Metastasis is the primary cause of mortality- with bone being the most common site of distant metastasis in breast and prostate cancer (BC, PC) patients. Standard therapies for bone metastasis offer palliative rather than curative care, and response to checkpoint-based immunotherapies have been underwhelming to date. Hence, there is an urgent need to understand the mechanisms of bone metastases and immune evasion in bone to develop superior and targeted therapeutic strategies.
Work in our laboratory has uncovered a mechanism of immune evasion in bone, whereby tumour cells shut down type I interferon (IFN) signalling to promote their survival and outgrowth. Type I IFNs are secreted cytokines that not only regulate immune cell activation and anti-cancer function but also dictate tumour cell immunogenicity. Hence, the tumour inherent dampening of IFN signalling may be responsible for the failure of current therapies, particularly immunotherapies. This project aims to uncover the timing of tumour IFN loss during metastasis, the mechanisms by which the pathway is suppressed in the bone niche, and the reversibility of such loss to restore tumour cells invisibility. Using syngeneic models of bone metastasis and patient derived breast and prostate cell lines linked to IFN reporter systems, we have profiled the expression of IFN regulators and targets in metastatic lines and the bone-specific mechanism of signalling loss.
By testing the stability of loss and impact of IFN inducers and chromatin modifying agents (including HDACi), we aim to uncover new therapeutic approaches to restore tumour cell immunogenicity and enhance the impact of immunotherapies in bone metastasis to reduce patient mortality.