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. 2023 Aug;620(7976):1063-1070.
doi: 10.1038/s41586-023-06421-w. Epub 2023 Aug 16.

Interferon-ε is a tumour suppressor and restricts ovarian cancer

Zoe R C Marks #  1   2 , Nicole K Campbell #  1   2 , Niamh E Mangan  1   2 , Cassandra J Vandenberg  3   4 , Linden J Gearing  1   2 , Antony Y Matthews  1   2 , Jodee A Gould  1   2 , Michelle D Tate  1   2 , Georgie Wray-McCann  1   2 , Le Ying  1   2 , Sarah Rosli  1   2 , Natasha Brockwell  5 , Belinda S Parker  5 , San S Lim  1   2 , Maree Bilandzic  2   6 , Elizabeth L Christie  5 , Andrew N Stephens  2   6 , Eveline de Geus  1   2 , Matthew J Wakefield  3   4 , Gwo-Yaw Ho  3   4   7 , Orla McNally  5   8 ; Australian Ovarian Cancer Study; Iain A McNeish  9 , David D L Bowtell  5 , Nicole A de Weerd  1   2 , Clare L Scott  3   4   8 , Nollaig M Bourke  1   2   10 , Paul J Hertzog  11   12
Collaborators, Affiliations

Interferon-ε is a tumour suppressor and restricts ovarian cancer

Zoe R C Marks et al. Nature. 2023 Aug.

Abstract

High-grade serous ovarian cancers have low survival rates because of their late presentation with extensive peritoneal metastases and frequent chemoresistance1, and require new treatments guided by novel insights into pathogenesis. Here we describe the intrinsic tumour-suppressive activities of interferon-ε (IFNε). IFNε is constitutively expressed in epithelial cells of the fallopian tube, the cell of origin of high-grade serous ovarian cancers, and is then lost during development of these tumours. We characterize its anti-tumour activity in several preclinical models: ovarian cancer patient-derived xenografts, orthotopic and disseminated syngeneic models, and tumour cell lines with or without mutations in Trp53 and Brca genes. We use manipulation of the IFNε receptor IFNAR1 in different cell compartments, differential exposure status to IFNε and global measures of IFN signalling to show that the mechanism of the anti-tumour activity of IFNε involves direct action on tumour cells and, crucially, activation of anti-tumour immunity. IFNε activated anti-tumour T and natural killer cells and prevented the accumulation and activation of myeloid-derived suppressor cells and regulatory T cells. Thus, we demonstrate that IFNε is an intrinsic tumour suppressor in the female reproductive tract whose activities in models of established and advanced ovarian cancer, distinct from other type I IFNs, are compelling indications of potential new therapeutic approaches for ovarian cancer.

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Comment in

  • Interferon with ovarian cancer.
    Baek AE. Baek AE. Sci Signal. 2023 Aug 29;16(800):eadk4659. doi: 10.1126/scisignal.adk4659. Epub 2023 Aug 29. Sci Signal. 2023. PMID: 37643242

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