Perforin‐dependent NK cell cytotoxicity is sufficient for anti‐metastatic effect of IL‐12

IL‐12 exerts a potent anti‐tumor effect, which is possibly mediated by multiple mechanisms including activation of NK and NKT cells, induction of cytotoxic T lymphocytes, and inhibition of angiogenesis. In the present study, we characterized the cytotoxic effector cells and mechanisms responsible for the anti‐metastatic effect of IL‐12. Administration of IL‐12 had a comparable inhibitory effect on experimental lung metastasis of B16 melanoma cells in wild‐type C57BL / 6 mice and RAG‐2 − / − mice that lack T and NKT cells, which was abolished by depletion of NK cells. Cytotoxic activity of liver and splenic mononuclear cells against B16 was induced by IL‐12 administration in RAG‐2 − / − mice at a level comparable to that in wild‐type mice, which was also abolished by depletion of NK cells. Moreover, the anti‐metastatic effect of IL‐12 was abrogated by perforin deficiency, but not by Fas ligand deficiency, in association with a lack of IL‐12‐induced cytotoxic activity of liver and splenic mononuclear cells against B16. These results suggest that perforin‐dependent cytotoxicity of IL‐12‐activated NK cells is sufficient for the anti‐metastatic effect of IL‐12.