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

Marian L. Burr(The University of Melbourne), Christina E. Sparbier(The University of Melbourne), Kah Lok Chan(The University of Melbourne), Yih-Chih Chan(Peter MacCallum Cancer Centre), Ariena Kersbergen(Walter and Eliza Hall Institute of Medical Research), Enid Y.N. Lam(The University of Melbourne), Elizabeth Azidis-Yates(Peter MacCallum Cancer Centre), Dane Vassiliadis(The University of Melbourne), Charles C. Bell(The University of Melbourne), Omer Gilan(The University of Melbourne), Susan Jackson(Peter MacCallum Cancer Centre), Lavinia Tan(The University of Melbourne), Stephen Q. Wong(The University of Melbourne), Sebastian Hollizeck(The University of Melbourne), Ewa M. Michalak(The University of Melbourne), Hannah V. Siddle(University of Southampton), Michael T. McCabe(GlaxoSmithKline (United States)), Rab K. Prinjha(GlaxoSmithKline (United Kingdom)), Glen Guerra(The University of Melbourne), Benjamin Solomon(The University of Melbourne), Shahneen Sandhu(The University of Melbourne), Sarah‐Jane Dawson(The University of Melbourne), Paul A. Beavis(The University of Melbourne), Richard W. Tothill(The University of Melbourne), Carleen Cullinane(The University of Melbourne), Paul J. Lehner, Kate D. Sutherland(The University of Melbourne), Mark A. Dawson(The University of Melbourne)
Cancer Cell
September 26, 2019
10.1016/j.ccell.2019.08.008
Cited by 632Open Access
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Abstract

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.

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