Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity

Abstract

Epigenetic dysregulation is a defining feature of tumorigenesis that has been implicated in immune escape1,2. To identify epigenetic factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumor models treated with immune checkpoint blockade (ICB). We identified the H3K9-methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape in tumor cells3–5. We also found that amplification of SETDB1 (1q21.3) in human tumors is associated with immune exclusion and resistance to ICB. SETDB1 represses broad genomic domains, many of which reside within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune gene clusters associated with segmental duplication events, a central mechanism of genome evolution6. SETDB1 loss derepresses latent TE-derived regulatory elements, immunostimulatory genes, and TE-encoded retroviral antigens in these regions, and triggers TE-specific cytotoxic T-cell responses in vivo. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses tumor cell immunogenicity by silencing TEs and evolving genomic loci, and thus represents a candidate target for immunotherapy.