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

TLDR

Loss of MHC‑I antigen presentation in cancer cells contributes to immunotherapy resistance, and bivalent chromatin at MHC‑I antigen processing genes is a normal developmental feature maintained during neural progenitor differentiation. 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. A genome‑wide CRISPR/Cas9 screen revealed that PRC2 coordinately silences the MHC‑I antigen processing pathway, enabling T‑cell evasion, and this conserved mechanism is exploited by cancers derived from primitive tissues to evade immunity.

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.