Restoration of Tumor Immunosurveillance via Targeting of Interleukin-13 Receptor-α2

S Fichtner-Feigl, M Terabe, A Kitani, CA Young, I Fuss… - Cancer research, 2008 - AACR
S Fichtner-Feigl, M Terabe, A Kitani, CA Young, I Fuss, EK Geissler, HJ Schlitt, JA Berzofsky
Cancer research, 2008AACR
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-13Rα2, on Gr …
Abstract
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-13Rα2, on Gr-1intermediate cells, because down-regulation of IL-13Rα2 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-13Rα2 expression is induced (in part) by tumor necrosis factor-α (TNF-α), we show that receptor expression and TGF-β1 production is inhibited by administration of a TNF-α–neutralizing substance, TNF-αR-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-αR-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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