Tissue localization of Natural Killer Cell cells dictates surveillance of lung metastasis

The lung is a common metastatic site for various cancer types. Successful immune surveillance of lung metastasis depends on Natural Killer (NK) cells, but the underlying mechanisms are elusive. Here, we show that the pulmonary vasculature recruits and maintains highly cytotoxic and differentiated CD11bhigh NK cells through the integrins Lymphocyte Function-associated Antigen 1 (LFA-1) and Very Late Antigen (VLA-4). These NK cells rapidly eradicate metastasizing tumor cells within the vasculature. However, after the initial clearing phase, pulmonary NK cells fail to track extravasated tumor cells and remain intravascular, outside of the emerging nodules. In contrast, metastatic nodules are preferentially infiltrated with bloodborne and less differentiated CD27high NK cells. Within the metastatic lung, CD11bhigh NK cells undergo a rapid impairment of their migratory and cytotoxic features, while the intranodular CD27high subset transitions towards a transforming growth factor ß (TGF-ß)-driven state with reduced capacity to persist in the tumor tissue. Our findings demonstrate that the compartmentalization of NK cells is key for effective tumor cell surveillance in lung metastasis and that the use of TGF-ß-resistant CD27high NK cells might be a novel strategy to enhance local anti-tumor activity. Overall design: Lungs were dissociated and Live NK1.1+NKp46+ cells were sorted from both lungs and blood. Lung and blood NK cells were distinguished with unique barcodes (Totalseq B0304 and B0306, Biolegend) before scRNA-seq using 10x Genomics platform.