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| Status |
Public on Mar 03, 2022 |
| Title |
ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
|
| Summary |
A disappointingly small proportion (10-30%) of patients with cancer show lasting responses to immune checkpoint blockade (ICB)-based monotherapies. The RNA-editing enzyme ADAR1 is an emerging determinant of resistance to ICB therapy, and prevents ICB responsiveness by repressing immunogenic double-stranded (ds)RNAs, such as those arising from the dysregulated expression of endogenous retroelements (EREs). These dsRNAs trigger an interferon (IFN)-dependent antitumor response by activating the A-form dsRNA (A-RNA) sensing proteins MDA-5, PKR, and OAS1. Here, we show that ADAR1 also prevents accrual of endogenous Z-form dsRNA elements (Z-RNAs) which were enriched in the 3’UTRs of IFN-stimulated mRNAs. Depleting ADAR1 resulted in Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, culminating in RIPK3-mediated necroptosis. As no clinically viable ADAR1 inhibitors currently exist, we searched for a compound that can override the requirement for ADAR1 inhibition and directly activate ZBP1. We identified a small molecule, the curaxin CBL0137, which potently activates ZBP1 by triggering Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and strongly reversed ICB unresponsiveness in mouse models of melanoma. Collectively, these results demonstrate that ADAR1 represses endogenous Z-RNAs and identifies ZBP1-mediated necroptosis as a new determinant of tumor immunogenicity masked by ADAR1. Therapeutic activation of ZBP1-induced necroptosis provides a readily-translatable avenue for rekindling immune responsiveness of ICB-resistant human cancers.
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| Overall design |
ChIP-seq of mouse embryonic fibroblasts(MEFs) with FLAG-tagged ZBP1 for two conditions: untreated cells (FLAG, IgG antibodies), cells treated with CBL0137 for 14 hours(FLAG, IgG, Z22 antibodies).
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| Web link |
https://www.nature.com/articles/s41586-022-04753-7
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| |
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| Contributor(s) |
Zhang T, Yin C, Fedorov A, Herbert A, Balachandran S, Studitsky V |
| Citation(s) |
35614224 |
| |
| Submission date |
Sep 28, 2021 |
| Last update date |
Jun 15, 2022 |
| Contact name |
Aleksandr Fedorov |
| Organization name |
HSE University
|
| Department |
Faculty of Computer Science
|
| Lab |
International Laboratory of Bioinformatics
|
| Street address |
11 Pokrovskiy Boulvard, office T908
|
| City |
Moscow |
| ZIP/Postal code |
109028 |
| Country |
Russia |
| |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (10)
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| This SubSeries is part of SuperSeries: |
| GSE184966 |
ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis |
|
| Relations |
| BioProject |
PRJNA767101 |
| SRA |
SRP339170 |
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