Journal article
An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer
Marian L Burr, Christina E Sparbier, Kah Lok Chan, Yih-Chih Chan, Ariena Kersbergen, Enid YN Lam, Elizabeth Azidis-Yates, Dane Vassiliadis, Charles C Bell, Omer Gilan, Susan Jackson, Lavinia Tan, Stephen Q Wong, Sebastian Hollizeck, Ewa M Michalak, Hannah Siddle, Michael T McCabe, Rab K Prinjha, Glen R Guerra, Benjamin J Solomon Show all
CANCER CELL | CELL PRESS | Published : 2019
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..
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Grants
Awarded by Cancer Research UK Clinician Scientist Fellowship
Awarded by Howard Hughes Medical Institute International Research Scholarship
Awarded by Wellcome Trust Principal Research Fellowship
Awarded by Maddie Riewoldt's Vision
Awarded by National Breast Cancer Foundation Fellowship
Awarded by NHMRC
Funding Acknowledgements
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 ECF17-005 (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.).