Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion.

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.
Competing Interests: Declaration of interests S.M.P is a co-founder and shareholder of Cellinta., a biotechnology start-up that is developing cancer therapeutics, including for glioblastoma, and acts as an advisor to the company. J.W.P is a co-founder and shareholder of Macomics. S.A.Q. is co-founder and shareholder and Chief Scientific Officer for Achilles Therapeutics. The other authors declare no competing interests.
(Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)