Poster Presentation 14th Lorne Infection and Immunity 2024

Interferon epsilon limits ovarian cancer metastasis via regulation of peritoneal immune cells (#121)

Nicole K Campbell 1 2 , Jamie Gearing 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 the female reproductive tract (FRT) epithelium. High grade serous ovarian cancer (HGSOC) is a cancer of the FRT which frequently presents with extensive metastasis throughout the peritoneal cavity, and carries a 5-year survival rate of <40%. We recently published research describing the anti-metastatic properties of IFNε in HGSOC, which was largely mediated through regulation of the anti-tumour immune response1. To identify which immune cells and molecular pathways determine the mechanism of action of IFNε in HGSOC we performed single-cell RNA sequencing (scRNAseq) analysis of peritoneal cells from control and IFNε-treated mice.

Peritoneal cells were isolated from healthy female C57BL/6J mice treated with intraperitoneally (i.p.) injected PBS or IFNε for 4 hours, and from mice which were i.p. injected with ID8Tp53-/-Brca2-/- ovarian cancer cells, and treated with either i.p. PBS or IFNε for two weeks. Gene expression within different populations of peritoneal immune and tumour cells was analysed via scRNAseq.

Increased expression of interferon stimulated genes (ISGs) was observed in all peritoneal immune cell populations following treatment with IFNε for 4 hours, with the highest levels of ISG expression observed in myeloid cells. In the early metastatic setting, IFNε treatment induced significant remodelling of the peritoneal myeloid cells, particularly macrophages and monocytes. Peritoneal myeloid cells from IFNε-treated mice displayed upregulated expression of gene signatures associated with metabolic pathways (e.g. glycolysis, oxidative phosphorylation, fatty acid oxidation), reduced expression of gene signatures associated with TGFβ and IL6/STAT3 signalling, and reduced expression of genes encoding apolipoproteins, including Apoe. Alterations were also observed in the peritoneal T cell and NK cell populations within IFNε-treated mice, which demonstrated increased expression of genes associated with activation and cytotoxicity.

Remodelling of peritoneal macrophages and monocytes, and promotion of anti-tumour immune responses by T cells and NK cells, may determine the anti-metastatic mechanism of action by IFNε in HGSOC. Further studies are required to elucidate the contributions of these key peritoneal immune cell populations and molecular pathways towards the suppression of peritoneal carcinomatosis.

  1. Marks, Z.R.C.*, Campbell, N.K.*, Mangan, N.E., Vandenberg, C.J., Gearing, L.J., Matthews, A.Y., Gould, J.A., Tate, M.D., Wray-McCann, G., Ying, L., Rosli, S., Brockwell, N., Parker, B.S., Lim, S.S., Bilandzic, M., Christie, E.L., Stephens, A.N. de Geus, E., Wakefield, M.J., Ho, G-Y., McNally, O., Australian Ovarian Cancer Study, McNeish, I.A., Bowtell, D.D.L., de Weerd, N.A., Scott, C.L., Bourke, N.M. & Hertzog, P.J. Interferon-ε is a tumour suppressor and restricts ovarian cancer. Nature (2023)