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

Summary

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.

Graphical Abstract

Highlights

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  PRC2 maintains bivalency at MHC-I antigen-processing genes silencing MHC-I expression

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  Cancer cells co-opt this conserved, lineage-specific PRC2 function to evade T cells

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  Pharmacological inhibition of PRC2 in MHC-I low cancers restores anti-tumor immunity

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  Immunotherapy resistance may arise via non-genomic routes that exploit PRC2 activity

Abstract

Burr et al. show that cancer cells co-opt PRC2 to evade immune surveillance. PRC2 maintains bivalency at the promoters of MHC-I antigen-processing pathway (MHC-I APP) genes to repress their basal and cytokine-activated expression. Inhibition of PRC2 restores the MHC-I APP and T cell-mediated anti-tumor immunity.