Abstract
Dendritic cells (DCs) play a role in natural killer (NK) cell activation, while NK cells are also able to activate and mature DCs. Toll-like receptors (TLRs) on the surface of DCs and NK cells induce the maturation and activation of these cells when engaged with their cognate ligand. We investigated to generate potent DCs by maturation with NK cells in the presence of TLR agonist in vitro and tested the efficacy of these DC vaccinations in mouse colon cancer model. The optimal ratios of DCs versus NK cells were 1:1 to 1:2. Immature DCs were mature with NK cells in the presence of lipopolysaccharide, which is TLR4 agonist, and further addition of IL-2 induced phenotypically and functionally mature bone marrow-derived DCs. These potent DCs exhibited not only high expression of several costimulatory molecules and high production of IL-12p40 and IL-12p70, but also high allogeneic T cells stimulatory capacity, and the induction of the high activities to generate tumor-specific CTLs. Consistently, vaccination with these DCs efficiently inhibited CT-26 tumor growth in mouse colon cancer model when compared to other vaccination strategies. Interestingly, combination therapy of these DC-based vaccines and with low-dose cyclophosphamide showed dramatic inhibition effects of tumor growth. These results suggest that the DCs maturated with NK cells in the presence of TLR agonist are potent inducer of antitumor immune responses in mouse model and may provide a new source of DC-based vaccines for the development of immunotherapy against colon cancer.
Highlights
Dendritic cells (DCs)-based vaccines continue to be considered an attractive tool for cancer immunotherapy (Ridgway, 2003; Cranmer et al, 2004)
The levels of CD40, CD80, CD86 and I-Ad expression on mature DCs were markedly increased at the ratios of 1:1 to 1:2, and IL-12p70 was significantly increased at the ratio of 1:2 compared to the other ratios (Figure 1A and Supplemental data Figure S1)
The addition of IL-2 to DCNK+LPS (DCNK+LPS+IL-2) further increased the expression of these surface molecules. This pattern of the surface molecules indicated that mature bone marrow (BM)-derived DCs were generated by co-cultured with natural killer (NK) cells in the presence of Toll-like receptor (TLR) agonist
Summary
Dendritic cells (DCs)-based vaccines continue to be considered an attractive tool for cancer immunotherapy (Ridgway, 2003; Cranmer et al, 2004). Toll-like receptors (TLRs) are pattern-recognition receptors that trigger innate immune responses as well as the adaptive immune system by the induction of DC recruitment and maturation (Akira and Hemmi, 2003; Schuurhuis et al, 2006). TLRs have been implicated in pathogen recognition by NK cells. Human and murine NK cells constitutively express functional TLRs, produce IFN-γ, and induce cytotoxic activities in response to TLR ligands (Chalifour et al, 2004; Schmidt et al, 2004; Sivori et al, 2004; Lauzon et al, 2006). NK cells can be directly activated by TLRs, monocytes play an essential role in the activation of effector functions.
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