NF-κB activation triggers NK-cell stimulation by monocyte-derived dendritic cells
NF-κB activation triggers NK-cell stimulation by monocyte-derived dendritic cells
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DOI：
10.1177/1758835919891622
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发表时间：
2019-12-01
影响因子：
4.9
通讯作者：
Doerrie, Jan
中科院分区：
文献类型：
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作者：
Bosch, Naomi C.;Voll, Reinhard E.;Doerrie, Jan
背景资料：在治疗性癌症疫苗接种中，单核细胞衍生的树突状细胞（moDC）有效地激活特异性T细胞应答;然而，优化先天免疫细胞的激活可以支持和改善抗肿瘤作用。用标准细胞因子混合物（由IL-1 β、IL-6、TNF α和PGE组成（2））成熟的moDC的主要缺点是它们不能分泌IL-12 p70。IL-12显著激活天然杀伤（NK）细胞，这在先天性抗肿瘤免疫中至关重要，因为它们充当诱导细胞毒性T淋巴细胞（CTL）应答的辅助细胞，并且还能够直接杀死肿瘤。研究方法：以前我们已经表明，通过转染编码组成型活性IKK β（caIKK β）的mRNA触发moDC中的NF-κ B途径导致IL-12 p70分泌，并提高树突状细胞激活和扩增具有记忆样表型的CTL的能力。在这项研究中，我们研究了这种树突状细胞是否可以激活自体NK细胞。结果如下：用标准细胞因子混合物成熟后用caIKK β-RNA转染的moDC能够激活自体NK细胞，这通过NK细胞上的CD 54、CD 69和CD 25的上调、它们分泌IFN γ的能力和它们的高裂解活性来检测。此外，NK细胞活化的能力并没有被同时的T细胞活化所削弱。结论：caIKK β-DC激活适应性和先天性免疫应答的能力表明临床功效的增强潜力。
Background: In therapeutic cancer vaccination, monocyte-derived dendritic cells (moDCs) efficiently activate specific T-cell responses; however, optimizing the activation of innate immune cells could support and improve the antitumor effects. A major disadvantage of moDCs matured with the standard cytokine cocktail (consisting of IL-1 beta, IL-6, TNF alpha, and PGE(2)) is their inability to secrete IL-12p70. IL-12 prominently activates natural killer (NK) cells, which are crucial in innate antitumor immunity, as they act as helper cells for the induction of a cytotoxic T lymphocyte (CTL) response and are also able to directly kill the tumor. Methods: Previously we have shown that triggering the NF-kappa B pathway in moDCs by transfection of mRNA encoding constitutively active IKK beta (caIKK beta) led to IL-12p70 secretion and improved the dendritic cells' capability to activate and expand CTLs with a memory-like phenotype. In this study, we examined whether such dendritic cells could activate autologous NK cells. Results: moDCs matured with the standard cytokine cocktail followed by transfection with the caIKK beta-RNA were able to activate autologous NK cells, detected by the upregulation of CD54, CD69, and CD25 on the NK cells, their ability to secrete IFN gamma, and their high lytic activity. Moreover, the ability of NK-cell activation was not diminished by simultaneous T-cell activation. Conclusion: The capacity of caIKK beta-DCs to activate both the adaptive and innate immune response indicates an enhanced potential for clinical efficacy.