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

Meredith L. Stone, Katherine B. Chiappinelli, Huili Li, Lauren M. Murphy, Meghan E. Travers, Michael J. Topper, Dimitrios Mathios, Michael Lim, Ie Ming Shih, Tian Li Wang, Chien Fu Hung, Vipul Bhargava, Karla R. Wiehagen, Glenn S. Cowley, Kurtis E. Bachman, Reiner Strick, Pamela L. Strissel, Stephen B. Baylin, Cynthia A. Zahnow

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)E10981-E10990
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number51
DOIs
StatePublished - Dec 19 2017

Keywords

  • 5-azacytidine
  • Histone deacetylase inhibitors
  • Immunosuppression
  • Ovarian cancer
  • Type I interferon

ASJC Scopus subject areas

  • General

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