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Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity.
Griffin, Gabriel K; Wu, Jingyi; Iracheta-Vellve, Arvin; Patti, James C; Hsu, Jeffrey; Davis, Thomas; Dele-Oni, Deborah; Du, Peter P; Halawi, Aya G; Ishizuka, Jeffrey J; Kim, Sarah Y; Klaeger, Susan; Knudsen, Nelson H; Miller, Brian C; Nguyen, Tung H; Olander, Kira E; Papanastasiou, Malvina; Rachimi, Suzanna; Robitschek, Emily J; Schneider, Emily M; Yeary, Mitchell D; Zimmer, Margaret D; Jaffe, Jacob D; Carr, Steven A; Doench, John G; Haining, W Nicholas; Yates, Kathleen B; Manguso, Robert T; Bernstein, Bradley E.
Afiliação
  • Griffin GK; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Wu J; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Iracheta-Vellve A; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Patti JC; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Hsu J; Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Davis T; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Dele-Oni D; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Du PP; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Halawi AG; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ishizuka JJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Kim SY; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Klaeger S; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Knudsen NH; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Miller BC; Department of Internal Medicine (Oncology), Yale Cancer Center and Yale School of Medicine, New Haven, CT, USA.
  • Nguyen TH; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Olander KE; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Papanastasiou M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Rachimi S; Department of Medicine and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Robitschek EJ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Schneider EM; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Yeary MD; Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Zimmer MD; Department of Immunology and Evergrande Center for Immunological Diseases, Harvard Medical School, Boston, MA, USA.
  • Jaffe JD; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Carr SA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Doench JG; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Haining WN; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Yates KB; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Manguso RT; Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
  • Bernstein BE; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nature ; 595(7866): 309-314, 2021 07.
Article em En | MEDLINE | ID: mdl-33953401
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Histona-Lisina N-Metiltransferase / Inativação Gênica / Neoplasias Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Nature Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Histona-Lisina N-Metiltransferase / Inativação Gênica / Neoplasias Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans Idioma: En Revista: Nature Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos