Loss of ADAR1 in tumor cells activates cDC1s and sensitizes pancreatic cancer to immunotherapy
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ABSTRACT:
PROVIDER: PRJNA1222324 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR32308467_1.fastq.gz | Fastqsanger.gz | |||
| SRR32308467_2.fastq.gz | Fastqsanger.gz | |||
| SRR32308468_1.fastq.gz | Fastqsanger.gz | |||
| SRR32308468_2.fastq.gz | Fastqsanger.gz | |||
| SRR32308469_1.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic cancer is notoriously resistant to immunotherapy, primarily due to inadequate antigen presentation and the exclusion of immunogenic cells from the tumor microenvironment. Strategies to enhance antigen presentation and promote the infiltration of cytotoxic CD8+ T cells may improve the efficacy of immunotherapy in pancreatic cancer. In this study, we show that ADAR1 is overexpressed in pancreatic cancer, and higher ADAR1 expression correlates with poorer survival outcomes in patients. Depletion of ADAR1 in tumor cells leads to an accumulation of endogenous double-stranded RNA (dsRNA), which triggers the MDA5-mediated type I interferon (IFN) response and results in excessive IFNβ production. Tumor-derived IFNβ then promotes the recruitment and activation of cDC1s, thereby enhancing CD8+ T cell infiltration and activation, and ultimately sensitizing pancreatic cancer to CD8+ T cell-based immunotherapy. These findings suggest that combining ADAR1 inhibition with immunotherapy may offer a promising therapeutic strategy for pancreatic cancer.
2025-04-11 | GSE289275 | GEO
Project description:Cancer immunotherapy efficacy is often limited by primary and acquired resistance. The RNA-editing enzyme ADAR1 has emerged as a key regulator of tumor immune evasion, yet therapeutic targeting is challenged by the essential physiological roles of its constitutively expressed p110 isoform. Here, we identify the interferon-inducible p150 isoform and its Zα domain as a precise therapeutic vulnerability. We demonstrate that ADAR1 p150 is frequently overexpressed in human cancers and correlates with an immunosuppressive tumor microenvironment. Genetic ablation of ADAR1 p150 intrinsically inhibits tumor proliferation and extrinsically triggers a robust type I interferon response and profound remodeling of the tumor immune landscape, converting immunologically "cold" tumors to "hot." Furthermore, we establish that myeloid-specific ADAR1 deletion synergizes with anti-PD-1 therapy by enhancing antigen presentation and fostering a pro-inflammatory microenvironment. Crucially, we delineate the Zα domain as the essential structural determinant for dsRNA editing fidelity. Targeted disruption of this domain alone, without affecting the catalytic deaminase domain, is sufficient to recapitulate the potent antitumor effects of complete ADAR1 ablation, leading to accumulation of immunogenic dsRNA, activation of cytosolic sensors (MDA5/PKR), and potent anti-tumor immunity. Our work provides a compelling preclinical rationale for selectively targeting the ADAR1 p150-Zα axis to reverse malignant RNA editing and overcome resistance to immunotherapy, offering a refined strategy with a potentially superior therapeutic index.
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Project description:ADAR1-p150 isoform, an interferon-stimulated double-stranded RNA-editing enzyme, contributes to immunotherapy resistance by suppressing interferon signaling. While genetic depletion of ADAR1 overcomes immunotherapy resistance in preclinical models, therapeutic targeting of ADAR1 has not been achieved to date in clinical setting. In this study, we found that the FDA-approved all-trans retinoic acid (ATRA) promoted ADAR1 protein degradation in different types of cancer. In addition, ATRA also induces the transcription of PD-L1 in cancer cells and the combination of ATRA and PD-1 blockade reprogrammed the tumor microenvironment to unleash antitumor immunity, thereby impeding tumor growth in vivo. Mechanistically, we identified deubiquitinase USP7 as a key regulator for ADAR1 protein stability. ATRA disrupts the USP7-ADAR1 interaction, promoting ADAR1 degradation. Notably, the regulation of ADAR1 protein degradation by ATRA is independent of its canonical receptors. Instead, ATRA treatment leads to ADAR1 retinoylation, a post-translational modification by conjugation of retinoids, which results in the disruption of USP7-ADAR1 complex to promote ADAR1polyubiquitination. Importantly, clinical data shows a positive correlation between USP7 and ADAR1 protein expression in various cancers, supporting USP7's role in ADAR1 stabilization. Overall, this study sheds light on the control of ADAR1 protein turnover and proposes a mechanism-driven combination therapy using ATRA and PD-1/PD-L1 blockade to convert immunologically cold into hot tumors, holding potential for clinical translation.
