Breast cancer mortality is most commonly attributed to metastasis to distant organs, which frequently includes the bone. The bone has been identified as a site that harbours dormant tumour cells that initiate relapse – making disseminated cells in the bone attractive targets for anti-metastatic therapies.
Our recent data suggest that disseminated tumour cells can evade immune detection through suppression of the innate type-1 interferon (IFN) pathway. Enforced expression of the master regulator of this pathway (interferon regulatory factor-7) in tumour cells of the syngeneic 4T1.2 model significantly reduced metastasis to bone; as did systemic IFNα1 treatment. This anti-metastatic effect was shown to be IFN-dependent as mice lacking the type-1 IFN receptor (Ifnar1) showed no reduction in metastasis. Additionally, metastasis was accelerated in mice lacking a functional immune system or depleted of CD8+ and NK cells, suggesting that tumour cell secreted IFNs mediate an anti-tumour immune response.
Our current work aims to identify the targets of tumour cell interferon secretion that are responsible for restricting bone metastasis and the key steps in the metastatic cascade where IFN signalling exerts its anti-tumour effects. This includes a comparison of the immune activation and metastasis suppressive effects of various tumour cell-secreted type-1 IFNs. To determine the best way to restore anti-tumour immune responses therapeutically, we will test the efficacy of systemic administration of IFNs and their agonists, such as Poly(I:C), in models that mimic the adjuvant or metastatic treatment setting. Finally, we will establish a biomarker for women who have lost primary tumour IFN secretion and are likely to develop bone metastasis to better target these potential IFN-based therapies. In summary, our work aims to provide pre-clinical evidence for the potential of type I IFN-based therapies in metastatic breast cancer and will lead into studies that identify patients that could benefit from such approaches.