IL-12-INDUCED TUMOR-REGRESSION CORRELATES WITH IN-SITU ACTIVITY OF IFN-GAMMA PRODUCED BY TUMOR-INFILTRATING CELLS AND ITS SECONDARY INDUCTION OF ANTITUMOR PATHWAYS

Administration of recombinant interleukin-12 (rIL-12) into CSAIM fibro sarcoma-bearing mice results in complete regression of growing tumors, This tumor regression is associated with massive lymphoid cell infilt ration to tumor sites and is completely blocked by injection of anti-i nterferon-gamma (TFN-gamma) monoclonal antibody (mAb). We investigated whether anti-IFN-gamma mAb exerts its suppressive effect on tumor reg ression by blocking the IL-12-induced lymphoid cell migration to tumor sites or by inhibiting the secondary effects of IFN-gamma produced by infiltrating cells. Injection of anti-IFN-gamma mAb to CSA1M-bearing mice before IL-12 treatment prevented the induction of tumor regressio n, whereas this treatment affected only marginally the infiltration of lymphoid cells to tumor masses. In accordance with this, IFN-gamma mR NA was expressed inside tumor masses by infiltrating cells after IL-12 therapy irrespective of whether anti-IFN-gamma mAb was injected. Howe ver, anti-IFN-gamma mAb treatment almost completely abrogated the in s itu expression of inducible nitric oxide synthase (iNOS) as well as IF N-inducible protein-10 (IP-10) genes as examples of IFN-gamma-inducibl e genes, Immunohistochemical analyses also revealed that the expressio n of iNOS protein was completely inhibited by anti-IFN-gamma injection , These results suggest that the implementation of in situ IFN-gamma a ctivity and its secondary induction of anti-tumor pathways such as iNO S and IP-10 expression are important processes in the IL-12-induced tu mor regression.