IFNε Suppresses Ovarian Cancer and Activates Antitumor Immunity

High-grade serous ovarian cancer (HGSOC) has a low survival rate, in part, due to prevalent chemoresistance and a lack of targeted therapies. In an effort to provide insight into the pathogenesis of HGSOC and help guide the development of new treatments, Marks, Campbell, and colleagues sought to determine the role of IFNε, a type I IFN family cytokine expressed in the female reproductive tract, in HGSOC and showed that, although IFNε is highly expressed in fallopian tube epithelial cells, the cells of origin for HGSOC, its expression is reduced in HGSOC. Knockout of Ifne in preclinical models, including ovarian cancer patient-derived xenografts (PDX), orthotopic, syngeneic HGSOC mouse models, and cell lines, revealed antitumor effects, including reduced peritoneal metastases, in both developing and established disease, and a trend toward decreased primary tumor growth, that are not affected by common oncogenes like Trp53 and Brca. Evaluation of the mode of action of IFNε in modulating tumor growth demonstrated that IFNε increased the proportion and activation of antitumor immune cells, including CD4⁺ and CD8⁺ T cells as well as natural killer cells, with ex vivo experiments determining that IFNε-stimulated immune cells killed tumor cells more effectively. IFNε also displayed tumor cell–intrinsic effects, as IFNε treatment decreased proliferation and induced apoptosis of tumor cells. Further investigation into the indirect and direct antitumor activity of IFNε indicated that both mice lacking Ifnar1, the critical receptor for IFN signaling, as well as wild-type mice had reduced metastases after IFNε treatment although not to the same extent, signifying that both direct and indirect effects mediate IFNε-induced HGSOC antitumor immunity. Additionally, Ifnar1-null tumors were found to be as effectively cleared as Ifnar1 wild-type tumors due to repression of immune-suppressive cells, suggesting that the immunomodulatory functions of IFNε may be more crucial in mediating the antitumor effects of IFNε. In summary, this study shows that IFNε acts as a tumor suppressor in ovarian cancer and proposes that IFNε-directed therapies may be clinically beneficial for the treatment of HGSOC.

Marks ZRC, Campbell NK, Mangan NE, Vandenberg CJ, Gearing LJ, Matthews AY, et al. Interferon-ε is a tumour suppressor and restricts ovarian cancer. Nature 2023 Aug 16 [Epub ahead of print].

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