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

ABSTRACT: 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.

SUBMITTER: Anaelle Dumas

PROVIDER: S-SCDT-EMBOJ-2019-103790 | biostudies-other |

REPOSITORIES: biostudies-other

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

Project description: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. 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 induce mTOR signalling in the microglia but not bone marrow-derived macrophages in both in vitro and in vivo GBM mouse models. mTOR-dependent regulation of STAT3 and NF-κB 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 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 GBM-initiating cells. These results raise the possibility that microglia could be the primary target of mTOR inhibition, rather than the intrinsic tumour cells in GBM.

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

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

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

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Glioblastoma-educated mesenchymal stem-like cells promote glioblastoma infiltration via extracellular matrix remodelling in the tumour microenvironment.

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Project description:Immunotherapy has revolutionised the treatment of cancers by harnessing the power of the immune system to eradicate malignant tissue. However, it is well recognised that some cancers are highly resistant to these therapies, which is in part attributed to the immunosuppressive landscape of the tumour microenvironment (TME). The contexture of the TME is highly heterogeneous and contains a complex architecture of immune, stromal, vascular and tumour cells in addition to acellular components such as the extracellular matrix. While understanding the dynamics of the TME has been instrumental in predicting durable responses to immunotherapy and developing new treatment strategies, recent evidence challenges the fundamental paradigms of how tumours can effectively subvert immunosurveillance. Here, we discuss the various immunosuppressive features of the TME and how fine-tuning these mechanisms, rather than ablating them completely, may result in a more comprehensive and balanced anti-tumour response.

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Revealing and Harnessing Tumour-Associated Microglia/Macrophage Heterogeneity in Glioblastoma.

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