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An evolutionarily conserved function of polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer


Burr, ML; Sparbier, CE; Chan, KL; Chan, YC; Kersbergen, A; Lam, EYN; Azidis-Yates, E; Vassiliadis, D; Bell, CC; Gilan, O; Jackson, S; Tan, L; Wong, SQ; Hollizeck, S; Michalak, EM; Siddle, HV; McCabe, MT; Prinjha, RK; Guerra, GR; Solomon, BJ; Sandhu, S; Dawson, SJ; Beavis, PA; Tothill, RW; Cullinane, C; Lehner, PJ; Sutherland, KD; Dawson, MA
2019-09-24
Cancer Cell
Journal Article
36
4
385-401.e8
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.
Cell Press
Cancer Biology and Stem Cells
10.1016/j.ccell.2019.08.008
31564637
Refer to copyright notice on published article.

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Creation Date 2019-10-23 02:22:50 Last Modified 2019-10-23 02:31:55