Loss of ADAR1 in tumours overcomes resistance to immune checkpoint blockade
Open accessAbstract
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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Pooled in vivo and in vitro CRISPR-Cas9 based screening have nominated several tumour intrinsic drivers of resistance to immunotherapy, but therapeutic applications of these findings remain limited.
“Pooled in vivo and in vitro CRISPR-Cas9 based screening have nominated several tumour intrinsic drivers of resistance to immunotherapy 4,8-11 , but therapeutic applications of these findings remain limited.”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [8]
The Abstract (page unavailable) says a pooled in vivo CRISPR screen identified several tumour-cell genes that could affect immunotherapy response, including Adar1. Our copy does not describe a pooled in vitro screen that nominated resistance drivers; the in vitro work described in Methods consists of validation experiments. The statement about limited therapeutic applications follows the citation and is not assessed as attributed to this source. (LLM, conf=0.84)
Experimental — accuracy not yet measuredTumour-specific loss of TBK1 did not result in dramatic remodeling of the immune compartment, in contrast to other recently characterized immune evasion genes.
“In contrast to other recently characterized immune evasion genes 4,8,45 , tumour-specific loss of TBK1 did not result in dramatic remodeling of the immune compartment.”
From Targeting TBK1 to overcome resistance to cancer immunotherapy (2023) · cites this paper as [8]
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- Authors
- Ishizuka, J. J., Manguso, R. T., Cheruiyot, C. K., Bi, K., Panda, A., Iracheta-Vellve, A., Miller, B. C., Du, P. P., Yates, K. B., Dubrot, J., Buchumenski, I., Comstock, D. E., Brown, F. D., Ayer, A., Kohnle, I. C., Pope, H. W., Zimmer, M. D., Sen, D. R., Lane-Reticker, S. K., Robitschek, E. J., Griffin, G. K., Collins, N. B., Long, A. H., Doench, J. G., Kozono, D., Levanon, E. Y., & Haining, W. N.
- Affiliations
- Broad Institute (US)
- Bar-Ilan University (IL)
- Dana-Farber Cancer Institute (US)
- Corresponding author
- Haining, W. Nicholas
- ORCID
- Ishizuka, Jeffrey J.
- Manguso, Robert T.
- Cheruiyot, Collins K.
- Bi, Kevin
- Miller, Brian C.
- Du, Peter P.
- Yates, Kathleen B.
- Dubrot, Juan
- Buchumenski, Ilana
- Comstock, Dawn E.
- Ayer, Austin
- Zimmer, Margaret D.
- Sen, Debattama R.
- Lane-Reticker, Sarah K.
- Robitschek, Emily J.
- Griffin, Gabriel K.
- Collins, Natalie B.
- Long, Adrienne H.
- Doench, John G.
- Kozono, David
- Levanon, Erez Y.
- Haining, W. Nicholas
- Venue
- Nature
- Published
- 2018-12-17
- Volume
- 565
- Issue
- 7737
- Pages
- 43-48
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7241251
- OpenAlex
- W2904139947
- Cited by
- 697
- References
- 39
- Citations by year
- 2026: 78 · 2025: 97 · 2024: 76 · 2023: 118 · 2022: 85 · 2021: 105 · 2020: 84 · 2019: 51 · 2013: 1
- FWCI
- 23.17
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Human Genome Research Institute (T32HG002295)
- National Cancer Institute (T32CA009172)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- ADAR1, A-to-I RNA editing, immune checkpoint inhibitor resistance, anti-PD-1 therapy, PKR, MDA5, double-stranded RNA sensing, tumor inflammation, antigen presentation, tumor immunosuppression, cancer immunotherapy
- MeSH terms
- Interferon-Induced Helicase, IFIH1, Adenosine Deaminase, Animals, Female, Immunotherapy, Inflammation, Interferons, Melanoma, Experimental, Mice, Inbred C57BL, Phenotype, RNA, Double-Stranded, Histocompatibility Antigens Class I, RNA-Binding Proteins, RNA Editing, Drug Resistance, Neoplasm, Receptors, G-Protein-Coupled, Cell Line, Tumor, Mice, Cell Cycle Checkpoints, Programmed Cell Death 1 Receptor, CRISPR-Cas Systems
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