IFN-gamma and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy

Systemic administration of IL-12 and intermittent doses of IL-2 induce comp lete regression of metastatic murine renal carcinoma. Here, we show that ov ert tumor regression induced by IL-12/pulse IL-2 is preceded by recruitment of CD8(+) T cells, vascular injury disrupted tumor neovascularization, and apoptosis of both endothelial and tumor cells. The IL-12/IL-2 combination synergistically enhances cell surface FasL expression on CD8(+) T lymphocyt es in vitro and induces Fas and FasL expression within tumors via an IFN-ga mma -dependent mechanism in vivo. This therapy also inhibits tumor neovascu larization and induces tumor regression by mechanisms that depend criticall y on endogenous IFN-gamma production and an intact Fas/FasL pathway. The ab ility of IL-12/pulse IL-2 to induce rapid destruction of rumor-associated e ndothelial cells and regression of established metastatic tumors is ablated in mice with a dysregulated Fas/FasL pathway. The common, critical role fo r endogenous IFN-gamma and the Fas/FasL pathway in early antiangiogenic eff ects and in antitumor responses suggests that early, cytokine-driven innate immune mechanisms and CD8(+) T cell-mediated responses are interdependent. Definition of critical early molecular events engaged by IL-12/IL-2 may pr ovide new perspective into optimal therapeutic engagement of a productive h ost-antitumor immune response.