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. 2018 Apr;15(4):5105-5110.
doi: 10.3892/ol.2018.7954. Epub 2018 Feb 5.

Novel TLR7 agonist stimulates activity of CIK/NK immunological effector cells to enhance antitumor cytotoxicity

Dong Gao  1 , Yongguang Cai  2 , Yanyuan Chen  1 , Wang Li  1 , Chih-Chang Wei  1 , Xiaoling Luo  1 , Yuhuan Wang  1
Affiliations

Novel TLR7 agonist stimulates activity of CIK/NK immunological effector cells to enhance antitumor cytotoxicity

Dong Gao et al. Oncol Lett. 2018 Apr.

Abstract

Toll-like receptor (TLR) 7/8 agonists have been applied in combination with chemo-, radio- or immunotherapy for lymphoma, and used as topical drugs for the treatment of viral skin lesions and skin tumors. In the present study, the role of an adenine analog, 9-(4-carboxyphenyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine [termed Gao Dong (GD)], a novel TLR7 agonist, in the activation of cytokine-induced killer/natural killer (CIK/NK) cells was determined. The results of the present study indicated that GD was able to activate CIK/NK cells. The proportion of GD-induced CD3+CD56+ CIK and CD3-CD56+ NK cells was ~4% higher respectively compared with the control. Notably, combination therapy with CIK/NK cells stimulated by GD, markedly suppressed the proliferation of the chronic myelogenous leukemia K562 cell line. Following GD treatment, the cytotoxicity improved by ~25 and 21% when the effector/target ratio was 20:1 and 10:1, respectively. The results of the present study suggested a novel protocol for CIK/NK cell proliferation and revealed that GD may serve as a potent innate and adaptive immunomodulator in immunocyte culture.

Keywords: Toll-like receptor 7; combination therapy; cytokine-induced killer cells; cytotoxicity; natural killer cells.

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Figures

Figure 1.
Figure 1.
Molecular structure of GD, 9-(4-carboxyphenyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine.
Figure 2.
Figure 2.
Cell proliferation following three distinct treatments of peripheral blood mononuclear cells derived from three human donors. *P<0.05, vs. ‘none’. GD, 9-(4-carboxyphenyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine; IFN-γ, interferon-γ.
Figure 3.
Figure 3.
(A-F) Proportions of CIK, NK and T cells on days 0, 7 and 15 of culture. *P<0.05, vs. ‘none’. GD, 9-(4-carboxyphenyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine; IFN-γ, interferon-γ; CIK, cytokine-induced killer; NK, natural killer.
Figure 4.
Figure 4.
Phenotype of CIK, NK and T-cells in group ‘+GD’ on days 0, 7 and 15 of culture. Results are representative of three experiments. CIK, cytokine-induced killer; NK, natural killer; GD, 9-(4-carboxyphenyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine; FITC, fluorescein isothiocyanate; CD, cluster of differentiation; APC, allophycocyanin; PE, phycoerythrin; PerCP, peridinin chlorophyll protein complex.
Figure 5.
Figure 5.
Cytotoxicity of CIK/NK cells towards the K562 cell line. *P<0.05, vs. ‘none’. GD, 9-(4-carboxyphenyl)-8-hydroxy-2-(2-methoxyethoxy)-adenine; IFN-γ, interferon-γ; CIK, cytokine-induced killer; NK, natural killer; E:T, effector/target ratio.
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