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Ref Type Journal Article
PMID (30559380)
Authors Ishizuka JJ, Manguso RT, Cheruiyot CK, Bi K, Panda A, Iracheta-Vellve A, Miller BC, Du PP, Yates KB, Dubrot J, Buchumenski I, Comstock DE, Brown FD, Ayer A, Kohnle IC, Pope HW, Zimmer MD, Sen DR, Lane-Reticker SK, Robitschek EJ, Griffin GK, Collins NB, Long AH, Doench JG, Kozono D, Levanon EY, Haining WN
Title Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade.
Journal Vol Issue Date Pages Journal Short Title
Nature 565 7737 2019 01 43-48 Nature
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
B2M del melanoma resistant GVAX + unspecified PD-1 antibody Preclinical Actionable In a preclinical study, GVAX in combination with an anti-PD1 treatment did not inhibit tumor growth or increase survival in a syngeneic mouse model of melanoma harboring B2M deletion (PMID: 30559380). 30559380