Microglia promote glioblastoma via mTOR-mediated immunosuppression of the tumour microenvironment

Area of Science:

• Neuro-oncology
• Immunology
• Cellular Signaling

Background:

• Tumor-associated microglia/macrophages (TAM) are key components of the glioblastoma (GBM) tumor microenvironment.
• The mTOR pathway is upregulated in GBM, but its role in TAM remains unclear.

Purpose of the Study:

• To investigate the role of the mTOR pathway in TAM within the GBM microenvironment.
• To determine if GBM-initiating cells influence mTOR signaling in microglia and macrophages.

Main Methods:

• Utilized in vitro and in vivo GBM mouse models.
• Examined mTOR signaling, STAT3 and NF-κB activity in microglia and macrophages.
• Analyzed human GBM transcriptome data and a novel in vitro model using patient-derived GBM cells and stem cell-derived microglia-like cells.

Main Results:

• GBM-initiating cells induce mTOR signaling specifically in microglia, not bone marrow-derived macrophages.
• mTOR-dependent regulation of STAT3 and NF-κB drives an immunosuppressive microglial phenotype.
• This immunosuppression hinders T-cell responses, facilitating tumor immune evasion and growth in mouse models.
• Human GBM data and the in vitro model corroborate these findings.

Conclusions:

• Microglia, not tumor cells, may be the primary target for mTOR inhibition in GBM.
• Targeting microglial mTOR signaling could be a novel therapeutic strategy for glioblastoma.