Antimetastatic effect of CpG DNA mediated by type IIFN

The mechanisms involved in the antimetastatic effect of CpG-containing DNA were investigated in a mouse model of experimental metastasis, Tumor cell c olony formation in lungs or livers of mice after i.v. inoculation with syng eneic fibrosarcoma or thymoma cells was determined. The i.v. injection of p lasmid DNA or synthetic oligodeoxynucleotides (ODNs) containing unmethylate d CpG motifs before tumor cell application strongly inhibited metastasis, B ecause synthetic CpG-ODN was not directly tumor cytotoxic, the target cells for this CpG-ODN effect were determined. The cytotoxic activity on standar d natural killer (NK) targets as well as on fibrosarcoma cells of splenic N K cells and NKT cell-containing liver mononuclear cells derived from CpG-OD N-treated mice was strongly enhanced. Participation of NK/NKT cells in the CpG-induced antimetastatic effect was demonstrated by reduction of the anti metastatic effect in mice depleted of NK/NKT cells and beta (2)-microglobul in-deficient mice. Neutralization of interleukin 12, interleukin 18, or IFN -gamma did not interfere with the CpG-induced antimetastatic effect. Howeve r, in sera of CpG-ODN-treated mice, high levels of IFN-alpha were detected, and in IFN-alpha/beta receptor-deficient mice, the CpG-ODN-induced antimet astatic effect was strongly reduced. These data indicate that CpG-ODNs acti vate NK/NKT cells for antimetastatic activity indirectly via IFN-alpha/beta receptor activation. The exploitation of the stimulatory activity of CpG-O DN for the innate immune system might be a useful strategy for antimetastat ic therapy.