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Restoration of Tumor Immunosurveillance via Targeting of Interleukin-13 Receptor-₂

¹ Department of Surgery, University of Regensburg, Regensburg, Germany; and ² Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases and ³ Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Stefan Fichtner-Feigl, Department of Surgery, University of Regensburg Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany. Phone: 49-941-9440; Fax: 49-941-944-6802; E-mail: stefan.fichtner{at}klinik.uni-regensburg.de.

Key Words: cytotoxicity • IL-13Receptor-2 • metastasis

In previous studies, we described a "counter-immunosurveillance" mechanism initiated by tumor-activated, interleukin-13 (IL-13)–producing natural killer T cells that signal Gr-1⁺ cells to produce transforming growth factor-β₁ (TGF-β₁), a cytokine that suppresses the activity of tumor-inhibiting cytolytic CD8⁺ T cells. Here, we show that in two tumor models (the CT-26 metastatic colon cancer and the 15-12RM fibrosarcoma regressor models), this counter-surveillance mechanism requires the expression of a novel IL-13 receptor, IL-13R₂, on Gr-1^intermediate cells, because down-regulation of IL-13R₂ expression or the activator protein-1 signal generated by the receptor via in vivo administration of specific small interfering RNA or decoy oligonucleotides leads to loss of TGF-β₁ production. Furthermore, acting on prior studies showing that IL-13R₂ expression is induced (in part) by tumor necrosis factor- (TNF-), we show that receptor expression and TGF-β₁ production is inhibited by administration of a TNF-–neutralizing substance, TNF-R-Fc (etanercept). Taking advantage of this latter fact, we then show in the CT-26 model that counter-immunosurveillance can be inhibited, anti-CT-26–specific CD8⁺ cytolytic activity can be restored, and CT-26 metastatic tumor nodules can be greatly decreased by administration of TNF-R-Fc. Corroborative data were obtained using the 15-12RM fibrosarcoma model. These studies point to the prevention of metastatic cancer with an available agent with already known clinically acceptable adverse effects and toxicity. [Cancer Res 2008;68(9):3467–75]

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