Microglia promote glioblastoma growth via mTOR-mediated immunosuppressive conditioning of the tumor microenvironment.

Tumor-associated microglia and macrophages (TAM) are the most numerous non-neoplastic populations in the tumor microenvironment of glioblastoma (GBM), the most common malignant brain tumor in adulthood. The mTOR pathway, an important regulator of cell survival and proliferation, is known to be upregulated in GBM, but little is known about a 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-Macrophages (TAM-BMDM) in in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-ĸB activity promotes an immunosuppressed phenotype in TAM-MG which hinders effector T cell proliferation and immune reactivity, thereby contributing to tumor immune evasion and promoting tumor growth in a mouse model. The translational value of these results is demonstrated in whole transcriptome datasets of human GBM and in a novel in vitro model whereby IPSC-derived microglia-like cells are conditioned by syngeneic patient-derived GIC. These results raise the possibility that tumor cells might not be the primary target of mTOR inhibition, and TAM-MG should be considered instead. Intracranial injections of GL261 cells in Cx3cr1-cre;Rheb1-loxp mice 3 weeks post-tamoxifen injections. GL261 cells were injected at a concentration of 2x10e4 cells/5µl in PBS at 6 weeks of age. samples were collected 3 weeks post tumor initiation. Mouse models have been previously reported (Bowman et al., 2016, Yona, Kim et al., 2013, Zou, Zhou et al., 2011) TAM-MG were sorted by gating on single live CD11b+ CD45low cells.