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Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade

Author

Listed:
  • Jeffrey J. Ishizuka

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Robert T. Manguso

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Collins K. Cheruiyot

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Kevin Bi

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Arpit Panda

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

  • Arvin Iracheta-Vellve

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Brian C. Miller

    (Dana-Farber Cancer Institute
    Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Peter P. Du

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Kathleen B. Yates

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Juan Dubrot

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Ilana Buchumenski

    (Bar-Ilan University)

  • Dawn E. Comstock

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

  • Flavian D. Brown

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

  • Austin Ayer

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Ian C. Kohnle

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Hans W. Pope

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Margaret D. Zimmer

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Debattama R. Sen

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

  • Sarah K. Lane-Reticker

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Emily J. Robitschek

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • Gabriel K. Griffin

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology
    Brigham and Women’s Hospital)

  • Natalie B. Collins

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology
    Children’s Hospital, Boston)

  • Adrienne H. Long

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology)

  • John G. Doench

    (Broad Institute of Harvard and Massachusetts Institute of Technology)

  • David Kozono

    (Dana-Farber Cancer Institute)

  • Erez Y. Levanon

    (Bar-Ilan University)

  • W. Nicholas Haining

    (Dana-Farber Cancer Institute
    Broad Institute of Harvard and Massachusetts Institute of Technology
    Children’s Hospital, Boston)

Abstract

Most patients with cancer either do not respond to immune checkpoint blockade or develop resistance to it, often because of acquired mutations that impair antigen presentation. Here we show that loss of function of the RNA-editing enzyme ADAR1 in tumour cells profoundly sensitizes tumours to immunotherapy and overcomes resistance to checkpoint blockade. In the absence of ADAR1, A-to-I editing of interferon-inducible RNA species is reduced, leading to double-stranded RNA ligand sensing by PKR and MDA5; this results in growth inhibition and tumour inflammation, respectively. Loss of ADAR1 overcomes resistance to PD-1 checkpoint blockade caused by inactivation of antigen presentation by tumour cells. Thus, effective anti-tumour immunity is constrained by inhibitory checkpoints such as ADAR1 that limit the sensing of innate ligands. The induction of sufficient inflammation in tumours that are sensitized to interferon can bypass the therapeutic requirement for CD8+ T cell recognition of cancer cells and may provide a general strategy to overcome immunotherapy resistance.

Suggested Citation

  • Jeffrey J. Ishizuka & Robert T. Manguso & Collins K. Cheruiyot & Kevin Bi & Arpit Panda & Arvin Iracheta-Vellve & Brian C. Miller & Peter P. Du & Kathleen B. Yates & Juan Dubrot & Ilana Buchumenski & , 2019. "Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade," Nature, Nature, vol. 565(7737), pages 43-48, January.
    • Handle: RePEc:nat:nature:v:565:y:2019:i:7737:d:10.1038_s41586-018-0768-9
    DOI: 10.1038/s41586-018-0768-9
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    Cited by:

    1. Yanan Liu & Longmiao Hu & Zhengzhen Wu & Kun Yuan & Guangliang Hong & Zhengke Lian & Juanjuan Feng & Na Li & Dali Li & Jiemin Wong & Jiekai Chen & Mingyao Liu & Jiangping He & Xiufeng Pang, 2023. "Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Tanaz Sharifnia & Mathias J. Wawer & Amy Goodale & Yenarae Lee & Mariya Kazachkova & Joshua M. Dempster & Sandrine Muller & Joan Levy & Daniel M. Freed & Josh Sommer & Jérémie Kalfon & Francisca Vazqu, 2023. "Mapping the landscape of genetic dependencies in chordoma," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    3. Jianheng Liu & Tao Huang & Jing Yao & Tianxuan Zhao & Yusen Zhang & Rui Zhang, 2023. "Epitranscriptomic subtyping, visualization, and denoising by global motif visualization," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Nina Frey & Luigi Tortola & David Egli & Sharan Janjuha & Tanja Rothgangl & Kim Fabiano Marquart & Franziska Ampenberger & Manfred Kopf & Gerald Schwank, 2022. "Loss of Rnf31 and Vps4b sensitizes pancreatic cancer to T cell-mediated killing," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Lei Zhang & Li Jiang & Liang Yu & Qin Li & Xiangjun Tian & Jingquan He & Ling Zeng & Yuqin Yang & Chaoran Wang & Yuhan Wei & Xiaoyue Jiang & Jing Li & Xiaolu Ge & Qisheng Gu & Jikun Li & Di Wu & Antho, 2022. "Inhibition of UBA6 by inosine augments tumour immunogenicity and responses," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. Dzana Dervovic & Ahmad A. Malik & Edward L. Y. Chen & Masahiro Narimatsu & Nina Adler & Somaieh Afiuni-Zadeh & Dagmar Krenbek & Sebastien Martinez & Ricky Tsai & Jonathan Boucher & Jacob M. Berman & K, 2023. "In vivo CRISPR screens reveal Serpinb9 and Adam2 as regulators of immune therapy response in lung cancer," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    7. Christos Miliotis & Yuling Ma & Xanthi-Lida Katopodi & Dimitra Karagkouni & Eleni Kanata & Kaia Mattioli & Nikolas Kalavros & Yered H. Pita-Juárez & Felipe Batalini & Varune R. Ramnarine & Shivani Nan, 2024. "Determinants of gastric cancer immune escape identified from non-coding immune-landscape quantitative trait loci," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    8. Marlon S. Zambrano-Mila & Monika Witzenberger & Zohar Rosenwasser & Anna Uzonyi & Ronit Nir & Shay Ben-Aroya & Erez Y. Levanon & Schraga Schwartz, 2023. "Dissecting the basis for differential substrate specificity of ADAR1 and ADAR2," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    9. Yazhong Cui & Yang Miao & Longzhi Cao & Lifang Guo & Yue Cui & Chuanzhe Yan & Zhi Zeng & Mo Xu & Ting Han, 2023. "Activation of melanocortin-1 receptor signaling in melanoma cells impairs T cell infiltration to dampen antitumor immunity," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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