Epigenetic Activation of Transposable Elements to Reverse Immune Evasion in Ovarian Cancer
Open AccessNovel 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 DNMTs activates transcription of double-stranded (ds)RNA, including transposable elements. These dsRNAs activate sensors in the cytoplasm and trigger type I interferon signaling, recruiting host immune cells to kill the tumor cells. Adenosine deaminase 1 (ADAR1) is induced by interferon (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. Thus, I hypothesized that decreasing ADAR1 editing would enhance the DNMTi-induced immune response. Using human OC cell lines, I demonstrated that DNMT inhibition increases RNA editing of immunogenic RNA, and that TP53 mutant cells are more sensitive to type I IFN compared to TP53 wild-type cells. Furthermore, using in vitro human and murine OC models, I showed that ADAR1 loss restores type I IFN signaling with DNMT inhibition. I next showed that combination Adar1 loss with combination DNMTi significantly increases pro-inflammatory cytokine/chemokine production, T cell migration, and sensitivity to IFN- compared to either perturbation alone. Further, 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 tumor-specific, cytotoxic CD8+ T cells. In summary, I showed that the survival benefit from DNMTi plus ADAR1 inhibition is dependent on type I interferon 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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