Tumors with loss of ADAR1 (an enzyme that converts adenosine to inosine and prevents sensing of double-stranded RNA [dsRNA]) expressed elevated levels of IFNβ and IFNγ, which in turn upregulated the transcription of dsRNA species; dsRNA remained unedited and was detected by dsRNA sensors PKR (leading to tumor growth arrest) and MDA5 (resulting in increased tumor inflammation and immune cell infiltration). Lack of ADAR1 sensitized tumors to irradiation or anti-PD-1 therapy, and overcame adaptive resistance to immunotherapy even when tumor cells could not be recognized by CD8+ T cells due to B2m loss.

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.

Author Info: (1) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard

Author Info: (1) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (2) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (3) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (4) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (5) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. (6) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (7) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (8) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (9) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (10) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (11) Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. (12) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. (13) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. (14) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (15) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (16) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (17) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (18) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. (19) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (20) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (21) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA. (22) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. Division of Pediatric Hematology and Oncology, Children's Hospital, Boston, Massachusetts, USA. (23) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (24) Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. (25) Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (26) Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. (27) Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. nicholas_haining@dfci.harvard.edu. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA. nicholas_haining@dfci.harvard.edu. Division of Pediatric Hematology and Oncology, Children's Hospital, Boston, Massachusetts, USA. nicholas_haining@dfci.harvard.edu.

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