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Published on: August 2, 2024
Interferon-ε is a tumour suppressor and restricts ovarian cancer
Zoe R C Marks1,2, Nicole K Campbell1,2, Niamh E Mangan1,2
1Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
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.
Insights
Interferon-epsilon (IFNε) acts as a tumor suppressor in ovarian cancer by directly inhibiting tumor cells and activating anti-tumor immunity. Its loss during tumor development highlights its therapeutic potential for advanced ovarian cancer.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- High-grade serous ovarian cancers (HGSOC) exhibit poor survival due to late detection and chemoresistance.
- Novel therapeutic strategies are needed, informed by a deeper understanding of HGSOC pathogenesis.
- Interferon-epsilon (IFNε), a protein constitutively expressed in fallopian tube epithelium, is lost during HGSOC development.
Purpose of the Study:
- To investigate the intrinsic tumor-suppressive activities of interferon-epsilon (IFNε) in ovarian cancer.
- To elucidate the mechanisms underlying IFNε's anti-tumor effects.
- To explore the therapeutic potential of IFNε for ovarian cancer.
Main Methods:
- Characterization of IFNε's anti-tumor activity in diverse preclinical models (xenografts, syngeneic models, cell lines).
- Manipulation of the IFNε receptor (IFNAR1) and assessment of IFN signaling.
- Analysis of immune cell populations, including T cells, natural killer cells, myeloid-derived suppressor cells, and regulatory T cells.
Main Results:
- IFNε demonstrates significant anti-tumor activity across multiple preclinical ovarian cancer models.
- IFNε exerts its effects through direct action on tumor cells and activation of anti-tumor immunity.
- IFNε promotes anti-tumor T and natural killer cell activity while suppressing myeloid-derived suppressor cells and regulatory T cells.
Conclusions:
- Interferon-epsilon (IFNε) functions as an intrinsic tumor suppressor in the female reproductive tract.
- IFNε's distinct mechanisms of action, separate from other type I interferons, offer promising therapeutic avenues for ovarian cancer.
- Targeting IFNε may provide novel treatment strategies for established and advanced ovarian cancer.
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