4.7 Article

Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer

Journal

JOURNAL FOR IMMUNOTHERAPY OF CANCER
Volume 10, Issue 11, Pages -

Publisher

BMJ PUBLISHING GROUP
DOI: 10.1136/jitc-2022-004974

Keywords

genital neoplasms; female; tumor microenvironment; lymphocytes; tumor-infiltrating; interferon inducers; adjuvants; pharmaceutic

Funding

  1. George Washington University Cancer Center
  2. School of Medicine and Health Sciences
  3. NCI Cancer Center Support Grant from the National Center for Research Resources (NCRR), of the National Institutes of Health (NIH) [P30 CA91842]
  4. NIH Roadmap for Medical Research

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This study demonstrates that decreasing ADAR1 editing enhances the immune response induced by DNMTi in ovarian cancer cells, leading to inhibition of tumor growth and prolonged survival. The findings suggest that inducing transposable element transcription and inhibiting RNA editing can reverse immune evasion in ovarian cancer, providing a novel therapeutic strategy for this disease.
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 Trp53(-/-) mouse OC cells. Control cells (shGFP) or shAdar1 cells were tested with mock or DNMTi treatment. Tumor-infiltrating immune cells were immunophenotyped using flow cytometry and cell culture supernatants were analyzed for secreted chemokines/cytokines. Mice were injected with syngeneic shAdar1 ID8 Trp53(-/-) cells and treated with tetrahydrouridine/DNMTi while given anti-interferon alpha and beta receptor 1, anti-CD8, or anti-NK1.1 antibodies every 3 days. 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-beta 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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