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NKT cell–mediated repression of tumor immunosurveillance by IL-13 and the IL-4R–STAT6 pathway

Abstract

Using a mouse model in which tumors show a growth-regression-recurrence pattern, we investigated the mechanisms for down-regulation of cytotoxic T lymphocyte–mediated tumor immuno-surveillance. We found that interleukin 4 receptor (IL-4R) knockout and downstream signal transducer and activator of transcription 6 (STAT6) knockout, but not IL-4 knockout, mice resisted tumor recurrence, which implicated IL-13, the only other cytokine that uses the IL-4R–STAT6 pathway. We confirmed this by IL-13 inhibitor (sIL-13Rα2–Fc) treatment. Loss of natural killer T cells (NKT cells) in CD1 knockout mice resulted in decreased IL-13 production and resistance to recurrence. Thus, NKT cells and IL-13, possibly produced by NKT cells and signaling through the IL-4R–STAT6 pathway, are necessary for down-regulation of tumor immunosurveillance. IL-13 inhibitors may prove to be a useful tool in cancer immunotherapy.

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Figure 1: The development of tumors in mice treated with anti-CD4.
Figure 2: The development of tumors in IL-4–deficient, IL-4R and STAT6-deficient mice.
Figure 3: Cytokine production of T cells from 15-12RM–injected BALB/c mice with anti-CD3 stimulation.
Figure 4: The effect of IL-13 inhibitor on tumor recurrence.
Figure 5: Production of IL-13 by NKT cells.
Figure 6: Cytokine production of CD4+ T cells from 15-12RM–injected wild-type BALB/c mice and CD1-deficient mice stimulated with anti-CD3.
Figure 7: The development of tumors in CD1-deficient mice.
Figure 8: CTL activity of CD1-deficient mice injected with 15-12RM.

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Acknowledgements

We thank W. Strober for reading the manuscript and helpful discussions; A. Sher, J. Ahlers, L. Van den Broeke and T. Okazaki for discussion and advice; the Research Supporting Team at the Genetics Institute for making and providing sIL-13Rα2–Fc; and L. Smith for help with preparing the manuscript.

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Correspondence to Jay A. Berzofsky.

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Terabe, M., Matsui, S., Noben-Trauth, N. et al. NKT cell–mediated repression of tumor immunosurveillance by IL-13 and the IL-4R–STAT6 pathway. Nat Immunol 1, 515–520 (2000). https://doi.org/10.1038/82771

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