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Glioblastoma multiforme (GBM) is an aggressive brain tumor for which current immunotherapy approaches have been unsuccessful. Here, we explore the mechanisms underlying immune evasion in GBM. By serially transplanting GBM stem cells (GSCs) into immunocompetent hosts, we uncover an acquired capability of GSCs to escape immune clearance by establishing an enhanced immunosuppressive tumor microenvironment. Mechanistically, this is not elicited via genetic selection of tumor subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in GSCs are enforced following immune attack. These changes launch a myeloid-affiliated transcriptional program, which leads to increased recruitment of tumor-associated macrophages. Furthermore, we identify similar epigenetic and transcriptional signatures in human mesenchymal subtype GSCs. We conclude that epigenetic immunoediting may drive an acquired immune evasion program in the most aggressive mesenchymal GBM subtype by reshaping the tumor immune microenvironment.

Original publication

DOI

10.1016/j.cell.2021.03.023

Type

Journal article

Journal

Cell

Publication Date

04/2021

Volume

184

Pages

2454 - 2470.e26

Addresses

Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK; CRUK Edinburgh Centre, Institute of Genetics and Molecular Medicine, Crewe Road South, University of Edinburgh, Edinburgh EH42XR, UK.

Keywords

Tumor Cells, Cultured, Myeloid Cells, Animals, Mice, Inbred NOD, Humans, Mice, Mice, SCID, Glioblastoma, Brain Neoplasms, Xenograft Model Antitumor Assays, Gene Expression Profiling, Apoptosis, Cell Proliferation, DNA Methylation, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Male, Neoplastic Stem Cells, Immune Evasion, Tumor Microenvironment, Biomarkers, Tumor