MassIVE MSV000086580

Partial Public

Epigenetic Silencing by SETDB1 Suppresses Tumor-cell Intrinsic Immunogenicity

Description

Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, Dele-Oni D, Du PP, Halawi A, Ishizuka JJ, Kim S, Klaeger S, Knudsen NH, Miller BC, Nguyen T, Olander K, Papanastasiou M, Rachimi S, Robitschek EJ, Schneider EM, Yeary M, Zimmer M, Jaffe JD, Carr SA, Doench JG, Haining WN, Yates KB, Manguso RT, Bernstein BE. 2020. Epigenetic dysregulation is a defining feature of tumorigenesis and has been implicated in immune escape, yet mechanisms that drive immune evasion are poorly understood. To systematically identify epigenetic factors that modulate the immune sensitivity of tumor cells, we performed in vivo CRISPR-Cas9 screens targeting 936 chromatin regulators in mouse tumor models treated with immune checkpoint blockade. We identified the H3K9-methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as cell-intrinsic mediators of immune escape in tumor cells. We also found that amplification of SETDB1 (1q21) in human tumors is associated with reduced cytotoxic T-cell infiltration and resistance to immune checkpoint blockade. Mechanistically, we demonstrate that SETDB1 represses broad domains, hundreds of kilobases in size, many of which reside within the open genome compartment. These SETDB1 domains are enriched for transposable elements (TEs) and immune gene clusters associated with segmental duplication events, a central mechanism of mammalian genome evolution. SETDB1 loss derepresses latent TE-encoded regulatory elements and proximal immune genes within these repetitive regions, including canonical co-stimulatory ligands, and induces hundreds of putative TE-encoded viral antigens. Our study establishes SETDB1 as an epigenetic checkpoint that suppresses intrinsic immunogenicity in cancer cells, and thus represents a candidate target for immunotherapy. [doi:10.25345/C5KV3J] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TMT11 ; Immunopeptidome

Contact

Principal Investigators:
(in alphabetical order)
Steven A. Carr, Broad Institute of MIT and Harvard, United States
Submitting User: clauser

Publications

Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, Dele-Oni D, Du PP, Halawi AG, Ishizuka JJ, Kim SY, Klaeger S, Knudsen NH, Miller BC, Nguyen TH, Olander KE, Papanastasiou M, Rachimi S, Robitschek EJ, Schneider EM, Yeary MD, Zimmer MD, Jaffe JD, Carr SA, Doench JG, Haining WN, Yates KB, Manguso RT, Bernstein BE.
Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.
Nature. 2021 Jul;595(7866):309-314. Epub 2021 May 5.

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