Griffin, Wu, Iracheta-Vellve et al. have performed an in vivo CRISPR screen to identify epigenetic modulators in cancer cells other than those already known that affect response to immune checkpoint blockade (ICB). They transduced single-guide RNAs targeting 936 chromatin modulator genes in B16 melanoma or Lewis lung carcinoma (LLC) cells, which were transplanted into mice. Tumour growth was recorded in response to tumour cell vaccination (GVAX) and PD1 blockade (B16) or PD1 and CTLA4 blockade (LLC) and compared with controls. The top ranked gene in both cell lines that was affecting ICB sensitivity and validated in follow-up experiments in vivo encoded the histone H3K9 methyltransferase SETDB1. SETDB1 was amplified in human cancers. Chromatin immunoprecipitation and sequencing analysis of Setdb1 knockout cells compared with controls showed that domains with SETDB1-dependent H3K9 peaks were enriched for transposable elements (TEs) and for segmental duplications that harboured genes involved in immune-related processes. Analysis of the MHCI-specific peptidome showed that 5 of the 10 most upregulated MHCI peptides in Setdb1 knockout cells compared with controls were TE-encoded, and were recognized by tumour-infiltrating T cells leading to increased cytotoxicity in vivo. Overall these findings identified SETDB1 as an immunosuppressive epigenetic modulator in cancer.
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