An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer

被引：501

作者：

Burr, Marian L. ^{[1
,2
,3
]}

Sparbier, Christina E. ^{[1
,2
]}

Chan, Kah Lok ^{[1
,2
]}

Chan, Yih-Chih ^{[1
]}

Kersbergen, Ariena ^{[4
]}

Lam, Enid Y. N. ^{[1
,2
]}

Azidis-Yates, Elizabeth ^{[1
]}

Vassiliadis, Dane ^{[1
,2
]}

Bell, Charles C. ^{[1
,2
]}

Gilan, Omer ^{[1
,2
]}

Jackson, Susan ^{[1
]}

Tan, Lavinia ^{[1
,2
]}

Wong, Stephen Q. ^{[1
,2
]}

Hollizeck, Sebastian ^{[1
,2
]}

Michalak, Ewa M. ^{[1
,2
]}

Siddle, Hannah, V ^{[5
,11
]}

McCabe, Michael T. ^{[6
]}

Prinjha, Rab K. ^{[6
,7
]}

Guerra, Glen R. ^{[1
,2
]}

Solomon, Benjamin J. ^{[1
,2
]}

Sandhu, Shahneen ^{[1
,2
]}

Dawson, Sarah-Jane ^{[1
,2
,8
]}

Beavis, Paul A. ^{[1
,2
]}

Tothill, Richard W. ^{[2
,8
,9
]}

Cullinane, Carleen ^{[1
,2
]}

Lehner, Paul J. ^{[3
]}

Sutherland, Kate D. ^{[4
,10
]}

Dawson, Mark A. ^{[1
,2
,8
]}

机构：

[1] Peter MacCallum Canc Ctr, 305 Grattan St, Melbourne, Vic 3000, Australia

[2] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3052, Australia

[3] Cambridge Inst Med Res, Cambridge Biomed Campus,Hills Rd, Cambridge CB2 0XY, England

[4] Walter & Eliza Hall Inst Med Res, ACRF Canc Biol & Stem Cell Div, Parkville, Vic 3052, Australia

[5] Univ Southampton, Dept Biol Sci, Southampton, Hants, England

[6] GlaxoSmithKline, Oncol R&D, Epigenet Res Unit, Collegeville, PA USA

[7] GlaxoSmithKline, Epigenet Res Unit, Stevenage, Herts, England

[8] Univ Melbourne, Ctr Canc Res, Parkville, Vic, Australia

[9] Univ Melbourne, Dept Clin Pathol, Melbourne, Vic, Australia

[10] Univ Melbourne, Dept Med Biol, Parkville, Vic 3010, Australia

[11] Univ Southampton, Inst Life Sci, Southampton, Hants, England

来源：

CANCER CELL | 2019年 / 36卷 / 04期

基金：

澳大利亚国家健康与医学研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

CELL LUNG-CANCER; REPRESSIVE COMPLEX 2; PD-1; BLOCKADE; INNATE IMMUNITY; ESSENTIAL GENES; DOWN-REGULATION; TUMOR-CELLS; T-CELLS; RESISTANCE; EXPRESSION;

D O I：

10.1016/j.ccell.2019.08.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.

引用

页码：385 / +

页数：25

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