IRF-1 Expression Is Essential for Natural Killer Cells to Suppress Metastasis

IFN-gamma promotes tumoral immune surveillance, but its involvement in controlling metastases is less clear. Using a mouse model of pulmonary metastases, we show that local IFN-gamma treatment inhibits formation of metastases through its regulation of IRF-1 in tumor cells. IRF-1 is an IFN-gamma-induced transcription factor pivotal in the regulation of infection and inflammation. IRF-1 blockade abolished the inhibitory effect of IFN-gamma on tumor metastases, whereas ectopic expression of IRF-1 phenocopied the inhibitory effects of IFN-gamma. IRF-1 did not affect the survival of tumor cells in the circulation or their infiltration into lungs, but it was essential to support the pulmonary attraction and activation of natural killer (NK) cells. Depleting NK cells from mice abolished the protective effect of IFN-gamma or IRF-1 on metastases. In addition, cytotoxicity assays revealed that tumor cells expressing IRF-1 were targeted more effectively by NK cells than IRF-1 nonexpressing tumor cells. Moreover, NK cells isolated from lungs inoculated with IRF-1-expressing tumor cells exhibit a greater cytotoxic activity. Mechanistic investigations revealed that IRF-1-induced NK cell cytotoxicity was independent of perforin and granzyme B but dependent on the NK cell activating receptor DNAM-1. Taken together, our findings establish IRF-1 as an essential mediator of the cross-talk between tumor cells and NK cells that mediate immune surveillance in the metastatic niche. Cancer Res; 71(20); 6410-8. (C) 2011 AACR.