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ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE184962 | GEO | 2022/03/03

REPOSITORIES: GEO

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ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

Project description: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.

2022-03-03 | GSE184964 | GEO

ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

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ADAR1 mutation causes ZBP1-dependent immunopathology I

Project description:The RNA editing enzyme ADAR1 is essential for suppression of innate immune activation and pathology caused by aberrant recognition of self-RNA, a role it carries out by disrupting the duplex structure of endogenous double-stranded RNA species. A point mutation in the Z-nucleic-acid binding domain (ZBD) of ADAR1 is associated with severe autoinflammatory disease. ZBP1 is the only other ZBD-containing mammalian protein and its activation can trigger both cell death and transcriptional responses via the kinases RIPK1 and RIPK3, and the protease caspase-8. Here, we show that the pathology caused by ADAR1 ZBD mutation is driven by activation of ZBP1. We found that ablation of ZBP1 fully rescued the overt pathology caused by ADAR1 mutation, without reversing the underlying inflammatory program caused by this mutation. While loss of RIPK3 partially phenocopied the protective effects of ZBP1 ablation, combined deletion of caspase-8 and RIPK3, or of caspase-8 and MLKL, unexpectedly exacerbated the pathogenic effects of ADAR1 mutation. These findings indicate that ADAR1 is a negative regulator of sterile ZBP1 activation, and that ZBP1-dependent signaling underlies the autoinflammatory pathology caused by mutation of ADAR1.

2022-08-10 | GSE200985 | GEO

ADAR1 mutation causes ZBP1-dependent immunopathology

2022-06-11 | GSE200854 | GEO

ADAR1 mutation causes ZBP1-dependent immunopathology II

2022-08-10 | GSE200986 | GEO

RNA-sequencing of splenic RNA from mice with compound mutations in ADAR1 and ZBP1

Project description:The purpose of this study was to examine the role of ZBP1 in the phenotype that develops when ADAR1 activity is missing, in particular when the Zα domain of ADAR1 is mutated. Mice homozygous for a Zα domain-mutant allele of Adar1 (Adar1mZα/mZα mice) were compared with control mice carrying one mZα allele and one wild type allele of Adar1 (Adar1wt/mZα mice) and with mice carrying one mZα and one null Adar1 allele (Adar1-/mZα mice). Adar1-/mZα mice were also compared with mice additionally deficient in ZBP1 (Adar1-/mZα Zbp1-/- mice). Given the early postnatal lethal phenotype that develops in Adar1-/mZα mice, comparisons were made in RNA isolated from spleen tissue from newborn mice of each genotype (5 mice per genotype).

2022-04-27 | E-MTAB-10953 | biostudies-arrayexpress

RNA-sequencing of brain RNA from mice with compound mutations in ADAR1 and MAVS or ZBP1

Project description:The purpose of this study was to examine the role of MAVS and ZBP1 in the phenotype that develops when ADAR1 activity is missing, in particular when the Za domain of ADAR1 is mutated. Mice homozygous for a Za domain-mutant allele of Adar1 (Adar1mZa/mZa mice) were compared with control mice carrying one mZa allele and one wild type allele of Adar1 (Adar1wt/mZa mice) and with mice carrying one mZa and one null Adar1 allele (Adar1-/mZa mice). Adar1-/mZa mice were also compared with mice additionally deficient in ZBP1 (Adar1-/mZa Zbp1-/- mice) or MAVS (Adar1-/mZa Mavs-/- mice). Given the early postnatal lethal phenotype that develops in Adar1-/mZa mice, comparisons were made in RNA isolated from brain tissue from newborn mice of each genotype (4 mice per genotype).

2022-04-27 | E-MTAB-11537 | biostudies-arrayexpress

RNA-sequencing of lung RNA from mice with compound mutations in ADAR1 and MAVS, ZBP1 or RIPK3.

Project description:The purpose of this study was to examine the role of MAVS, ZBP1 and RIPK3 in the phenotype that develops when ADAR1 activity is impaired, in particular when the Za domain of ADAR1 is mutated. Mice homozygous for a Za domain-mutant allele of Adar1 (Adar1mZa/mZa mice) and mice carrying one mZa and one null Adar1 allele (Adar1-/mZa mice) were compared with control mice that were either wild type or heterozygous for the Adar1 mZa allele (Adar1wt/mZa mice). The effects of MAVS deficiency, RIPK3 deficiency, ZBP1 deficiency or ZBP1 Za domain mutations were assessed by analysing compound mutant mice. Given the early postnatal lethal phenotype that develops in Adar1-/mZa mice, comparisons were made in RNA isolated from lung tissue from newborn mice of each genotype (5 mice per genotype). As Adar1-/mZa mice additionally lacking Mavs or Zbp1 are viable, adult mice (15-20 weeks of age) were also used for several compound mutations as donors of lung tissue.

2022-06-09 | E-MTAB-11540 | biostudies-arrayexpress

ADAR1 restricts ZBP1–mediated immune response and PANoptosis to promote tumorigenesis

Project description:Cell death provides host defense and maintains homeostasis. Zα-containing molecules are essential for these processes. ZBP1 activates inflammatory cell death, PANoptosis, while ADAR1 serves as an RNA editor to maintain homeostasis. Here, we identify and characterize ADAR1’s interaction with ZBP1, defining its role in cell death regulation and tumorigenesis. Combining IFNs and nuclear export inhibitors (NEIs) activates ZBP1–dependent PANoptosis. ADAR1 suppresses PANoptosis by interacting with the Zα2 domain of ZBP1 to limit ZBP1 and RIPK3 interactions. Adar1fl/flLysMcre mice are resistant to development of colorectal cancer and melanoma, but deletion of the ZBP1 Zα2 domain restores tumorigenesis in these mice. In addition, treating wildtype mice with IFN-γ and the NEI KPT-330 regresses melanoma in a ZBP1–dependent manner. Our findings suggest that ADAR1 suppresses ZBP1–mediated PANoptosis, promoting tumorigenesis. Defining the functions of ADAR1 and ZBP1 in cell death is fundamental to inform therapeutic strategies for cancer and other diseases.

2021-10-19 | GSE184323 | GEO

ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

Project description:ADAR1 masks the cancer immunotherapeutic promise of ZBP1-driven necroptosis

| PRJNA767104 | ENA