Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden

Stone ML, Chiappinelli KB, Li H, Murphy LM, Travers ME, Topper MJ, Mathios D, Lim M, Shih IM, Wang TL, Hung CF, Bhargava V, Wiehagen KR, Cowley GS, Bachman KE, Strick R, Strissel P, Baylin SB, Zahnow CA (2017)


Publication Type: Journal article

Publication year: 2017

Journal

Book Volume: 114

Pages Range: E10981-E10990

Journal Issue: 51

DOI: 10.1073/pnas.1712514114

Abstract

Ovarian cancer is the most lethal of all gynecological cancers, and there is an urgent unmet need to develop new therapies. Epithelial ovarian cancer (EOC) is characterized by an immune suppressive microenvironment, and response of ovarian cancers to immune therapies has thus far been disappointing. We now find, in a mouse model of EOC, that clinically relevant doses of DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi, respectively) reduce the immune suppressive microenvironment through type I IFN signaling and improve response to immune checkpoint therapy. These data indicate that the type I IFN response is required for effective in vivo antitumorigenic actions of the DNMTi 5-azacytidine (AZA). Through type I IFN signaling, AZA increases the numbers of CD45+ immune cells and the percentage of active CD8+ T and natural killer (NK) cells in the tumor microenvironment, while reducing tumor burden and extending survival. AZA also increases viral defense gene expression in both tumor and immune cells, and reduces the percentage of macrophages and myeloid-derived suppressor cells in the tumor microenvironment. The addition of an HDACi to AZA enhances the modulation of the immune microenvironment, specifically increasing T and NK cell activation and reducing macrophages over AZA treatment alone, while further increasing the survival of the mice. Finally, a triple combination of DNMTi/HDACi plus the immune checkpoint inhibitor α-PD-1 provides the best antitumor effect and longest overall survival, and may be an attractive candidate for future clinical trials in ovarian cancer.

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APA:

Stone, M.L., Chiappinelli, K.B., Li, H., Murphy, L.M., Travers, M.E., Topper, M.J.,... Zahnow, C.A. (2017). Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden. Proceedings of the National Academy of Sciences of the United States of America, 114(51), E10981-E10990. https://dx.doi.org/10.1073/pnas.1712514114

MLA:

Stone, Meredith L., et al. "Epigenetic therapy activates type I interferon signaling in murine ovarian cancer to reduce immunosuppression and tumor burden." Proceedings of the National Academy of Sciences of the United States of America 114.51 (2017): E10981-E10990.

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