Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity

Gabriel K. Griffin, Jingyi Wu, Arvin Iracheta-Vellve, James C. Patti, Jeffrey Hsu, Thomas Davis, Deborah Dele-Oni, Peter P. Du, Aya G. Halawi, Jeffrey J. Ishizuka, Sarah Y. Kim, Susan Klaeger, Nelson H. Knudsen, Brian C. Miller, Tung H. Nguyen, Kira E. Olander, Malvina Papanastasiou, Suzanna Rachimi, Emily J. Robitschek, Emily M. Schneider, Mitchell D. Yeary, Margaret D. Zimmer, Jacob D. Jaffe, Steven A. Carr, John G. Doench, W. Nicholas Haining, Kathleen B. Yates, Robert T. Manguso () and Bradley E. Bernstein ()
Additional contact information
Gabriel K. Griffin: Broad Institute of MIT and Harvard
Jingyi Wu: Broad Institute of MIT and Harvard
Arvin Iracheta-Vellve: Broad Institute of MIT and Harvard
James C. Patti: Broad Institute of MIT and Harvard
Jeffrey Hsu: Broad Institute of MIT and Harvard
Thomas Davis: Broad Institute of MIT and Harvard
Deborah Dele-Oni: Broad Institute of MIT and Harvard
Peter P. Du: Broad Institute of MIT and Harvard
Aya G. Halawi: Broad Institute of MIT and Harvard
Jeffrey J. Ishizuka: Dana-Farber Cancer Institute and Harvard Medical School
Sarah Y. Kim: Broad Institute of MIT and Harvard
Susan Klaeger: Broad Institute of MIT and Harvard
Nelson H. Knudsen: Broad Institute of MIT and Harvard
Brian C. Miller: Broad Institute of MIT and Harvard
Tung H. Nguyen: Broad Institute of MIT and Harvard
Kira E. Olander: Broad Institute of MIT and Harvard
Malvina Papanastasiou: Broad Institute of MIT and Harvard
Suzanna Rachimi: Broad Institute of MIT and Harvard
Emily J. Robitschek: Broad Institute of MIT and Harvard
Emily M. Schneider: Broad Institute of MIT and Harvard
Mitchell D. Yeary: Broad Institute of MIT and Harvard
Margaret D. Zimmer: Broad Institute of MIT and Harvard
Jacob D. Jaffe: Broad Institute of MIT and Harvard
Steven A. Carr: Broad Institute of MIT and Harvard
John G. Doench: Broad Institute of MIT and Harvard
W. Nicholas Haining: Broad Institute of MIT and Harvard
Kathleen B. Yates: Broad Institute of MIT and Harvard
Robert T. Manguso: Broad Institute of MIT and Harvard
Bradley E. Bernstein: Broad Institute of MIT and Harvard

Nature, 2021, vol. 595, issue 7866, 309-314

Abstract: Abstract Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape1,2. Here, to identify factors that modulate the immune sensitivity of cancer cells, we performed in vivo CRISPR–Cas9 screens targeting 936 chromatin regulators in mouse tumour models treated with immune checkpoint blockade. We identified the H3K9 methyltransferase SETDB1 and other members of the HUSH and KAP1 complexes as mediators of immune escape3–5. We also found that amplification of SETDB1 (1q21.3) in human tumours is associated with immune exclusion and resistance to immune checkpoint blockade. SETDB1 represses broad domains, primarily within the open genome compartment. These domains are enriched for transposable elements (TEs) and immune 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 tumour-intrinsic immunogenicity, and thus represents a candidate target for immunotherapy.

Date: 2021
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DOI: 10.1038/s41586-021-03520-4

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