Liver metastases reprogram neutrophils to potentiate cancer progression

Abstract Liver metastases are associated with poor overall survival and increased disease progression, regardless of primary tumor type. 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 the metastatic cascade and subsequent disease progression. To investigate how liver metastases reprogram the immune system to potentiate disease progression, we use a preclinical polymetastatic murine model of liver metastasis that spontaneously progresses to the lungs. Using B16F10 melanoma, 4T1 triple negative breast cancer, and LLC non-small cell lung cancer in syngeneic C57Bl/6 or BALB/c mice, we observed that the presence of liver metastases increased lung metastatic burden. We hypothesized liver metastases potentiate the formation of a tumorigenic, immunosuppressive premetastatic niche in distant sites. We conducted single cell RNA sequencing, flow cytometry, and immunofluorescence of the liver, peripheral blood, and lungs of mice with or without liver metastases. These data suggest an association between Ly6g+Ly6c- neutrophils and progression in mice with liver metastases. Future efforts will define the contribution of neutrophils to disease progression with the ultimate goal of understanding and addressing the immunosuppression promoted by liver metastases.