Loss of MHC class I (MHC-I) antigen presentation in cancer cells is a frequent cause of primary and acquired resistance to immunotherapy. Using a genome-wide CRISPR/Cas9 screen we identify a critical role for polycomb repressive complex 2 (PRC2) in the coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP) in a range of cancers that lack cell surface MHC-I expression. This evolutionarily conserved function of PRC2 promotes evasion of T-cell mediated immunity, facilitating tumour transmission to non-histocompatible recipients in a mouse model of small cell lung cancer (SCLC) and Tasmanian Devil Facial Tumour. MHC-I APP gene promoters in MHC-I low cancers harbour bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine induced MHC-I upregulation. We find that bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during differentiation to neural progenitors. This physiological silencing of MHC-I expression highlights a conserved mechanism by which cancers arising from these primitive tissues co-opt PRC2 activity to enable immune evasion.
In summary, we show that cancer cells exploit an evolutionarily conserved, lineage specific function of the PRC2 complex to silence the MHC-I antigen processing pathway. Importantly, PRC2-mediated repression of MHC-I APP genes is reversible following pharmacological inhibition of EED or EZH2/EZH1 leading to re-establishment of effective T-cell mediated anti-tumour immunity, providing a rationale for combining inhibitors of the PRC2 complex with immunotherapy to treat these aggressive MHC-I deficient malignancies. Our findings suggest that resistance to cancer immunotherapies may occur not only through genomic mutations that inactivate the MHC-I APP but also through non-genomic mechanisms that exploit the activity of repressive chromatin complexes such as PRC2.