Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Fichtner-Feigl, S. et al.

Stefan Fichtner-Feigl, Masaki Terabe, Atsushi Kitani, Cheryl A. Young, Ivan Fuss, Edward K. Geissler, Hans-Jürgen Schlitt, Jay A. Berzofsky, Warren Strober,

Restoration of tumor immunosurveillance via targeting of interleukin-13 receptor-alpha 2.

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-beta(1) (TGF-beta(1)), 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-13R alpha(2), on Gr-1(intermediate) cells, because down-regulation of IL-13R alpha(2) 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-beta(1) production. Furthermore, acting on prior studies showing that IL-13R alpha(2) expression is induced (in part) by tumor necrosis factor-alpha (TNF-alpha), we show that receptor expression and TGF-beta(1) production is inhibited by administration of a TNF-alpha-neutralizing substance, TNF-alpha 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-alpha 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.[1]

References

Restoration of tumor immunosurveillance via targeting of interleukin-13 receptor-alpha 2. Fichtner-Feigl, S., Terabe, M., Kitani, A., Young, C.A., Fuss, I., Geissler, E.K., Schlitt, H.J., Berzofsky, J.A., Strober, W. Cancer Res. (2008) [Pubmed]

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