Hepato-entrained B220⁺CD11c⁺NK1.1⁺ 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.