DFMO and 5-azacytidine increase M1 macrophages in the tumor microenvironment of murine ovarian cancer.
2019
Although ovarian cancer has a low incidence rate, it remains the most deadly gynecologic malignancy. Previous work has demonstrated that the DNMTi 5-Azacytidine (AZA) activates type I interferon signaling to increase IFNγ+ T cells and 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 decarboxylaseinhibitor, 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, AZA 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 therapyhad a striking increase in survival when compared to single agent treatment, despite a smaller difference in recruited lymphocytes. Instead,
combination therapyled 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 antibodyreduced the efficacy of AZA+DFMO treatment and resulted in fewer M1 macrophages in the
tumor microenvironment. These observations suggest our novel
combination therapymodifies
macrophage polarizationin the
tumor microenvironment, recruiting M1 macrophages and prolonging survival.
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