Induction of antibody-dependent cellular cytotoxicity in vivo by IFN-α and its antitumor efficacy against established B16 melanoma liver metastases when combined with specific anti-B16 monoclonal antibody

We have previously shown the ability of different cytokines to induce antibody-dependent cellular cytotoxicity (ADCC) in murine cells in vitro. In addition we found that the administration of mice of IL-2-induced cells which mediated ADCC and that these cells were phenotypically similar to the cells induced in vitro. In the present study we tested the ability of various cytokines, including IL-1, TNF, IFN-α, and IFN-γ to induce ADCC in vivo. We found that both IFN-α and IFN-γ induced ADCC in the livers and spleens of C3H/Hen-treated mice and that these cytokines together with TNF enhanced the IL-2-induced ADCC in vivo. In C57BL/6 mice which, as previously shown, exhibit relatively low ADCC activity, IFN-α and IFN-γ increased the IL-2-induced ADCC only when 100,000 U of IL-2 were used for priming. The effect of IFN-α on ADCC was dose dependent and was optimal after the administration of 200,000 U of the cytokine given three times a day for 3 days. Similar to the cells induced in vivo by IL-2, the precursors of the cells mediating ADCC were asialo GM1⁺ whereas the effectors were mainly non-adherent, Thy-1⁺ cells. IFN-α-generated cells mediating ADCC in the liver and spleen and, when combined with IL-2, ADCC was induced in the thymus as well. This effect of IFN-α on the induction of ADCC was exploited in an immunotherapy model in which we found that INF-α significantly enhanced the antibody-mediated antitumor effect on established B16 melanoma liver micrometastases. Furthermore, when IL-2 and IFN-α administration was combined with the administration of mAb, a significantly reduced number of established 6- to 8-day B16 melanoma liver macrometastases and prolonged survival of tumor-bearing mice were seen. These studies imply that the administration of appropriate cytokine combinations may be a useful adjunct to the administration of mAb for the treatment of cancer in humans.