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Gene Ther. 2010 Aug;17(8):991-9. doi: 10.1038/gt.2010.54. Epub 2010 Apr 22.

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

Author information

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

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.

PMID:
20410929
DOI:
10.1038/gt.2010.54
[Indexed for MEDLINE]

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