Defining mechanisms and immunotherapeutic targets of tumour-microenvironment interaction driving immune tolerance in liver metastases

Patients with melanoma liver metastases have inferior response to checkpoint inhibitors (CPI) compared to those without, resulting in decreased survival. The liver plays a regulatory role in the immune system. Its unique cell populations modulate local and systemic immune tolerance.

Goals:

1. To examine how liver stromal/parenchymal cells interact with melanoma cells resulting in changes in signalling/metabolic pathways and production of inflammatory mediators.

2. To assess how factors identified in Goal #1 drive changes in immunosuppressive cell types and/or T-cell dysfunction both within the liver and at extrahepatic sites.

3. To leverage mechanistic understanding of liver-directed immune tolerance to develop new treatment strategies and biomarkers.

I have developed reductionist in vitro co-culture assays and a syngeneic mouse model of concurrent liver and subcutaneous tumours, which recapitulates resistance to anti-PD-1 therapy seen in patients. I will use functional assays to explore how stromal, parenchymal and immune interactions drive immune tolerance and resistance to CPI in liver metastases. To assess clinical relevance, I will correlate these observations with analyses in human samples. This work will inform novel liver-directed strategies to target CPI resistance in patients with liver metastases.