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 Y.N. Lam, Elizabeth Azidis-Yates, Dane Vassiliadis, Charles C. Bell, Omer Gilan, Susan Jackson, Lavinia Tan, Stephen Q. Wong, Sebastian Hollizeck, Ewa M. Michalak, Hannah V. Siddle, Michael T. McCabe, Rab K. Prinjha, Glen R. Guerra, Benjamin J. SolomonShahneen Sandhu, Sarah-Jane Dawson, Paul A. Beavis, Richard W. Tothill, Carleen Cullinane, Paul J. Lehner, Kate D. Sutherland, Mark A. Dawson

Research output: Contribution to journalArticleResearchpeer-review

140 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)385-401.e8
Number of pages25
JournalCancer Cell
Volume36
Issue number4
DOIs
Publication statusPublished - 14 Oct 2019
Externally publishedYes

Keywords

  • antigen presentation
  • bivalency
  • cancer
  • epigenetic repression
  • EZH2
  • histone methyltransferase
  • immune evasion
  • immunotherapy
  • MHC class I
  • polycomb

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