Hepato‐entrained B220 + CD 11c + NK 1.1 + cells regulate pre‐metastatic niche formation in the lung

Abstract

© 2018 The Authors. Published under the terms of the CC BY 4.0 license Primary tumours establish metastases by interfering with distinct organs. In pre-metastatic organs, a tumour-friendly microenvironment supports metastatic cells and is prepared by many factors including tissue resident cells, bone marrow-derived cells and abundant fibrinogen depositions. However, other components are unclear. Here, we show that a third organ, originally regarded as a bystander, plays an important role in metastasis by directly affecting the pre-metastatic soil. In our model system, the liver participated in lung metastasis as a leucocyte supplier. These liver-derived leucocytes displayed liver-like characteristics and, thus, were designated hepato-entrained leucocytes (HepELs). HepELs had high expression levels of coagulation factor X (FX) and vitronectin (Vtn) and relocated to fibrinogen-rich hyperpermeable regions in pre-metastatic lungs; the cells then switched their expression from Vtn to thrombospondin, both of which were fibrinogen-binding proteins. Cell surface marker analysis revealed that HepELs contained B220 + CD11c + NK1.1 + cells. In addition, an injection of B220 + CD11c + NK1.1 + cells successfully eliminated fibrinogen depositions in pre-metastatic lungs via FX. Moreover, B220 + CD11c + NK1.1 + cells demonstrated anti-metastatic tumour ability with IFNγ induction. These findings indicate that liver-primed B220 + CD11c + NK1.1 + cells suppress lung metastasis.