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Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion.
- Source :
-
Cell [Cell] 2021 Apr 29; Vol. 184 (9), pp. 2454-2470.e26. Date of Electronic Publication: 2021 Apr 14. - Publication Year :
- 2021
-
Abstract
- 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.<br />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.<br /> (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Apoptosis
Biomarkers, Tumor genetics
Biomarkers, Tumor metabolism
Brain Neoplasms genetics
Brain Neoplasms metabolism
Brain Neoplasms pathology
Cell Proliferation
DNA Methylation
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Glioblastoma genetics
Glioblastoma metabolism
Glioblastoma pathology
Humans
Male
Mice
Mice, Inbred NOD
Mice, SCID
Myeloid Cells metabolism
Myeloid Cells pathology
Neoplastic Stem Cells metabolism
Neoplastic Stem Cells pathology
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
Brain Neoplasms immunology
Epigenesis, Genetic
Glioblastoma immunology
Immune Evasion immunology
Myeloid Cells immunology
Neoplastic Stem Cells immunology
Tumor Microenvironment immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1097-4172
- Volume :
- 184
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Cell
- Publication Type :
- Academic Journal
- Accession number :
- 33857425
- Full Text :
- https://doi.org/10.1016/j.cell.2021.03.023