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Early exposure of high-dose interleukin-4 to tumor stroma reverses myeloid cell-mediated T-cell suppression

Gene Therapy volume 17, pages 991–999 (2010)Cite this article

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Abstract

Myeloid-derived suppressor cells (MDSCs) inhibit T-cell activity and promote tumor growth in tumor-bearing hosts. We sought to determine how to prevent the generation of these cells and modulate anti-tumor immunity at different times during tumor growth. Interleukin-4 (IL-4), a cytokine closely associated with the differentiation of myeloid cells, was expressed locally at the tumor site with its dose and expression time tightly regulated by a tet-off system. Early exposure of high-dose IL-4 to the tumor stromal cells effectively prevented the generation of myeloid suppressor cells and led to a T-cell-mediated tumor rejection. However, IL-4 had no effect a few days after tumor growth, when myeloid suppressor cells had been generated and T cells were tolerized. Importantly, coinoculation of IL-4 receptor (IL-4R)-deficient tumor cells with IL-4R competent, but not IL-4R-deficient myeloid cells led to IL-4-mediated tumor regression in IL-4R-deficient mice, indicating that IL-4 acts directly on myeloid cells. These results show a novel way to prevent T cells from MDSC-induced suppression, with important indications for cancer therapy.

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Acknowledgements

We sincerely express our gratitude to Professor Thomas Blankenstein for his continuous help. We thank Yu Lu, Shubai Liu, Xueqiang Zhao, Xiaopu Zhao, Chen Lin, Jingjing Deng, Xiaoman Liu and Fan Wu for helpful discussions; Chunchun Liu for flow cytometer analysis and Xinyi Wu for technical assistance in performing some animal experiments. This work was supported by Chinese Academy of Sciences (KSCX2-YW-R-42), National Natural Science Foundation of China (30771972 and 30700287), Ministry of Science and Technology of China (2006CB504304, 2006CB910901, and 2009CB918900) and Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

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  1. J Jiang and Z Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. National Laboratory of Biomacromolecules, Chinese Academy of Sciences, Beijing, China

    J Jiang, Z Wang, Z Li, J Zhang, C Wang, X Xu & Z Qin

  2. China-Japan Joint Laboratory of Structural Virology and Immunology, Chinese Academy of Sciences, Beijing, China

    J Jiang, Z Wang, Z Li, J Zhang, C Wang, X Xu & Z Qin

  3. Graduate School of the Chinese Academy of Sciences, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    J Jiang, Z Wang, Z Li & C Wang

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Correspondence to Z Qin.

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Jiang, J., Wang, Z., Li, Z. et al. Early exposure of high-dose interleukin-4 to tumor stroma reverses myeloid cell-mediated T-cell suppression. Gene Ther 17, 991–999 (2010). https://doi.org/10.1038/gt.2010.54

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