Human suppressor of cytokine signaling 1 controls immunostimulatory activity of monocyte-derived dendritic cells.
Human suppressor of cytokine signaling 1 controls immunostimulatory activity of monocyte-derived dendritic cells.
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DOI：
10.1158/0008-5472.can-09-1507
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发表时间：
2009-10-15
期刊：
影响因子：
11.2
通讯作者：
Huang XF
中科院分区：
文献类型：
--
作者：
Hong B;Ren W;Song XT;Evel-Kabler K;Chen SY;Huang XF
基于树突状细胞（DC）的肿瘤疫苗仅实现了有限的临床功效，这强调了刺激策略在引发针对自身肿瘤相关抗原的有效细胞毒性T淋巴细胞（CTL）应答方面的局限性。在这里，我们调查的作用，人类细胞因子信号转导抑制因子（SOCS）1，JAK/STAT信号通路的反馈抑制剂，在调节抗原呈递的人DC。我们发现，人SOCS 1沉默的DC具有增强的刺激能力，在体外和SCID-hu小鼠模型中引发自身抗原特异性CTL。由SOCS 1沉默的DC而不是野生型DC激活的人CTL对天然抗原表达肿瘤细胞具有活性裂解活性。我们进一步发现，人DC引发CTL的能力可能受SOCS 1限制的促炎细胞因子如IL-12的产生和信号传导控制。这些结果表明人SOCS 1在负调节DC的免疫刺激能力中的关键作用，并暗示了这种替代的SOCS 1沉默策略开发有效DC疫苗的翻译潜力。
Dendritic cell (DC)-based tumor vaccines have only achieved limited clinical efficacy, underscoring the limitation of stimulatory strategies to elicit effective cytotoxic T lymphocyte (CTL) responses against self tumor-associated antigens. Here we investigate the role of human suppressor of cytokine signaling (SOCS) 1, a feedback inhibitor of the JAK/STAT signaling pathway, in regulating antigen presentation by human DCs. We find that human SOCS1-silenced DCs have an enhanced stimulatory ability to prime self antigen-specific CTLs in vitro and in an SCID-hu mouse model. Human CTLs activated by SOCS1-silenced DCs, but not wild-type DCs, have an active lytic activity to natural antigen-expressing tumor cells. We further find that the capacity of human DCs to prime CTLs is likely controlled by SOCS1 restricted production and signaling of proinflammatory cytokines such as IL-12. These results indicate a critical role of human SOCS1 in negatively regulating the immunostimulatory capacity of DCs and imply a translational potential of this alternative, SOCS1 silencing strategy to develop effective DC vaccines.