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

Ester Gangoso; Benjamin Southgate; Leanne Bradley; Stefanie Rus; Felipe Galvez-Cancino; Niamh McGivern; Esra Güç; Chantriolnt-Andreas Kapourani; Adam Byron; Kirsty M. Ferguson; Neza Alfazema; Gillian Morrison; Vivien Grant; Carla Blin; IengFong Sou; Maria Angeles Marques-Torrejon; Lucia Conde; Simona Parrinello; Javier Herrero; Stephan Beck; Sebastian Brandner; Paul M. Brennan; Paul Bertone; Jeffrey W. Pollard; Sergio A. Quezada; Duncan Sproul; Margaret C. Frame; Alan Serrels; Steven M. Pollard

doi:10.1016/j.cell.2021.03.023

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

Ester Gangoso, Benjamin Southgate, Leanne Bradley, Stefanie Rus, Felipe Galvez-Cancino, Niamh McGivern, Esra Güç, Chantriolnt-Andreas Kapourani, Adam Byron, Kirsty M. Ferguson, Neza Alfazema, Gillian Morrison, Vivien Grant, Carla Blin, IengFong Sou, Maria Angeles Marques-Torrejon, Lucia Conde, Simona Parrinello, Javier Herrero, Stephan BeckSebastian Brandner, Paul M. Brennan, Paul Bertone, Jeffrey W. Pollard, Sergio A. Quezada, Duncan Sproul, Margaret C. Frame, Alan Serrels, Steven M. Pollard

Division of Molecular & Cellular Function (L5)

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	2454-2470.e26
Journal	Cell
Volume	184
Issue number	9
DOIs	https://doi.org/10.1016/j.cell.2021.03.023
Publication status	Published - 29 Apr 2021

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cell.2021.03.023Licence: CC BY-NC-ND

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Gangoso, E., Southgate, B., Bradley, L., Rus, S., Galvez-Cancino, F., McGivern, N., Güç, E., Kapourani, C.-A., Byron, A., Ferguson, K. M., Alfazema, N., Morrison, G., Grant, V., Blin, C., Sou, I., Marques-Torrejon, M. A., Conde, L., Parrinello, S., Herrero, J., ... Pollard, S. M. (2021). Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion. Cell, 184(9), 2454-2470.e26. https://doi.org/10.1016/j.cell.2021.03.023

@article{f4c603d68bbd4f6d96d8813bb07183c5,

title = "Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion",

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.",

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

author = "Ester Gangoso and Benjamin Southgate and Leanne Bradley and Stefanie Rus and Felipe Galvez-Cancino and Niamh McGivern and Esra G{\"u}{\c c} and Chantriolnt-Andreas Kapourani and Adam Byron and Ferguson, {Kirsty M.} and Neza Alfazema and Gillian Morrison and Vivien Grant and Carla Blin and IengFong Sou and Marques-Torrejon, {Maria Angeles} and Lucia Conde and Simona Parrinello and Javier Herrero and Stephan Beck and Sebastian Brandner and Brennan, {Paul M.} and Paul Bertone and Pollard, {Jeffrey W.} and Quezada, {Sergio A.} and Duncan Sproul and Frame, {Margaret C.} and Alan Serrels and Pollard, {Steven M.}",

year = "2021",

month = apr,

day = "29",

doi = "10.1016/j.cell.2021.03.023",

language = "English",

volume = "184",

pages = "2454--2470.e26",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "9",

}

Gangoso, E, Southgate, B, Bradley, L, Rus, S, Galvez-Cancino, F, McGivern, N, Güç, E, Kapourani, C-A, Byron, A, Ferguson, KM, Alfazema, N, Morrison, G, Grant, V, Blin, C, Sou, I, Marques-Torrejon, MA, Conde, L, Parrinello, S, Herrero, J, Beck, S, Brandner, S, Brennan, PM, Bertone, P, Pollard, JW, Quezada, SA, Sproul, D, Frame, MC, Serrels, A & Pollard, SM 2021, 'Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion', Cell, vol. 184, no. 9, pp. 2454-2470.e26. https://doi.org/10.1016/j.cell.2021.03.023

TY - JOUR

T1 - Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion

AU - Gangoso, Ester

AU - Southgate, Benjamin

AU - Bradley, Leanne

AU - Rus, Stefanie

AU - Galvez-Cancino, Felipe

AU - McGivern, Niamh

AU - Güç, Esra

AU - Kapourani, Chantriolnt-Andreas

AU - Byron, Adam

AU - Ferguson, Kirsty M.

AU - Alfazema, Neza

AU - Morrison, Gillian

AU - Grant, Vivien

AU - Blin, Carla

AU - Sou, IengFong

AU - Marques-Torrejon, Maria Angeles

AU - Conde, Lucia

AU - Parrinello, Simona

AU - Herrero, Javier

AU - Beck, Stephan

AU - Brandner, Sebastian

AU - Brennan, Paul M.

AU - Bertone, Paul

AU - Pollard, Jeffrey W.

AU - Quezada, Sergio A.

AU - Sproul, Duncan

AU - Frame, Margaret C.

AU - Serrels, Alan

AU - Pollard, Steven M.

PY - 2021/4/29

Y1 - 2021/4/29

N2 - 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.

AB - 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.

KW - Animals

KW - Apoptosis

KW - Biomarkers, Tumor/genetics

KW - Brain Neoplasms/genetics

KW - Cell Proliferation

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Glioblastoma/genetics

KW - Humans

KW - Immune Evasion/immunology

KW - Male

KW - Mice

KW - Mice, Inbred NOD

KW - Mice, SCID

KW - Myeloid Cells/immunology

KW - Neoplastic Stem Cells/immunology

KW - Tumor Cells, Cultured

KW - Tumor Microenvironment/immunology

KW - Xenograft Model Antitumor Assays

U2 - 10.1016/j.cell.2021.03.023

DO - 10.1016/j.cell.2021.03.023

M3 - Article

C2 - 33857425

SN - 0092-8674

VL - 184

SP - 2454-2470.e26

JO - Cell

JF - Cell

IS - 9

ER -

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

Abstract

Keywords

UN SDGs

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