Continuous sensing of IFNa 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 (IFNa) administration, intravascularly control invading CRC cells through its direct action on liver sinusoidal endothelial cells (LSECs). Mechanistically, steady IFNa 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, IFNa 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. Overall design: We analyzed total RNA from CD31+ sorted LSECs from WT and Cdh5(PAC)-CreERT2-Ifnar1-fl/fl mice seven days after IFNa treatment.

肝转移是结直肠癌（colorectal cancer, CRC）的标志性不良预后特征，因此亟需开发可降低结直肠癌肝脏定植风险的新型策略。本研究证实，辅助性持续性干扰素-α（interferon-alpha, IFNa）可通过直接作用于肝窦内皮细胞（liver sinusoidal endothelial cells, LSECs），在血管腔内抑制侵袭性结直肠癌细胞。机制层面，持续性IFNa可促进血管抗转移微环境的形成，该微环境以肝窦内皮细胞开窗消失、细胞外基质重塑及糖萼沉积为特征，能够强化肝脏血管屏障，阻碍结直肠癌细胞的跨内皮迁移。此外，IFNa可介导肝窦内皮细胞调控天然免疫与适应性免疫应答，包括抗原加工与呈递过程，结合早期血管腔内肿瘤负荷的降低，可促进抗肿瘤CD8+ T细胞交叉致敏，并产生具有保护作用的长期抗肿瘤记忆应答。实验整体设计：我们对干扰素-α处理7天后的野生型（wild type, WT）及Cdh5(PAC)-CreERT2-Ifnar1-fl/fl小鼠的经CD31阳性分选的肝窦内皮细胞的总RNA进行了分析。