Ifn-γ production by lung NK cells is critical for the natural resistance to pulmonary metastasis of B16 melanoma in mice

NK cells are effector lymphocytes playing a critical role in the natural resistance against tumors. However, the precise mechanisms underlying NK cell-mediated natural resistance against tumor metastasis are still unrevealed. B16 cells, mouse melanoma cells, were resistant to freshly isolated NK cell-mediated killing; nevertheless, NK cells were critical for natural resistance against experimental lung metastasis of B16 cells. We found that lung metastasis was increased significantly in IFN _-γ ^-/- mice but not pfp ^-/-, IFN _-αR ^-/-, or IL-12/IL-18 ^-/- mice. Interestingly, freshly isolated lung NK cells, but not spleen or liver NK cells, displayed augmented IFN _-γ production after B16 inoculation. Adoptive transfer of pfp ^-/- NK cells, but not IFN _-γ ^-/- NK cells, significantly decreased B16 lung metastasis in IFN _-γ ^-/- and pfp/IFN _-γ ^-/- mice. Lung metastases of IFN _-γRDN B16 was also increased in NK cell-depleted or IFN _-γ ^-/- mice, suggesting that the IFN _-γ response of host cells was required in the NK cell and IFN _-γ-mediated antimetastatic effect. Our results demonstrate that IFN _-γ production from lung resident NK cells is a key response in the natural resistance to the experimental lung metastasis of NK cell-resistant tumor cells.