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 (GBM), the most common malignant brain tumour in adulthood. The mTOR pathway, an important regulator of cell survival/proliferation, is upregulated in GBM, but little is known about the potential role of this pathway in TAM. Here, we show that GBM-initiating cells (GIC) induce mTOR signalling in TAM-Microglia (TAM-MG) but not TAM-Bone Marrow-derived Macrophages (TAM-BMDM) in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-?B activity promotes an immunosuppressed phenotype in TAM-MG. This hinders effector T cell infiltration, proliferation, and immune reactivity, thereby contributing to tumour immune evasion and promoting tumour growth in a mouse model. The translational value of our results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model, whereby expanded-potential stem cells (EPSC)-derived microglia-like cells are conditioned by syngeneic patient-derived GIC. These results raise the possibility that TAM-MG could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM.