Tumor-mediated inhibition of human dendritic cell differentiation and function is consistently counteracted by combined p38 MAPK and STAT3 inhibition.
Tumor-mediated inhibition of human dendritic cell differentiation and function is consistently counteracted by combined p38 MAPK and STAT3 inhibition.
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DOI：
10.4161/onci.20365
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发表时间：
2012-08-01
期刊：
影响因子：
7.2
通讯作者：
de Gruijl TD
中科院分区：
文献类型：
--
作者：
Oosterhoff D;Lougheed S;van de Ven R;Lindenberg J;van Cruijsen H;Hiddingh L;Kroon J;van den Eertwegh AJ;Hangalapura B;Scheper RJ;de Gruijl TD
通过释放抑制因子靶向树突状细胞（DC）是肿瘤逃避免疫控制的有效手段。我们评估了通过JAK 2/STAT 3和p38 MAPK通路的下游信号传导在肿瘤诱导的人DC发育抑制中的参与。尽管JAK 2/STAT 3通路在小鼠研究中被确定为骨髓抑制的关键调节因子，但在人类DC中，这一点还不太确定。我们研究了STAT 3抑制对由四种主要抑制因子的短列表介导的单核细胞来源的DC分化的抑制的影响，发现药理学STAT 3抑制只能抵消IL-6的作用。因此，在测试源自代表各种类型实体瘤的11种细胞系的一组上清液时，STAT 3抑制仅适度影响少数上清液的抑制作用。重要的是，STAT 3和p38通路的联合干扰完全阻止了所有测试上清液对DC分化的抑制，并实现了上级DC功能，这通过增加的同种异体T细胞反应性以及升高的IL-12 p70/IL-10比率和Th 1偏斜来证明。联合STAT 3和p38抑制还提供了上级保护，以对抗原发性胶质瘤和黑色素瘤上清液的抑制作用，并诱导转移性黑色素瘤单细胞悬液中从CD 14+细胞向CD 1a+细胞的转变，表明肿瘤微环境中DC分化的改善潜力。我们得出结论，STAT 3和p38 MAPK信号通路的联合干扰是克服DC前体中肿瘤诱导的抑制性信号传导的一种有前途的方法，并可能支持临床免疫策略。
Targeting dendritic cells (DC) through the release of suppressive factors is an effective means for tumors to escape immune control. We assessed the involvement of downstream signaling through the JAK2/STAT3 and p38 MAPK pathways in tumor-induced suppression of human DC development. Whereas the JAK2/STAT3 pathway has been pinpointed in mouse studies as a key regulator of myeloid suppression, in human DC this is less well established. We studied the effects of STAT3 inhibition on the suppression of monocyte-derived DC differentiation mediated by a short-list of four predominant suppressive factors and found that pharmacological STAT3 inhibition could only counteract the effects of IL-6. Accordingly, in testing a panel of supernatants derived from 11 cell lines representing various types of solid tumors, STAT3 inhibition only modestly affected the suppressive effects of a minority of supernatants. Importantly, combined interference in the STAT3 and p38 pathways completely prevented inhibition of DC differentiation by all tested supernatants and effected superior DC function, evidenced by increased allogeneic T cell reactivity with elevated IL-12p70/IL-10 ratios and Th1 skewing. Combined STAT3 and p38 inhibition also afforded superior protection against the suppressive effects of primary glioma and melanoma supernatants and induced a shift from CD14+ cells to CD1a+ cells in metastatic melanoma single-cell suspensions, indicating a potential for improved DC differentiation in the tumor microenvironment. We conclude that combined interference in the STAT3 and p38 MAPK signaling pathways is a promising approach to overcome tumor-induced inhibitory signaling in DC precursors and will likely support clinical immunotherapeutic strategies.
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影响因子：
8
作者：
Niu, GL;Wright, KL;Yu, H
通讯作者：
Yu, H
影响因子：
11.2
作者：
Hussain, S. Farzana;Kong, Ling-Yuan;Heimberger, Amy B.
通讯作者：
Heimberger, Amy B.
影响因子：
4.4
作者：
Nefedova, Y;Cheng, PY;Gabrilovich, DI
通讯作者：
Gabrilovich, DI
影响因子：
50.5
作者：
Baars, A;Claessen, AME;Pinedo, HM
通讯作者：
Pinedo, HM
影响因子：
11.2
作者：
Sinha, Pratima;Clements, Virginia K.;Ostrand-Rosenberg, Suzanne
通讯作者：
Ostrand-Rosenberg, Suzanne