An Evolutionarily Conserved Function of Polycomb Silences the MHC Class I Antigen Presentation Pathway and Enables Immune Evasion in Cancer

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…

• HH
  Howard Hughes Medical Institute

  Award: 55008729
• VC
  Victorian Cancer Agency
• WT
  Wellcome Trust

  Awards: 101835/Z/13/Z, 101835
• NB
  NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research
• CR
  Cancer Research UK

  Award: C53779/A20097
• NI
  National Institute for Health and Care Research
• LF
  Leukaemia Foundation
• NB
  National Breast Cancer Foundation

  Award: ECF-17-005
• UO
  University of Tasmania
• CI
  Cambridge Institute for Medical Research, University of Cambridge
• NH
  National Health and Medical Research Council

  Awards: 1128984, 1085015, 1106444
• AC
  Addenbrooke's Charitable Trust, Cambridge University Hospitals
• NC
  NIHR Cambridge Biomedical Research Centre