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DFMO and 5-Azacytidine Increase M1 Macrophages in the Tumor Microenvironment of Murine Ovarian Cancer.
Travers, Meghan; Brown, Stephen M; Dunworth, Matthew; Holbert, Cassandra E; Wiehagen, Karla R; Bachman, Kurtis E; Foley, Jackson R; Stone, Meredith L; Baylin, Stephen B; Casero, Robert A; Zahnow, Cynthia A.
Afiliación
  • Travers M; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
  • Brown SM; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
  • Dunworth M; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
  • Holbert CE; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
  • Wiehagen KR; Janssen Research & Development, Spring House, Pennsylvania.
  • Bachman KE; Janssen Research & Development, Spring House, Pennsylvania.
  • Foley JR; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
  • Stone ML; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
  • Baylin SB; Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
  • Casero RA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland.
  • Zahnow CA; Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland. zahnoci@jhmi.edu rcasero@jhmi.edu.
Cancer Res ; 79(13): 3445-3454, 2019 07 01.
Article en En | MEDLINE | ID: mdl-31088836
Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (5AZA-C) activates type I interferon signaling to increase IFNγ+ T cells and natural killer (NK) cells and reduce the percentage of macrophages in the tumor microenvironment. To improve the efficacy of epigenetic therapy, we hypothesized that the addition of α-difluoromethylornithine (DFMO), an ornithine decarboxylase inhibitor, may further decrease immunosuppressive cell populations improving outcome. We tested this hypothesis in an immunocompetent mouse model for ovarian cancer and found that in vivo, 5AZA-C and DFMO, either alone or in combination, significantly increased survival, decreased tumor burden, and caused recruitment of activated (IFNγ+) CD4+ T cells, CD8+ T cells, and NK cells. The combination therapy had a striking increase in survival when compared with single-agent treatment, despite a smaller difference in recruited lymphocytes. Instead, combination therapy led to a significant decrease in immunosuppressive cells such as M2 polarized macrophages and an increase in tumor-killing M1 macrophages. In this model, depletion of macrophages with a CSF1R-blocking antibody reduced the efficacy of 5AZA-C + DFMO treatment and resulted in fewer M1 macrophages in the tumor microenvironment. These observations suggest our novel combination therapy modifies macrophage polarization in the tumor microenvironment, recruiting M1 macrophages and prolonging survival. SIGNIFICANCE: Combined epigenetic and polyamine-reducing therapy stimulates M1 macrophage polarization in the tumor microenvironment of an ovarian cancer mouse model, resulting in decreased tumor burden and prolonged survival.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Protocolos de Quimioterapia Combinada Antineoplásica / Cistadenocarcinoma Seroso / Modelos Animales de Enfermedad / Microambiente Tumoral / Inmunidad Innata / Macrófagos Límite: Animals Idioma: En Revista: Cancer Res Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Protocolos de Quimioterapia Combinada Antineoplásica / Cistadenocarcinoma Seroso / Modelos Animales de Enfermedad / Microambiente Tumoral / Inmunidad Innata / Macrófagos Límite: Animals Idioma: En Revista: Cancer Res Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos