ArticleJournal for immunotherapy of cancer2022
Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer.
Article in Journal for immunotherapy of cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 37 citations in OpenAlex.
- The therapeutic potential of transposable element activity modulation.EMBO molecular medicine · 2026Review
- Tumour-associated dsRNA accumulation and innate immune activation: mechanistic basis and therapeutic strategies.EBioMedicine · 2026Review
- Epigenetic mechanisms and clinical translation in ovarian cancer: from molecular pathways to precision therapy.Bioscience reports · 2026Review
- Distinguishing self from non-self RNA by editing-specific inosine patterns.Nucleic acids research · 2026Article
- Transposable Element Activation: A Hallmark of Cancer.Cancer discovery · 2026Review
- Immune Evasion in Ovarian Cancer Peritoneal Metastasis: Mechanisms and Biomarker-Guided Therapeutic Matching.Journal of cellular physiology · 2026Review
- mNature communications · 2026Article
- Review
- Chromatin Accessibility in Cancer: Biological Functions, Mechanisms, Therapeutic Potential, and Future Directions.MedComm · 2026Review
- PARPi Combining Nanoparticle LIN28B siRNA for the Management of Malignant Ascites.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Identification of ADAR1i-124: The first effective A-to-I RNA editing inhibitor with promising cancer therapeutic potential.iScience · 2026Article
- Inflammatory milieu and role of epigenetic modifications in high-grade serous ovarian cancer.Clinical epigenetics · 2026Review
- RNA editing: an emerging frontier in cancer therapy - explorations, opportunities, and challenges.International journal of surgery (London, England) · 2026Article
- The context-dependent role of the dsRNA response in linking A-to-I editing and ADAR to normal hematopoiesis and leukemia.Frontiers in cell and developmental biology · 2026Review
- Epigenetic regulation in gynecological cancers: a paradigm shift in immunotherapy strategies.Journal of experimental & clinical cancer research : CR · 2025Review
- Targeting RNA adenosine editing and modification enzymes for RNA therapeutics.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Cancer cell type-specific derepression of transposable elements by inhibition of chromatin modifier enzymes.Communications biology · 2025Article
- Role of tumor microenvironment in ovarian cancer metastasis and clinical advancements.Journal of translational medicine · 2025Review
- Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models.The Journal of clinical investigation · 2025Article
- Immunomodulatory role of RNA modifications in sex hormone-dependent cancers.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundNovel therapies are urgently needed for ovarian cancer (OC), the fifth deadliest cancer in women. Preclinical work has shown that DNA methyltransferase inhibitors (DNMTis) can reverse the immunosuppressive tumor microenvironment in OC. Inhibiting DNA methyltransferases activate transcription of double-stranded (ds)RNA, including transposable elements. These dsRNAs activate sensors in the cytoplasm and trigger type I interferon (IFN) signaling, recruiting host immune cells to kill the tumor cells. Adenosine deaminase 1 (ADAR1) is induced by IFN signaling and edits mammalian dsRNA with an A-to-I nucleotide change, which is read as an A-to-G change in sequencing data. These edited dsRNAs cannot be sensed by dsRNA sensors, and thus ADAR1 inhibits the type I IFN response in a negative feedback loop. We hypothesized that decreasing ADAR1 editing would enhance the DNMTi-induced immune response.
methodsHuman OC cell lines were treated in vitro with DNMTi and then RNA-sequenced to measure RNA editing. Adar1 was stably knocked down in ID8
resultsWe show that ADAR1 edits transposable elements in human OC cell lines after DNMTi treatment in vitro. Combining ADAR1 knockdown with DNMTi significantly increases pro-inflammatory cytokine/chemokine production and sensitivity to IFN-β compared with either perturbation alone. Furthermore, DNMTi treatment and Adar1 loss reduces tumor burden and prolongs survival in an immunocompetent mouse model of OC. Combining Adar1 loss and DNMTi elicited the most robust antitumor response and transformed the immune microenvironment with increased recruitment and activation of CD8+ T cells.
conclusionIn summary, we showed that the survival benefit from DNMTi plus ADAR1 inhibition is dependent on type I IFN signaling. Thus, epigenetically inducing transposable element transcription combined with inhibition of RNA editing is a novel therapeutic strategy to reverse immune evasion in OC, a disease that does not respond to current immunotherapies.
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