Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade

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, Dawn E. Comstock, Flavian D. Brown, Austin Ayer, Ian C. Kohnle, Hans W. Pope, Margaret D. Zimmer, Debattama R. Sen, Sarah K. Lane-Reticker, Emily J. Robitschek, Gabriel K. Griffin, Natalie B. Collins, Adrienne H. Long, John G. Doench, David Kozono, Erez Y. Levanon and W. Nicholas Haining ()
Additional contact information
Jeffrey J. Ishizuka: Dana-Farber Cancer Institute
Robert T. Manguso: Dana-Farber Cancer Institute
Collins K. Cheruiyot: Dana-Farber Cancer Institute
Kevin Bi: Dana-Farber Cancer Institute
Arpit Panda: Dana-Farber Cancer Institute
Arvin Iracheta-Vellve: Dana-Farber Cancer Institute
Brian C. Miller: Dana-Farber Cancer Institute
Peter P. Du: Dana-Farber Cancer Institute
Kathleen B. Yates: Dana-Farber Cancer Institute
Juan Dubrot: Dana-Farber Cancer Institute
Ilana Buchumenski: Bar-Ilan University
Dawn E. Comstock: Dana-Farber Cancer Institute
Flavian D. Brown: Dana-Farber Cancer Institute
Austin Ayer: Dana-Farber Cancer Institute
Ian C. Kohnle: Dana-Farber Cancer Institute
Hans W. Pope: Dana-Farber Cancer Institute
Margaret D. Zimmer: Dana-Farber Cancer Institute
Debattama R. Sen: Dana-Farber Cancer Institute
Sarah K. Lane-Reticker: Dana-Farber Cancer Institute
Emily J. Robitschek: Dana-Farber Cancer Institute
Gabriel K. Griffin: Dana-Farber Cancer Institute
Natalie B. Collins: Dana-Farber Cancer Institute
Adrienne H. Long: Dana-Farber Cancer Institute
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

Nature, 2019, vol. 565, issue 7737, 43-48

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-018-0768-9

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