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ML Burr, CE Sparbier, KL Chan, YC Chan, A Kersbergen, EYN Lam, E Azidis-Yates, D Vassiliadis, CC Bell, O Gilan, S Jackson, L Tan, SQ Wong, S Hollizeck, EM Michalak, HV Siddle, MT McCabe, RK Prinjha, GR Guerra, BJ Solomon, S Sandhu, SJ Dawson, PA Beavis, RW Tothill, C Cullinane, PJ Lehner, KD Sutherland and MA Dawson
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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