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Project description:Cancer immunotherapy efficacy is often limited by primary and acquired resistance. The RNA- editing enzyme ADAR1 has emerged as a key regulator of tumor immune evasion, yet therapeutic targeting is challenged by the essential physiological roles of its constitutively expressed p110 isoform. Here, we identify the interferon-inducible p150 isoform and its Zα domain as a critical therapeutic vulnerability. We demonstrate that ADAR1 p150 is frequently overexpressed in human cancers and correlates with an immunosuppressive tumor microenvironment. Genetic ablation of ADAR1 p150 intrinsically inhibits tumor proliferation and extrinsically triggers a robust type I interferon response and profound remodeling of the tumor immune landscape, converting immunologically "cold" tumors to "hot." Furthermore, we establish that myeloid-specific ADAR1 deletion synergizes with anti-PD-1 therapy by enhancing antigen presentation and fostering a pro-inflammatory microenvironment. Crucially, we delineate the Zα domain as the essential structural determinant for dsRNA editing selectivity. Targeted disruption of this domain alone, without affecting the catalytic deaminase domain, is sufficient to recapitulate the potent antitumor effects of complete ADAR1 ablation, leading to accumulation of immunogenic dsRNA, activation of cytosolic sensors (MDA5/PKR), and potent anti-tumor immunity. Our work provides a compelling rationale for selectively targeting the ADAR1 p150-Zα axis to reverse malignant RNA editing and overcome resistance to immunotherapy, offering a refined strategy with a potentially superior therapeutic index.
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Project description:Expression data from WT cDC1s, Zeb2 KO cDC1s, Nfil3 Zeb2 DKO cDC1s and Zeb2 Id2 DKO cDC1s
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Project description:We used microarrays to determine whether cDC1s from the two double KO are bona fide cDC1s, and what are the transcriptional changes within these cDC1s.
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Project description:Targeting the ADAR1 p150 isoform to overcome immunotherapy resistance
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Project description:Endogenous (self) double-stranded RNAs (dsRNAs) in human cells can activate innate immune responses. ADAR1, an A-to-I editing enzyme of dsRNAs, suppresses aberrant immune activation by self-dsRNAs. However, how ADAR1 influences the cellular dsRNA landscape remains unclear. We show that human ADAR1 downregulates self-dsRNA abundance through editing-dependent and editing-independent mechanisms. We further conducted quantitative dsRNA-sequencing on wild-type and ADAR1-deficient cells. dsRNAs are enriched in protein-coding mRNAs − especially those with repetitive elements and elongated 3’UTRs − and mitochondrial RNAs. ADAR1 loss markedly increased dsRNA quantity but minimally impacted dsRNA identity. ADAR1-regulated dsRNA transcripts consist of nuclear-encoded mRNAs and, unexpectedly, mitochondria-encoded RNAs rarely edited by ADAR1. Accordingly, dsRNAs accumulate to high levels within the mitochondria of ADAR1-deficient cells. Notably, ADAR1 loss sensitizes cells to inflammation under mitochondrial stress (e.g., mitochondrial herniation, X-ray radiation). Hence, we show that dsRNAs regulated by ADAR1 go beyond A-to-I edited transcripts, and that ADAR1 can control mitochondrial-dsRNAs.
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Project description:Function exhaustion and inefficient tumor infiltration rate limit NK cells based cancer immunotherapy. Even though the role of ADAR1 in immune cells and tumorigenesis is gradually gaining attention, its role on NK cells is elusive. In this study, we found ADAR1 expression level was upregulated in peripheral blood (PB)-NK cells from patients with melanoma. ADAR1 knockdown NK cells showed enhanced anti-tumor activity in vitro and in vivo. NK cells specific Adar1 deletion mice showed better tumor control and higher NK cells infiltration level. RNA-seq analysis revealed that NK shADAR1 cells exhibited an activation phenotype with highly cell migration potential. Higher tumor infiltration level of NK shADAR1 cells were verified in three-dimensional (3D) Matrigel-spheroid experiment. Mechanically, we also observed ADAR1 deficiency in NK cells accompanied by RIG-I signaling pathway inhibition and CD38 expression decline, resulting in higher cell mobility, proliferation, and tumor killing capacity. These data suggest ADAR1 may be an emerging therapeutic target for enhanced NK cell immunotherapy.
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