1. Interferon-ε is a tumour suppressor and restricts ovarian cancer.
- Author
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Marks ZRC, Campbell NK, Mangan NE, Vandenberg CJ, Gearing LJ, Matthews AY, Gould JA, Tate MD, Wray-McCann G, Ying L, Rosli S, Brockwell N, Parker BS, Lim SS, Bilandzic M, Christie EL, Stephens AN, de Geus E, Wakefield MJ, Ho GY, McNally O, McNeish IA, Bowtell DDL, de Weerd NA, Scott CL, Bourke NM, and Hertzog PJ
- Subjects
- Animals, Female, Humans, Cell Line, Tumor, Epithelial Cells metabolism, Fallopian Tubes metabolism, Genes, BRCA1, Genes, BRCA2, Genes, p53, Killer Cells, Natural immunology, T-Lymphocytes immunology, T-Lymphocytes, Regulatory, Interferon Type I immunology, Interferon Type I metabolism, Ovarian Neoplasms immunology, Ovarian Neoplasms metabolism, Tumor Suppressor Proteins immunology, Tumor Suppressor Proteins metabolism
- Abstract
High-grade serous ovarian cancers have low survival rates because of their late presentation with extensive peritoneal metastases and frequent chemoresistance
1 , 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., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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