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

被引：257

作者：

Gangoso, Ester ^{[1
,2
]}

Southgate, Benjamin ^{[1
,2
]}

Bradley, Leanne ^{[1
,2
]}

Rus, Stefanie ^{[1
,2
]}

Galvez-Cancino, Felipe ^{[3
]}

McGivern, Niamh ^{[2
]}

Guc, Esra ^{[7
]}

Kapourani, Chantriolnt-Andreas ^{[1
,2
]}

Byron, Adam ^{[2
]}

Ferguson, Kirsty M. ^{[1
,2
]}

Alfazema, Neza ^{[1
,2
]}

Morrison, Gillian ^{[1
,2
]}

Grant, Vivien ^{[1
,2
]}

Blin, Carla ^{[1
,2
]}

Sou, IengFong ^{[1
,2
]}

Marques-Torrejon, Maria Angeles ^{[1
,2
]}

Conde, Lucia ^{[4
]}

Parrinello, Simona ^{[5
]}

Herrero, Javier ^{[4
]}

Beck, Stephan ^{[6
]}

Brandner, Sebastian ^{[8
,9
]}

Brennan, Paul M. ^{[1
,2
]}

Bertone, Paul ^{[10
]}

Pollard, Jeffrey W. ^{[7
]}

Quezada, Sergio A. ^{[3
]}

Sproul, Duncan ^{[2
]}

Frame, Margaret C. ^{[2
]}

Serrels, Alan ^{[11
]}

Pollard, Steven M. ^{[1
,2
]}

机构：

[1] Univ Edinburgh, Ctr Regenerat Med, Inst Regenerat & Repair, 5 Little France Dr, Edinburgh EH16 4UU, Midlothian, Scotland

[2] Univ Edinburgh, CRUK Edinburgh Ctr, Inst Genet & Mol Med, Crewe Rd South, Edinburgh EH4 2XR, Midlothian, Scotland

[3] UCL, Res Dept Haematol, Canc Immunol Unit, Canc Inst, London WC1E 6BT, England

[4] UCL, Dept Canc Biol, Sill Lyons Informat Ctr, Canc Inst, London WC1E 6BT, England

[5] UCL, Dept Canc Biol, Samantha Dickson Brain Canc Unit, Canc Inst, London WC1E 6BT, England

[6] UCL, Dept Canc Biol, Med Genom Res Grp, Canc Inst, London WC1E 6BT, England

[7] Univ Edinburgh, Ctr Reprod Hlth, Queens Med Res Inst, Edinburgh Little France Crescent, Edinburgh EH16 4TJ, Midlothian, Scotland

[8] UCL, Div Neuropathol, UCL Queen Sq Inst Neurol, London, England

[9] UCL, Dept Neurodegenerat Dis, UCL Queen Sq Inst Neurol, London, England

[10] Brown Univ, Alpert Med Sch, Dept Med, Providence, RI 02903 USA

[11] Univ Edinburgh, Ctr Inflammat Res, Queens Med Res Inst, Edinburgh Little France Crescent, Edinburgh EH16 4TJ, Midlothian, Scotland

来源：

CELL | 2021年 / 184卷 / 09期

基金：

英国医学研究理事会;

关键词：

BIOCONDUCTOR PACKAGE; R PACKAGE; PROTEIN; CELLS; SEQ; DISCOVERY; ARRAY; NORMALIZATION; ANNOTATION; RESISTANCE;

D O I：

10.1016/j.cell.2021.03.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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.

引用

页码：2454 / +

页数：43

共 89 条

[21]

A framework for variation discovery and genotyping using next-generation DNA sequencing data [J].