Inhibiting DNA methylation improves antitumor immunity in ovarian cancer

Chiappinelli, Katherine B.; Baylin, Stephen B.

doi:10.1172/jci160186

Cited by 14 publications

(9 citation statements)

References 26 publications

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“… 75 Specifically, B cells and tertiary lymphoid structures in the TME may predict a response to immune checkpoint blockade. 34 Additionally, B cells can also play immunosuppressive roles in autoimmune diseases 76 and cancer. 77 These immunosuppressive B cells are called B regulatory cells (B regs ), and they are known to produce IL-10, which is a cytokine that suppresses T cells and the T helper 1 immune response.…”

Section: Resultsmentioning

confidence: 99%

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

Gomez

Cox

Walker

et al. 2022

J Immunother Cancer

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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 ID8Trp53-/-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 ID8Trp53-/-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-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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Section: Resultsmentioning

confidence: 99%

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

Gomez

Cox

Walker

et al. 2022

J Immunother Cancer

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“…The forest map showed that the feature score (HR = 1.69, 95% CI = 1.17–2.45, p = 0.006), the TNM staging system, and tumor recurrence (HR = 2.58, 95% CI = 1.79–3.72, p < 0.0001) were independent prognostic factors for LUAD, while smoking history and tumor subtype were not ( Figure 5E ). DNA methylation is closely related to tumor immune microenvironment ( Chiappinelli and Baylin, 2022 ; Li et al, 2022 ). We investigated the relationship between methylation feature scores and tumor immune infiltration.…”

Section: Resultsmentioning

confidence: 99%

An integrative analysis of DNA methylation and gene expression to predict lung adenocarcinoma prognosis

Huang

Zeng

et al. 2022

Front. Genet.

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Background: Abnormal DNA methylation of gene promoters is an important feature in lung adenocarcinoma (LUAD). However, the prognostic value of DNA methylation remains to be further explored. Objectives. We sought to explore DNA methylation characteristics and develop a quantifiable criterion related to DNA methylation to improve survival prediction for LUAD patients.Methods: Illumina Human Methylation450K array data, level 3 RNA-seq data and corresponding clinical information were obtained from TCGA. Cox regression analysis and the Akaike information criterion were used to construct the best-prognosis methylation signature. Receiver operating characteristic curve analysis was used to validate the prognostic ability of the DNA methylation-related feature score. qPCR was used to measure the transcription levels of the identified genes upon methylation.Results: We identified a set of DNA methylation features composed of 11 genes (MYEOV, KCNU1, SLC27A6, NEUROD4, HMGB4, TACR3, GABRA5, TRPM8, NLRP13, EDN3 and SLC34A1). The feature score, calculated based on DNA methylation features, was independent of tumor recurrence and TNM stage in predicting overall survival. Of note, the combination of this feature score and TNM stage provided a better overall survival prediction than either of them individually. The transcription levels of all the hypermethylated genes were significantly increased after demethylation, and the expression levels of 3 hypomethylated proteins were significantly higher in tumor tissues than in normal tissues, as indicated by immunohistochemistry data from the Human Protein Atlas. Our results suggested that these identified genes with prognostic features were regulated by DNA methylation of their promoters.Conclusion: Our studies demonstrated the potential application of DNA methylation markers in the prognosis of LUAD.

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“…DNA methyltransferase inhibitors (DNMTis), which are epigenetic modulators, have been shown to induce the cytoplasmic sensing double-stranded RNA (dsRNA) antiviral pathway, upregulate type I IFN (Chiappinelli et al, 2015), activate CD8 T-cell, increase the number of immune cells (Wright et al, 2016;Stone et al, 2017;Vergote et al, 2018), and synergistically downregulate programmed death ligands (PD-L1 and PD-L2) with ICIs to exert antitumor effects. In patients with recurrent chemoresistant OC, hypomethylating agents (HMAs) in combination with ICIs to increase immune signaling and improve the response to immune checkpoint blockade in OC also appear to be a viable therapeutic strategy (Chiappinelli et al, 2022). A phase II clinical trial including 35 patients with platinum-resistant OC (NCT02901899) combined guadecitabine, a secondgeneration HMA, with pembrolizumab, an inhibitor of PD-1 and found that 34% of patients obtained clinical benefit (Chiappinelli et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Targeted therapy and immunotherapy: Diamonds in the rough in the treatment of epithelial ovarian cancer

Huang

Shan

et al. 2023

Front. Pharmacol.

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Currently, for ovarian cancer, which has the highest mortality rate among all gynecological cancers, the standard treatment protocol is initial tumor cytoreductive surgery followed by platinum-based combination chemotherapy. Although the survival rate after standard treatment has improved, the therapeutic effect of traditional chemotherapy is very limited due to problems such as resistance to platinum-based drugs and recurrence. With the advent of the precision medicine era, molecular targeted therapy has gradually entered clinicians’ view, and individualized precision therapy has been realized, surpassing the limitations of traditional therapy. The detection of genetic mutations affecting treatment, especially breast cancer susceptibility gene (BRCA) mutations and mutations of other homologous recombination repair defect (HRD) genes, can guide the targeted drug treatment of patients, effectively improve the treatment effect and achieve a better patient prognosis. This article reviews different sites and pathways of targeted therapy, including angiogenesis, cell cycle and DNA repair, and immune and metabolic pathways, and the latest research progress from preclinical and clinical trials related to ovarian cancer therapy.

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Inhibiting DNA methylation improves antitumor immunity in ovarian cancer

Cited by 14 publications

References 26 publications

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

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

An integrative analysis of DNA methylation and gene expression to predict lung adenocarcinoma prognosis

Targeted therapy and immunotherapy: Diamonds in the rough in the treatment of epithelial ovarian cancer

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