IFN-γ and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy
Jon M. Wigginton, … , Timothy C. Back, Robert H. Wiltrout
Jon M. Wigginton, … , Timothy C. Back, Robert H. Wiltrout
Published July 1, 2001
Citation Information: J Clin Invest. 2001;108(1):51-62. https://doi.org/10.1172/JCI10128.
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Article

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

Abstract

Systemic administration of IL-12 and intermittent doses of IL-2 induce complete regression of metastatic murine renal carcinoma. Here, we show that overt 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 lymphocytes in vitro and induces Fas and FasL expression within tumors via an IFN-γ–dependent mechanism in vivo. This therapy also inhibits tumor neovascularization and induces tumor regression by mechanisms that depend critically on endogenous IFN-γ production and an intact Fas/FasL pathway. The ability of IL-12/pulse IL-2 to induce rapid destruction of tumor-associated endothelial cells and regression of established metastatic tumors is ablated in mice with a dysregulated Fas/FasL pathway. The common, critical role for endogenous IFN-γ and the Fas/FasL pathway in early antiangiogenic effects 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 provide new perspective into optimal therapeutic engagement of a productive host-antitumor immune response.

Authors

Jon M. Wigginton, Eilene Gruys, Lisa Geiselhart, Jeffrey Subleski, Kristin L. Komschlies, Jong-Wook Park, Theresa A. Wiltrout, Kunio Nagashima, Timothy C. Back, Robert H. Wiltrout

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Vascularity of advanced intrarenal Renca tumors and impact of IL-12/puls...
Vascularity of advanced intrarenal Renca tumors and impact of IL-12/pulse IL-2 administration on tumor neovascularization. (a–c) The extensive vascularity of untreated advanced (3.5 weeks old) intrarenal Renca tumors was visualized as described in Methods. Using these methods, the vascularity of established intrarenal Renca tumors was compared directly after treatment of mice with IL-12 (0.5 μg daily on days 8–12 and 15–18) plus pulse IL-2 (300,000 IU twice daily on days 8 and 15) (f) or vehicle alone (d and e). Quantitative assessment of the impact of IL-12/pulse IL-2 administration on vascularization of intrarenal Renca tumor implants (g). Cohorts of mice received subcapsular intrarenal Renca tumor implants and were treated with IL-12 (0.5 μg on days 12–16 and 19–22), pulse IL-2 (300,000 IU twice daily on days 12 and 19), or vehicle alone. At baseline (day 12) and after one (day 16) or two (day 22) cycles of therapy, cohorts of mice were euthanized, and latex suspension containing 111In-ox was infused as described in Methods. The normal and tumor-bearing kidneys were resected, and the amount of radioactivity in each organ was quantitated. Values for the tumor-bearing kidney were normalized to the non–tumor-bearing kidney in each animal. Open circles represent the respective values for individual mice euthanized at the indicated time point.