@article{993da27789384a4f9b61543a1d31aeae,
title = "An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer",
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.",
keywords = "antigen presentation, bivalency, cancer, epigenetic repression, EZH2, histone methyltransferase, immune evasion, immunotherapy, MHC class I, polycomb",
author = "Burr, {Marian L.} and Sparbier, {Christina E.} and Chan, {Kah Lok} and Yih-Chih Chan and Ariena Kersbergen and Lam, {Enid Y.N.} and Elizabeth Azidis-Yates and Dane Vassiliadis and Bell, {Charles C.} and Omer Gilan and Susan Jackson and Lavinia Tan and Wong, {Stephen Q.} and Sebastian Hollizeck and Michalak, {Ewa M.} and Siddle, {Hannah V.} and McCabe, {Michael T.} and Prinjha, {Rab K.} and Guerra, {Glen R.} and Solomon, {Benjamin J.} and Shahneen Sandhu and Sarah-Jane Dawson and Beavis, {Paul A.} and Tothill, {Richard W.} and Carleen Cullinane and Lehner, {Paul J.} and Sutherland, {Kate D.} and Dawson, {Mark A.}",
note = "Funding Information: We thank the Peter MacCallum Cancer Center Molecular Genomics Core and the flow cytometry facilities at the Peter MacCallum Cancer Center and Cambridge Institute for Medical Research. We thank Andrew Flies and Jocelyn Darby (University of Tasmania) for the DFT cells. We thank the following funders for fellowship, scholarship, and grant support: Cancer Research UK Clinician Scientist Fellowship C53779/A20097 (to M.L.B.), Leukaemia Foundation Australia Senior Fellowship and Howard Hughes Medical Institute International Research Scholarship 55008729 (to M.A.D.), Peter and Julie Alston Centenary fellowship (to K.D.S.), Wellcome Trust Principal Research Fellowship 101835/Z/13/Z (to P.J.L.), Peter MacCallum Postgraduate Scholarship (to C.E.S.), NHMRC Postgraduate Scholarship (to K.L.C.), Maddie Riewoldt's Vision 064728 (to Y.-C.C.), Victorian Cancer Agency (to E.Y.N.L.), CSL Centenary fellowship (to S.-J.D.), National Breast Cancer Foundation Fellowship ECF-17-005 (to P.A.B.), Addenbrooke's Charitable Trust and NIHR Cambridge BRC (to M.L.B. and P.J.L.), NHMRC grants 1085015, 1106444 (to M.A.D) and 1128984 (to M.A.D. and S.-J.D.). M.L.B. P.J.L. K.D.S. and M.A.D. designed the research and interpreted data. M.L.B. and M.A.D. supervised the research and wrote the manuscript. M.L.B. C.E.S. K.L.C. A.K. C.C.B. O.G. S.J. S.Q.W. L.T. S.H. G.R.G. and E.A.-Y. conducted experiments and analyzed data. M.L.B. conducted the CRISPR screen and E.Y.N.L. analyzed the screen data. Y.-C.C. D.V. and E.Y.N.L. analyzed the genomic data. A.K. and S.J. performed animal experiments supervised by K.D.S. and C.C. E.M.M. H.V.S. M.T.McC. R.K.P. B.J.S. S.S. S.-J.D. P.A.B. R.T. and C.C. provided critical expertise and/or reagents and contributed to manuscript preparation. M.T.M. and R.K.P. are employees of GlaxoSmithKline. M.A.D. has been a member of advisory boards for CTX CRC, Storm Therapeutics, Celgene, and Cambridge Epigenetix. Funding Information: We thank the Peter MacCallum Cancer Center Molecular Genomics Core and the flow cytometry facilities at the Peter MacCallum Cancer Center and Cambridge Institute for Medical Research. We thank Andrew Flies and Jocelyn Darby (University of Tasmania) for the DFT cells. We thank the following funders for fellowship, scholarship, and grant support: Cancer Research UK Clinician Scientist Fellowship C53779/A20097 (to M.L.B.), Leukaemia Foundation Australia Senior Fellowship and Howard Hughes Medical Institute International Research Scholarship 55008729 (to M.A.D.), Peter and Julie Alston Centenary fellowship (to K.D.S.), Wellcome Trust Principal Research Fellowship 101835/Z/13/Z (to P.J.L.), Peter MacCallum Postgraduate Scholarship (to C.E.S.), NHMRC Postgraduate Scholarship (to K.L.C.), Maddie Riewoldt's Vision 064728 (to Y.-C.C.), Victorian Cancer Agency (to E.Y.N.L.), CSL Centenary fellowship (to S.-J.D.), National Breast Cancer Foundation Fellowship ECF-17-005 (to P.A.B.), Addenbrooke's Charitable Trust and NIHR Cambridge BRC (to M.L.B. and P.J.L.), NHMRC grants 1085015 , 1106444 (to M.A.D) and 1128984 (to M.A.D. and S.-J.D.). Publisher Copyright: {\textcopyright} 2019 The Authors Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",
year = "2019",
month = oct,
day = "14",
doi = "10.1016/j.ccell.2019.08.008",
language = "English",
volume = "36",
pages = "385--401.e8",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "4",
}
