S-20 : Exploiting the type-1 interferon pathway as a biomarker and therapeutic target for metastatic cancer

It has been well described that the initiation and progression of some cancers is tightly controlled by tumour immunosurveillance. Our recent findings suggest that in breast cancer, the balance of pro-tumour and anti-tumour immune responses is critical in dictating metastatic cell survival and outgrowth. We revealed that tumour cells secrete type I IFN and that loss of this signalling is a tumour cell intrinsic mechanism of evading metastasis-specific immune responses and promoting bone metastasis. We have demonstrated that restored type I IFN signalling in mice bearing 4T1.2 breast tumour cells significantly reduces bone metastasis and that metastasis suppression is linked to NK cell activation and decreased accumulation of immune suppressor cells [1] . The key role of the host immune system in responding to tumour cell-derived IFN has also been verified using mice deficient in the type I IFN receptor (Ifnar1). In these studies, the lack of host Ifnar1 increased the incidence of bone metastasis in mice bearing breast tumours of varying metastatic potential. Our current investigations also extend to orthotopic models of prostate cancer where similar observations of increased metastasis are seen in Ifnar1 null animals. Subsequent ex-vivo studies have confirmed a crucial role of IFN signalling to NK cells in tumour cell recognition. These findings have clinical relevance as decreased primary tumour expression of the type I IFN signature or key interferon regulatory factors predict an increased risk of metastatic relapse in breast cancer patients. Additionally, we have now demonstrated potent anti-metastatic effects of IFN-based therapeutics alone or in combination with chemotherapeutics. Our studies are now focused on refining the prognostic markers that best predict metastatic relapse in patients and investigating the therapeutic window where restoring such immune responses is critical in metastasis suppression.