Oral Presentation Lorne Infection and Immunity 2022

Interferon epsilon limits ovarian cancer metastasis via tumour-extrinsic mechanisms (#32)

Nicole K Campbell 1 2 , Linden J Gearing 1 2 , Jodee A Gould 1 2 , Georgie Wray-McCann 1 , Nicole A de Weerd 1 2 , Paul J Hertzog 1 2
  1. Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia
  2. Department of Molecular and Translational Sciences, Monash University, Clayton, VIC, Australia

The novel type I interferon, interferon epsilon (IFNε), is a unique cytokine which is constitutively expressed by epithelial cells under hormonal regulation in the female reproductive tract (FRT)1. IFNε is known to be protective against FRT infections1,2, however its role as an anti-tumour cytokine is under investigation. High grade serous ovarian cancer (HGSOC) is a cancer of the FRT which is frequently characterised by extensive metastasis throughout the peritoneal cavity, and carries a five year survival rate of ~45%. Preliminary research has suggested that IFNε is protective against HGSOC metastasis through both intrinsic action on tumour cells, and extrinsic action via immune/stromal cells. However, the relative contribution of these intrinsic and extrinsic effects to the observed anti-tumour efficacy of IFNε is unclear. Moreover, analysis of human HGSOC tumours indicates a potentially high prevalence of resistance/insensitivity to type I IFNs which may limit treatment response to IFNε in a clinical setting. 

Here, the role of extrinsic anti-tumour activity by IFNε was investigated in a syngeneic mouse model of HGSOC. An IFN-insensitive ID8 mouse ovarian tumour cell line was generated via CRISPR-Cas9 knock-out of the type I IFN receptor subunit, IFNAR1. Mice were injected intraperitoneally with wild-type (WT) or IFNAR1-/- ID8 cells, and treated with PBS or IFNε thrice-weekly for 6 weeks. Analysis of disease scores, including tumour burden, ascites volume and peritoneal hemorrhaging, revealed that IFNε treatment effectively limited HGSOC metastasis and disease progression, with no loss of efficacy observed in mice bearing IFNAR1-/- tumours versus WT. Furthermore, IFNε treatment in both WT and IFNAR1-/- tumour-bearing mice was associated with marked alterations in peritoneal immune cells. PBS-treated mice displayed significant infiltration of immunosuppressive immune cells, alongside global suppression of immune cell proliferation - features which were reversed with IFNε treatment. Moreover, IFNε-treated mice displayed a greater frequency of activated immune cells such as CD8+ T cells. Together, these results indicate that the primary mechanism of action of IFNε in HGSOC is tumour-extrinsic, mediated through activity in immune and stromal cells, and is sufficient for effective tumour control versus IFN-insensitive tumours.

  1. Marks, Z. R. C. et al. PROPERTIES AND FUNCTIONS OF THE NOVEL TYPE I INTERFERON EPSILON. Semin. Immunol. 43, 101328 (2019).
  2. Fung, K. Y. et al. Interferon-ε protects the female reproductive tract from viral and bacterial infection. Science (80-. ). 339, 1088–1092 (2013).