Open AccessEpigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity
Author(s) -
Gabriel K. Griffin,
Jingyi Wu,
Arvin Iracheta-Vellve,
James C. Patti,
Jeffrey Hsu,
Thomas Davis,
Deborah DeleOni,
Peter Du,
Aya Halawi,
Jeffrey J. Ishizuka,
Sarah Kim,
Susan Klaeger,
Nelson H. Knudsen,
Brian C. Miller,
Tung H. Nguyen,
Kira E. Olander,
Malvina Papanastasiou,
Suzanna Rachimi,
Emily 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,
B Bernstein
Publication year - 2021
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-021-03520-4
Subject(s) - biology , epigenetics , immune checkpoint , immune system , chromatin , immunogenicity , cancer research , microbiology and biotechnology , cytotoxic t cell , crispr , genetics , immunotherapy , gene , in vitro
Epigenetic dysregulation is a defining feature of tumorigenesis that is implicated in immune escape 1,2 . 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 escape 3-5 . 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 evolution 6 . 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.