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

Tumour-associated microglia/macrophages (TAM) are the most numerous non-neoplastic populations in the tumour microenvironment in glioblastoma multiforme (GBM), the most common malignant brain tumour in adulthood. ThemTORpathway, an important regulator of cell survival/proliferation, is upregulated inGBM, but little is known about the potential role of this pathway inTAM. Here, we show thatGBM-initiating cells inducemTORsignalling in the microglia but not bone marrow-derived macrophages in bothin vitroandin vivoGBMmouse models.mTOR-dependent regulation ofSTAT3 and NF-kappa B activity promotes an immunosuppressive microglial phenotype. This hinders effector T-cell infiltration, proliferation and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in mouse models. The translational value of our results is demonstrated in whole transcriptome datasets of humanGBMand in a novelin vitromodel, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derivedGBM-initiating cells. These results raise the possibility that microglia could be the primary target ofmTORinhibition, rather than the intrinsic tumour cells in GBM.