide novel insight into the pathological significance of GBM cell-intrinsic MAP4K1 in driving tumor growth and immune evasion by remodeling cytokine-chemokine networks.
Insights
Mitogen-activated protein kinase kinase kinase 4 (MAP4K1) drives glioblastoma growth and immune evasion. Targeting MAP4K1 may offer new therapeutic strategies for glioblastoma multiforme (GBM) by modulating cytokine signaling and T-cell infiltration.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Glioblastoma multiforme (GBM) is an aggressive brain tumor with limited treatment options.
- The role of cancer cell-intrinsic MAP4K1 (MAP4K1) in GBM progression is not well understood.
- MAP4K1 is implicated as a potential target in cancer immunotherapy.
Purpose of the Study:
- To investigate the role of cancer cell-intrinsic MAP4K1 in glioblastoma multiforme (GBM) progression.
- To elucidate the molecular mechanisms by which MAP4K1 influences GBM growth and immune evasion.
- To explore MAP4K1 as a potential therapeutic target in GBM.
Main Methods:
- Analysis of MAP4K1 expression in human GBM specimens.
- MAP4K1 silencing and restoration experiments in GBM cells.
- Transcriptome analysis to identify MAP4K1-modulated pathways.
- Investigation of the PI3K-AKT pathway and cytokine signaling (IL-18R, IL-6R).
- Evaluation of T-cell migration and infiltration in mouse glioma models.
Main Results:
- MAP4K1 is highly expressed in GBM cells, correlating with poor prognosis in IDH-WT and non-codeletion gliomas.
- MAP4K1 silencing inhibits GBM cell proliferation and glioma growth.
- MAP4K1 modulates cytokine-receptor interactions (IL-18R, IL-6R) via the PI3K-AKT pathway, impacting GBM cell proliferation.
- MAP4K1 deficiency impairs GBM cell responses to IL-18 and reduces CD8+ T-cell infiltration in vivo.
- GBM cell-intrinsic MAP4K1 promotes tumor growth and immune evasion by altering cytokine-chemokine networks.
Conclusions:
- MAP4K1 plays a significant oncogenic role in GBM through the intrinsic IL-18/IL-18R pathway.
- MAP4K1 contributes to GBM immune evasion by impairing T-cell migration and infiltration.
- Targeting cancer cell-intrinsic MAP4K1 represents a promising therapeutic strategy for GBM.
