Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation
Soluble factors derived from neuroblastoma cell lines suppress dendritic cell differentiation and activation
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DOI：
10.1111/cas.13933
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发表时间：
2019-03-01
期刊：
影响因子：
5.7
通讯作者：
Motohashi, Shinichiro
中科院分区：
文献类型：
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作者：
Harada, Kazuaki;Ihara, Fumie;Motohashi, Shinichiro
树突状细胞（DC）在抗肿瘤免疫和免疫耐受的启动中起关键作用。已经证明，暴露于由肿瘤细胞产生的可溶性因子调节DC功能并诱导致耐受性DC分化。在这项研究中，我们研究了神经母细胞瘤细胞系来源的可溶性因子对DC分化的影响。将从健康志愿者中分离的单核细胞与白细胞介素（IL）-4和粒细胞-巨噬细胞集落刺激因子在神经母细胞瘤细胞系的培养上清液存在下孵育。NLF和后藤等神经母细胞瘤细胞系的培养上清部分阻断了CD 14的下调和CD 1a的上调，并显着降低了成熟DC的IL-12和肿瘤坏死因子（TNF）-α的产生，而SH-SY 5 Y细胞上清没有观察到任何影响。此外，在孵育后24小时，NLF和后藤细胞的上清液增加单核细胞的IL-6和IL-10产生。此外，我们通过刺激不变的自然杀伤T（iNKT）细胞来评估DC功能。与NLF细胞的上清液共培养的α-半乳糖神经酰胺脉冲的DC不能充分刺激iNKT细胞。iNKT细胞产生干扰素（IFN）-γ的能力下降后，刺激与神经母细胞瘤细胞系上清液培养的DC被逆转加入IL-12。通过添加外源性IFN-γ，NLF-超处理的DC中的CD 40表达和IL-12产生增加。这些结果表明，致耐受性DC在神经母细胞瘤肿瘤微环境中被诱导，并减弱iNKT细胞的抗肿瘤作用。iNKT细胞和α GalCer脉冲的DC之间的相互作用具有通过IFN-γ产生恢复致耐受性DC的免疫抑制的潜力。
Dendritic cells (DC) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates DC functions and induces tolerogenic DC differentiation. In this study, we investigated the effects of neuroblastoma cell line-derived soluble factors on DC differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as NLF and GOTO, partially blocked both downregulation of CD14 and upregulation of CD1a, and dramatically decreased IL-12 and tumor necrosis factor (TNF)-alpha production from mature DC, while no effect of SH-SY5Y cell supernatant was noted. In addition, IL-6 and IL-10 production from monocytes was increased by the supernatants of NLF and GOTO cells at 24 hours after incubation. Furthermore, we evaluated DC functions through stimulation of invariant natural killer T (iNKT) cells. alpha-Galactosylceramide-pulsed DC co-cultured with supernatants of NLF cells were unable to sufficiently stimulate iNKT cells. The decreased ability of iNKT cells to produce interferon (IFN)-gamma after stimulation with neuroblastoma cell line supernatant-cultured DC was reversed by addition of IL-12. CD40 expression and IL-12 production in NLF-sup-treated DC were increased by addition of exogenous IFN-gamma. These results indicate that tolerogenic DC are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of iNKT cells. Interactions between iNKT cells and alpha GalCer-pulsed DC have the potential to restore the immunosuppression of tolerogenic DC through IFN-gamma production.