Journal
GENE THERAPY
Volume 17, Issue 8, Pages 991-999Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/gt.2010.54
Keywords
interleukin-4; myeloid cells; tumor stroma; tet-off; anti-tumor immunity
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Funding
- Chinese Academy of Sciences [KSCX2-YW-R-42]
- National Natural Science Foundation of China [30771972, 30700287]
- Ministry of Science and Technology of China [2006CB504304, 2006CB910901, 2009CB918900]
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan
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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. Gene Therapy (2010) 17, 991-999; doi: 10.1038/gt.2010.54; published online 22 April 2010
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