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

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.