Interferon-epsilon is a tumour suppressor and restricts ovarian cancer

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; Australian Ovarian Cancer Study; McNeish, IA; Bowtell, DDL; de Weerd, NA; Scott, CL; Bourke, NM; Hertzog, PJ

Author(s): 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; Australian Ovarian Cancer Study; McNeish, IA; Bowtell, DDL; de Weerd, NA; Scott, CL; Bourke, NM; Hertzog, PJ;
Details: Publication Year 2023,Volume 620,Issue #7976,Page 1063-1070
Journal Title: Nature
Publication Type: Research article
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-epsilon (IFNepsilon). IFNepsilon 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 IFNepsilon receptor IFNAR1 in different cell compartments, differential exposure status to IFNepsilon and global measures of IFN signalling to show that the mechanism of the anti-tumour activity of IFNepsilon involves direct action on tumour cells and, crucially, activation of anti-tumour immunity. IFNepsilon 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 IFNepsilon 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.
Publisher: Springer Nature
Keywords: Animals; Female; Humans; Cell Line, Tumor; Epithelial Cells/metabolism; Fallopian Tubes/metabolism; Genes, BRCA1; Genes, BRCA2; Genes, p53; *Interferon Type I/immunology/metabolism; Killer Cells, Natural/immunology; *Ovarian Neoplasms/immunology/metabolism; T-Lymphocytes/immunology; T-Lymphocytes, Regulatory; *Tumor Suppressor Proteins/immunology/metabolism
Department(s): Laboratory Research; Medical Oncology
PubMed ID: 37587335
Publisher's Version: https://doi.org/10.1038/s41586-023-06421-w
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2023-11-21 05:54:21

Last Modified: 2024-07-09 05:57:57