Journal Article

Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade

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

2019

Overview

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. Deletion of the A-to-I double-stranded RNA-editing enzyme ADAR1 sensitizes tumour cells to immunotherapy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/106 / 13/44 / 38/91 / 45/91 / 631/250/580 / 631/67/580 / 64/60 / 96/31 / Adenosine Deaminase - deficiency / Adenosine Deaminase - genetics / Adenosine Deaminase - metabolism / Animals / Anticancer properties / Antigen presentation / Antigens / Bioinformatics / Biological response modifiers / Cancer / Cancer cells / Cancer patients / Cancer research / CD8 antigen / Cell Cycle Checkpoints - drug effects / Cell Line, Tumor / Cell recognition / Chemokines / CRISPR / CRISPR-Cas Systems - genetics / Cytotoxicity / Deactivation / Dimensional analysis / DNA methylation / Double-stranded RNA / Drug Resistance, Neoplasm - drug effects / Drug Resistance, Neoplasm - genetics / Editing / Enzymes / Female / Gene expression / Genetic aspects / Genomes / Growth inhibition / Histocompatibility Antigens Class I - immunology / Humanities and Social Sciences / Immune checkpoint / Immunity / Immunotherapy / Inactivation / Inflammation / Inflammation - genetics / Inflammation - immunology / Interferon / Interferon-Induced Helicase, IFIH1 - metabolism / Interferons - immunology / Ligands / Lymphocytes / Lymphocytes T / Melanoma, Experimental - drug therapy / Melanoma, Experimental - genetics / Melanoma, Experimental - immunology / Melanoma, Experimental - radiotherapy / Mice / Mice, Inbred C57BL / multidisciplinary / Mutation / PD-1 protein / Phenotype / Physiological aspects / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Receptors, G-Protein-Coupled - metabolism / Ribonucleic acid / RNA / RNA Editing / RNA, Double-Stranded - genetics / RNA-Binding Proteins - genetics / RNA-Binding Proteins - metabolism / Science / Science (multidisciplinary) / T cells / Tumors