Early exposure of high-dose interleukin-4 to tumor stroma reverses myeloid cell-mediated T-cell suppression.
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.
Jiang
J
J
National Laboratory of Biomacromolecules, Chinese Academy of Sciences, Beijing, China.
Wang
Z
Z
Li
Z
Z
Zhang
J
J
Wang
C
C
Xu
X
X
Qin
Z
Z
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D015316:Genetic Therapy; D007108:Immune Tolerance; D015847:Interleukin-4 / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D022423:Myeloid Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D009374:Neoplasms, Experimental / Q000276:immunology*; D019948:Receptors, Interleukin-4 / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014407:Tumor Cells, Cultured
D019948:Receptors, Interleukin-4; D015847:Interleukin-4