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Contributed by Stephen B. Baylin, November 4, 2017 (sent for review July 14, 2017; reviewed by Adam R. Karpf and Jonathan Licht)
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Significance
Therapies that activate the host immune system have shown tremendous promise for a variety of solid tumors. However, in most cancer types, fewer than half of patients respond to these immunotherapies. We propose epigenetic therapy as a mechanism to sensitize tumors to immune checkpoint therapy. We have shown that inhibiting DNA methylation triggers a viral defense pathway in tumors. Here we show that epigenetic therapy in a mouse model of ovarian cancer increases the numbers of activated immune cells, and that this is dependent on the interferon antiviral response. The combination of epigenetic therapy and immune checkpoint blockade leads to the greatest reduction in tumor burden and increase in survival, and may hold the greatest promise for patients.
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.
Footnotes
↵1M.L.S. and K.B.C. contributed equally to this work.
↵2Present address: Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
↵3Present address: Department of Microbiology, Immunology, and Tropical Medicine and the George Washington University Cancer Center, George Washington University, Washington, DC 20052.
- ↵4To whom correspondence may be addressed. Email: sbaylin{at}jhmi.edu or zahnoci{at}jhmi.edu.
Author contributions: M.L.S., K.B.C., M.J.T., D.M., K.R.W., S.B.B., and C.A.Z. designed research; M.L.S., K.B.C., H.L., L.M.M., M.E.T., V.B., K.R.W., G.S.C., K.E.B., R.S., P.L.S., and C.A.Z. performed research; D.M., M.L., I.-M.S., T.-L.W., C.-F.H., and P.L.S. contributed new reagents/analytic tools; M.L.S., K.B.C., H.L., M.E.T., V.B., K.R.W., R.S., P.L.S., S.B.B., and C.A.Z. analyzed data; and M.L.S., K.B.C., S.B.B., and C.A.Z. wrote the paper.
Reviewers: A.R.K., University of Nebraska Medical Center; and J.L., The University of Florida.
Conflict of interest statement: S.B.B. and C.A.Z. have a collaborative research agreement with Janssen. V.B., K.R.W., G.S.C., and K.E.B. are employed by Janssen.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1712514114/-/DCSupplemental.
Published under the PNAS license.
Epigenetic drugs reduce cancer immunosuppression
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