期刊
JOURNAL OF IMMUNOTHERAPY
卷 35, 期 9, 页码 670-679出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CJI.0b013e318270e135
关键词
dendritic cells; TLR-L; T cells; rodent; tumor immunotherapy
资金
- Wellington Medical Research Foundation
- Wellington division of the Cancer Society of New Zealand
- School of Biological Sciences Thesis Student Scholarship from Victoria University of Wellington
The cytokines granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 are frequently used for generating dendritic cells (DCs) for therapeutic vaccination against cancer. These in vitro DCs share several characteristics with inflammatory monocyte-derived DCs in vivo. In contrast, culture of bone marrow cells in Flt3-ligand (Flt3L) generates a heterogeneous population of DCs, which comprise conventional DCs (cDCs) and plasmacytoid DCs similar to the steady-state populations found in vivo. Although previous studies have identified combinations of toll-like receptor ligands (TLR-Ls) that induce optimal activation of GM-CSF/IL-4 DCs in vitro, the conditions for optimal activation of Flt3L-DCs have not been established. In this study, we show that various combinations of the TLR-Ls Pam3Cys, Poly I: C, lipopolysaccharide, and CpG all increased Flt3L-DC maturation, but only the combination of Pam3Cys/Poly I: C showed a trend to enhanced production of IL-12p70 and tumor necrosis factor-a by cDCs. Pam3Cys/Poly I: C-treated cDCs also displayed enhanced capacity to present antigen to CD4+ T cells, and cross-present to CD8+ T cells, increasing T-cell proliferation in vitro. Within a prophylactic vaccination setting, cDCs activated with Pam3Cys/Poly I: C conferred tumor protection in mice. However, the numbers of cDCs required for protection were higher than the numbers of optimally activated GM-CSF/IL-4 DCs required for a similar effect. Our results show that combined TLR stimulation can enhance both the phenotypic and functional properties of Flt3L-DCs, but even under conditions of optimal activation these cells are not superior in activity to GM-CSF/IL-4 DCs in vivo.
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