Comparison of clinical grade type I polarized and standard matured dendritic cells for cancer immunotherapy
Comparison of clinical grade type I polarized and standard matured dendritic cells for cancer immunotherapy
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DOI：
10.1016/j.vaccine.2012.11.053
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发表时间：
2013-01-11
期刊：
影响因子：
5.5
通讯作者：
Svane, Inge Marie
中科院分区：
文献类型：
--
作者：
Hansen, Morten;Hjorto, Gertrud Malene;Svane, Inge Marie
用于免疫治疗例如抗癌的单核细胞衍生的树突细胞（DC）通常通过促炎细胞因子（TNF-α、IL-1 β、IL-6）和前列腺素E-2成熟，尽管Toll样受体介导的活化的缺乏阻止了DC分泌IL-12和随后有效诱导1型效应T细胞。将标准成熟的临床级DC“sDC”与用两种1型极化成熟混合物中的任一种成熟的DC进行比较; α-1型DC“α DC 1”（TNF-α、IL-1 β、IFN-γ、IFN-α、Poly（I：C））和“mDC”（单磷酰脂质A（MPL）、IFN-γ）或含有MPL、IFN-γ和PGE的混合混合物-“mpDC”（2）。α DC 1和mDC直接分泌IL-12，并在用表达CD 40 L的细胞再刺激后分泌IL-12，它们主要分泌T效应细胞吸引趋化因子CXCL 10和CCL 5，而sDC主要分泌CCL 22，已知其吸引调节性T细胞。α DC 1和mDC在功能上上级于sDC，因为它们最有效地将初始CD 4（+）T细胞极化为T辅助1型效应细胞，并引发功能更强的MART-1特异性CD 8（+）T细胞，尽管供体之间存在差异。与标准成熟DC相比，α DC 1和mDC的CCL 21-指导的transwell迁移能力暂时较低，这可能是由于它们增加了介导CCR 7内化的CCL 19的分泌。mpDC在IL-12分泌和transwell迁移能力方面都介于标准DC和极化DC之间，但在功能上它们类似于sDC，并且显著地具有抑制性分子PD-L1和CD 25的最高表达。因此，1型极化DC的进一步研究有必要用于免疫治疗，但当与PGE 2组合时，如在mpDC中，它们似乎对DC的成熟不太理想。(C)2012爱思唯尔有限公司保留所有权利。
Monocyte-derived dendritic cells (DCs) used for immunotherapy e.g. against cancer are commonly matured by pro-inflammatory cytokines (TNF-alpha, IL-1 beta, IL-6) and prostaglandin E-2 although the absence of Toll-like receptor mediated activation prevents secretion of IL-12 from DCs and subsequent efficient induction of type 1 effector T cells. Standard matured clinical grade DCs "sDCs" were compared with DCs matured with either of two type 1 polarizing maturation cocktails; the alpha-type-1 DCs "alpha DC1s" (TNF-alpha, IL-1 beta, IFN-gamma, IFN-alpha, Poly(I:C)) and "mDCs" (monophosphoryl lipid A (MPL), IFN-gamma) or a mixed cocktail - "mpDCs", containing MPL, IFN-gamma and PGE(2). alpha DC1s and mDCs secreted IL-12 directly and following re-stimulation with CD40L-expressing cells and they mainly secreted the T effector cell attracting chemokines CXCL10 and CCL5 as opposed to sDCs that mainly secreted CCL22, known to attract regulatory T cells. alpha DC1s and mDCs were functionally superior to sDCs as they polarized naive CD4(+) T cells most efficiently into T helper type 1 effector cells and primed more functional MART-1 specific CD8(+) T cells although with variation between donors. alpha DC1s and mDCs were transiently less capable of CCL21-directed transwell migration than standard matured DCs, likely due to their increased secretion of CCL19, which mediate internalization of CCR7. mpDCs were intermediate between standard and polarized DCs both in terms of IL-12 secretion and transwell migratory ability but functionally they resembled sDCs and strikingly had the highest expression of the inhibitory molecules PD-L1 and CD25. Thus, further studies with type 1 polarized DCs are warranted for use in immunotherapy, but when combined with PGE2 as in mpDCs, they seems to be less optimal for maturation of DCs. (C) 2012 Elsevier Ltd. All rights reserved.