Continuous sensing of IFNα by hepatic endothelial cells shapes a vascular antimetastatic barrier

Hepatic metastases are a distinctive negative prognostic hallmark of colorectal cancer (CRC), thus there is an urgent need to develop new strategies aimed at reducing the risk of liver CRC colonization. Herein we demonstrate that adjuvant steady interferon-alpha (IFNα) administration, intravascularly control invading CRC cells through its direct action on liver sinusoidal endothelial cells (LSECs). Mechanistically, steady IFNα promotes the development of a vascular anti-metastatic niche, characterized by LSEC defenestration, extracellular matrix remodeling and glycocalyx deposition that reinforce the liver vascular barrier impairing CRC transendothelial migration. Furthermore, IFNα promotes LSEC-mediated innate and adaptive immunity, including antigen processing and presentation, that along with the early intravascular reduction of tumor burden, promote anti-tumor CD8+ T cell cross-priming and the generation of a protective long-term anti-tumor-memory response. We analyzed total RNA from CD31+ sorted LSECs from WT and Cdh5(PAC)-CreERT2-Ifnar1-fl/fl mice seven days after IFNα treatment.