PT  - JOURNAL ARTICLE
AU  - Ngoc Lan Tran
AU  - Lorena Maria Ferreira
AU  - Blanca Alvarez-Moya
AU  - Valentina Buttiglione
AU  - Barbara Ferrini
AU  - Paola Zordan
AU  - Andrea Monestiroli
AU  - Claudio Fagioli
AU  - Eugenia Bezzecchi
AU  - Giulia Maria Scotti
AU  - Antonio Esposito
AU  - Riccardo Leone
AU  - Chiara Gnasso
AU  - Andrea Brendolan
AU  - Luca G. Guidotti
AU  - Giovanni Sitia
TI  - Continuous sensing of IFNα by hepatic endothelial cells shapes a vascular antimetastatic barrier
AID  - 10.1101/2022.05.10.491298
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.05.10.491298
4099  - http://biorxiv.org/content/early/2022/05/11/2022.05.10.491298.short
4100  - http://biorxiv.org/content/early/2022/05/11/2022.05.10.491298.full
AB  - Hepatic metastases are a poor prognostic factor of colorectal carcinoma (CRC) and new strategies to reduce the risk of liver CRC colonization are highly needed. Herein, we used mouse models of hepatic metastatization to demonstrate that the continuous infusion of therapeutic doses of interferon-alpha (IFNα) controls CRC invasion by acting on hepatic endothelial cells (HECs). Mechanistically, IFNα promoted the development of a vascular antimetastatic niche characterized by liver sinusoidal endothelial cells (LSECs) defenestration extracellular matrix and glycocalyx deposition, thus strengthening the liver vascular barrier impairing CRC trans-sinusoidal migration, without requiring a direct action on tumor cells, hepatic stellate cells, hepatocytes, or liver dendritic cells (DCs), Kupffer cells (KCs) and liver capsular macrophages (LCMs). Moreover, IFNα endowed LSECs with efficient cross-priming potential that, along with the early intravascular tumor burden reduction, supported the generation of antitumor CD8+ T cells and ultimately led to the establishment of a protective long-term memory T cell response. These findings provide a rationale for the use of continuous IFNα therapy in perioperative settings to reduce CRC metastatic spreading to the liver.