Tumour-mediated disruption of dendritic cell function: Inhibiting the MEK1/2-p44/42 axis restores IL-12 production and Th1-generation
Tumour-mediated disruption of dendritic cell function: Inhibiting the MEK1/2-p44/42 axis restores IL-12 production and Th1-generation
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DOI：
10.1002/ijc.23530
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发表时间：
2008-08-01
影响因子：
6.4
通讯作者：
Patel, Poulam M.
中科院分区：
文献类型：
--
作者：
Jackson, Andrew Mark;Mulcahy, Lori Ann;Patel, Poulam M.
功能障碍性树突状细胞（DC）在癌症患者中很常见;然而，对潜在的分子靶点知之甚少。尽管如此，过继转移和就地接种疫苗的方案仍在继续，基本上没有解决免疫抑制问题。了解肿瘤介导的DC抑制将有助于下一代免疫治疗的合理设计。这项研究使用了过继免疫治疗的肿瘤裂解物负载DC模型以及许多肿瘤中常见的坏死细胞。检查患者来源的和健康供体单核细胞来源的DC中与其产生1型辅助T细胞群（Th 1）的能力相关的丝裂原活化蛋白激酶（MAPK）信号通路的破坏。黑色素瘤裂解物显著抑制TLR 4依赖性IL-12 p40和p70的产生。IL-12 p70的抑制独立于成熟标志物（例如，CD 40、CD 80、CD 83）与p35、p40转录抑制相关。IL-12分泌减少与肿瘤裂解物中的IL-10、TGF β、VEGF、PGE（2）或神经节苷脂无关，也与DC释放内源性PGE（2）无关。与HUVEC裂解物相比，黑素瘤裂解物处理的DC不太能够从幼稚T细胞产生Th 1应答。p44/42 MAPK被黑色素瘤裂解物过度激活，但不是HUVEC。用U 0126阻断p44/42的上游激酶MEK 12可阻止p44/42活化，恢复IL-12 p70，并允许有效产生Th 1应答。因此，p44/42 MAPK是肿瘤介导的DC免疫抑制的靶点，导致IL-12 p35和p40基因的转录下调，减少IL-12分泌并抑制Th 1应答。MEK-p44/42轴中的药理学干预可适用于使DC对肿瘤裂解物的抑制作用具有抗性，并且可形成组合免疫疗法的一部分。(C)2008 Wiley-Liss，Inc.
Disfunctional dendritic cells (DC) are common in cancer patients; however, the underlying molecular targets are poorly understood. Nevertheless, adoptive-transfer and in situ vaccination protocols continue, largely without addressing immune-suppression. Understanding tumour-mediated DC suppression would assist rational design of next generation immunotherapy. This study used a tumour-lysate loaded DC model of adoptive immunotherapy and also necrotic cells common in many tumours. Patient-derived and healthy-donor monocyte-derived DC were examined for disruptions in mitogen-activated protein kinase (MAPK) signalling pathways associated with their capacity to generate Type-1 helper-T cell populations (Th1). Melanoma-lysate markedly suppressed TLR4-dependent IL-12p40 and p70 production. Suppression of IL-12p70 occurred independently of maturation markers (e.g., CD40, CD80, CD83) and correlated with depressed p35 and p40 transcription. Decreased IL-12 secretion was not associated with IL-10, TGF beta, VEGF, PGE(2) or ganglioside in tumour lysates or attributable to endogenous PGE(2) release from DC. In contrast to HUVEC lysate, melanoma-lysate-treated DC were less able to generate Th1-responses from naive T-cells. The p44/42 MAPK was hyper-activated by melanoma lysate, but not that of HUVEC. Blockade of MEK1/2, the upstream kinase for p44/42, with U0126 prevented p44/42 activation, restored IL-12p70, and permitted effective generation of Th1-responses. Therefore the p44/42 MAPK is a target for tumour-mediated immune suppression of DC resulting in transcriptional down-regulation of IL-12 p35 and p40 genes, reduced IL-12 secretion and suppressed Th1-responses. Pharmacological intervention in the MEK-p44/42 axis may be applicable to render DC resistant to the suppressive effects of tumour lysates and may form part of a combination immunotherapy. (C) 2008 Wiley-Liss, Inc.