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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

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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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Figure 1

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Infiltration of CD8+ T lymphocytes in established Renca tumors after tre...
Infiltration of CD8+ T lymphocytes in established Renca tumors after treatment with IL-12/pulse IL-2. Cohorts of mice received subcutaneous Renca implants and were subsequently treated with IL-12 (0.5 μg daily on days 11–15 and 18–21), pulse IL-2 (300,000 IU twice daily on days 11 and 18), or vehicle alone. After two cycles of therapy, tumors were resected and stained for expression of CD8 or CD4. Anti-CD8 sections from control mice (c) and mice treated with IL-12/pulse IL-2 (d) and anti-CD4–stained sections from control (a) and IL-12/pulse IL-2–treated (b) mice are shown. ×200.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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