Liver Metastases Potentiate Cancer Progression

Abstract Metastases are the primary cause of cancer mortality, and different sites of metastasis are associated with different prognostic outcomes. In particular, liver metastases are associated with poor overall survival and increased disease progression. It is known that liver metastases suppress systemic antitumor immunity to limit immunotherapy efficacy on primary tumors through hepatic siphoning and deletion of CD8 +T cells, induction of T regulatory cells, and depletion of dendritic cells. However, it remains unclear how liver metastases promote subsequent disease progression and the metastatic cascade. To investigate how liver metastases reprogram the immune system to potentiate disease progression, we developed a preclinical polymetastatic murine model of liver and lung metastases. Using B16F10 melanoma in syngeneic C57Bl/6 mice, we observed that the presence of liver metastases increased the lung metastatic burden. We hypothesized that liver metastases potentiate the formation of a tumorigenic, immunosuppressive premetastatic niche in distant sites. We conducted single cell RNA (scRNA) sequencing and flow cytometry immune profiling of the liver, peripheral blood, and lungs of mice with or without liver metastases. Together, these data suggest an association between Ly6g +Ly6c −neutrophils and melanoma progression in mice with liver metastases. Future efforts will focus on defining the contribution of neutrophils to disease progression with the ultimate goal of understanding and addressing the immunosuppression promoted by liver metastases.