Immunotherapy has revolutionised cancer treatment, with sustained responses to immune checkpoint inhibitors (ICIs) reported in a number of malignancies. However, responses in the aggressive triple negative breast cancer (TNBC) subtype have been underwhelming and are difficult to predict. As with a number of solid malignancies, enhanced accumulation of tumour infiltrating lymphocytes has been associated with improved outcomes and response to therapy in TNBC. One class of cytokines, the type I interferons (IFN), are major dictators of immune infiltration and activation.
We profiled the tumour-immune landscape to uncover candidate biomarkers that could predict patient responses to therapies and also allow earlier implementation of alternate therapies to reduce patient mortality. We showed that tumour-inherent IFN signalling dramatically influences the immune microenvironment (TME) in TNBC models and patients. This work provided evidence that supported a link between IFN signalling and therapeutic response, whereby expression of an IFN regulatory factor, IRF9, in primary TNBC could not only predict an immune reactive TME, but also a decreased risk of metastatic spread and increased long-term chemotherapeutic response1. Therapeutic restoration of type I IFN signalling using alternative IFN inducers in combination with ICIs, was able to promote sustained anti-tumour responses in vivo2.
However, given the high failure rate of phase I clinical trials there is a clear disparity between in vivo efficacy and patient benefit. This highlights the need for new preclinical models which can accurately assess therapeutic efficacy at an individual patient level. Currently we are developing a new model, using human tissues, to study the interactions between cancer cells and immune cells- including tumour cell visibility and how different therapeutics can alter tumour heat. This model will also allow for validation of biomarkers of response. Development of this model will lead to real time testing of new therapeutics aimed at bolstering tumour immunity and offer a new pipeline for personalised immune therapies.