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

Lung NK cells are critical for rapid clearance of NK cell‐resistant lung melanoma cells although NK cells are not activated by tumor cells. 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.