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

Anaelle A. Dumas, Nicola Pomella, Gabriel Rosser, Loredana Guglielmi, Claire Vinel, Thomas O. Millner, Jeremy Rees, Natasha Aley, Denise Sheer, Jun Wei, Anantha Marisetty, Amy B. Heimberger, Robert L. Bowman, Sebastian Brandner, Johanna A. Joyce, Silvia Marino*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article numbere103790
JournalEMBO Journal
Volume39
Issue number15
DOIs
StatePublished - Aug 3 2020
Externally publishedYes

Keywords

  • T cells
  • TAM
  • glioblastoma
  • mTOR
  • microglia

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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