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Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity

Author

Listed:
  • Gabriel K. Griffin

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital and Harvard Medical School
    Brigham and Women’s Hospital and Harvard Medical School)

  • Jingyi Wu

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital and Harvard Medical School)

  • 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
    Yale Cancer Center and Yale School of Medicine)

  • 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
    Massachusetts General Hospital and Harvard Medical School)

  • Brian C. Miller

    (Broad Institute of MIT and Harvard
    Dana-Farber Cancer Institute and Harvard Medical School
    Dana-Farber Cancer Institute and Harvard Medical School
    Harvard Medical School)

  • 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
    Dana-Farber Cancer Institute and Harvard Medical School)

  • 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
    Inzen Therapeutics)

  • 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
    Dana-Farber Cancer Institute and Harvard Medical School
    Merck)

  • Kathleen B. Yates

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital and Harvard Medical School)

  • Robert T. Manguso

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital and Harvard Medical School)

  • Bradley E. Bernstein

    (Broad Institute of MIT and Harvard
    Massachusetts General Hospital and Harvard Medical School)

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.

Suggested Citation

  • 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 Klaeg, 2021. "Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity," Nature, Nature, vol. 595(7866), pages 309-314, July.
    • Handle: RePEc:nat:nature:v:595:y:2021:i:7866:d:10.1038_s41586-021-03520-4
    DOI: 10.1038/s41586-021-03520-4
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