IL-12 INDUCES T-HELPER 1-DIRECTED ANTITUMOR RESPONSE

Although IL-12 possesses the most potent single-cytokine antitumor eff icacy, the mechanism by which IL-12 exerts its antitumor activities re mains unclear. Using a complete tumor regression model induced by IL-1 2 treatment, we demonstrate that the antitumor response induced by IL- 12 is mediated by a Th1 cell-directed process, with the macrophage as the effector cell and nitric oxide produced by the activated macrophag e as the effector molecule. The induction of the Th1 response by IL-12 depends on the existence of a host T cell response to the tumor befor e IL-12 administration. IL-12 treatment causes the complete regression of 10-day established s.c. tumors (4-8 mm). Associated with the induc tion of tumor necrosis, activated macrophages expressing high levels o f inducible nitric oxide synthase were found surrounding the tumor. Th e importance of nitric oxide as the effector molecule was further conf irmed by the delay and loss of tumor regression in the presence of a n itric oxide synthase inhibitor in vivo. Examination of tumor-associate d T cells indicates that IL-12 induces production of the Th1 cytokine IFN-gamma and suppresses production of IL-2, IL-4, and IL-10 at the tu mor site, where these are found to be the predominant cytokines produc ed by tumor-associated T cells before IL-12 treatment. These findings demonstrate that IL-12 plays an essential role in the induction of an effective Th1 type of cell-mediated immune response against establishe d tumors.