期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 51, 页码 E10981-E10990出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1712514114
关键词
5-azacytidine; histone deacetylase inhibitors; type I interferon; ovarian cancer; immunosuppression
资金
- Defense Health Program, through the Department of Defense Ovarian Cancer Research Program, under Teal Innovator Award [OC130454/W81XWH-14-1-0385]
- National Cancer Institute [F32CA183214, K99CA204592, P30CA006973]
- Janssen
- SWCRF Collaboration for a Cure Grant
- Irving Hansen Fund
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
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 themodulation 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 alpha-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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