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

Marian L Burr1, Christina E Sparbier2, Kah Lok Chan2

  • 1Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC 3052, Australia; Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.

Cancer Cell
|October 1, 2019
PubMed

Insights

Cancer cells evade immune detection by silencing the MHC-I antigen processing pathway. Polycomb repressive complex 2 (PRC2) hijacks this developmental process, leading to immunotherapy resistance.

Area of Science:

  • Immunology
  • Cancer Biology
  • Epigenetics

Background:

  • Loss of MHC class I (MHC-I) antigen presentation is a key mechanism of cancer immune evasion and immunotherapy resistance.
  • The MHC-I antigen processing pathway (MHC-I APP) is crucial for presenting antigens to T cells.

Purpose of the Study:

  • To identify mechanisms by which cancer cells silence MHC-I antigen presentation.
  • To investigate the role of Polycomb Repressive Complex 2 (PRC2) in regulating MHC-I APP.

Main Methods:

  • Genome-wide CRISPR/Cas9 screening in cancer cells.
  • Analysis of histone modifications (H3K4me3, H3K27me3) at MHC-I APP gene promoters.
  • Comparison with epigenetic states in embryonic stem cells and neural progenitors.

Main Results:

  • A genome-wide CRISPR screen identified PRC2 as a mediator of coordinated transcriptional silencing of MHC-I APP.
  • MHC-I low cancers exhibit bivalent histone modifications (H3K4me3 and H3K27me3) at MHC-I APP gene promoters.
  • This bivalent chromatin state silences basal MHC-I expression and prevents cytokine-induced upregulation, mimicking developmental processes.

Conclusions:

  • PRC2 exploits a conserved developmental mechanism of bivalent chromatin silencing at MHC-I APP genes to promote cancer immune evasion.
  • This epigenetic reprogramming by PRC2 contributes to T cell-mediated immunity evasion and immunotherapy resistance in MHC-I low cancers.
Keywords:
EZH2MHC class Iantigen presentationbivalencycancerepigenetic repressionhistone methyltransferaseimmune evasionimmunotherapypolycomb

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