Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy.
Toll-like receptor 9 activation of signal transducer and activator of transcription 3 constrains its agonist-based immunotherapy.
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DOI：
10.1158/0008-5472.can-08-3031
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发表时间：
2009-03-15
期刊：
影响因子：
11.2
通讯作者：
Yu H
中科院分区：
文献类型：
--
作者：
Kortylewski M;Kujawski M;Herrmann A;Yang C;Wang L;Liu Y;Salcedo R;Yu H
尽管toll样受体（TLR）激动剂（例如CpG）在癌症和感染性疾病的临床试验中用作免疫抑制剂，但它们的作用是有限的，并且抑制CpG功效的潜在机制仍然不清楚。在这里，我们证明了信号转导和转录激活因子3（Stat 3）在下调CpG的免疫刺激作用中起着关键作用。在不存在IL-6和IL-10诱导的情况下，CpG在几分钟内通过TLR 9直接激活Stat 3。在造血细胞中表达Stat 3可通过CpG快速激活先天免疫，增强干扰素-γ、肿瘤坏死因子-α、白细胞介素-12的产生，并激活以Stat 1激活为标志的巨噬细胞、中性粒细胞和自然杀伤细胞。在具有Stat 3消融的造血系统的小鼠中由CpG诱导的先天免疫应答引起有效的抗肿瘤作用，导致在72小时内根除大的（> 1 cm）B16黑素瘤肿瘤。此外，在骨髓细胞中切除Stat 3增加CpG诱导的树突状细胞成熟、T细胞活化、肿瘤抗原特异性T细胞的产生和持久的抗肿瘤免疫。Stat 3在肿瘤微环境中介导某些细胞因子和生长因子的免疫抑制中的关键作用最近已被证明。通过证明TLR激动剂对Stat 3的直接和快速激活，我们确定了Stat 3介导的免疫抑制的第二水平。我们的研究结果进一步表明，靶向Stat 3可以大大改善基于CpG的免疫抑制方法。
Although toll-like receptor (TLR) agonists, such as CpG, are used as immunotherapeutic agents in clinical trials for cancer and infectious diseases, their effects are limited and the underlying mechanism(s) that restrains CpG efficacy remains obscure. Here we demonstrate that signal transducer and activator of transcription 3 (Stat3) plays a key role in downmodulating CpG’s immunostimulatory effects. In the absence of IL-6 and IL-10 induction, CpG directly activates Stat3 within minutes through TLR9. Ablating Stat3 in hematopoietic cells results in rapid activation of innate immunity by CpG, with enhanced production of interferon-γ, tumor necrosis factor-α, interleukin-12, and activation of macrophages, neutrophils and natural killer cells marked with Stat1 activation. Innate immune responses induced by CpG in mice with a Stat3-ablated hematopoietic system cause potent antitumor effects, leading to eradication of large (> 1 cm) B16 melanoma tumors within 72h. Moreover, ablating Stat3 in myeloid cells increases CpG-induced dendritic cell maturation, T cell activation, generation of tumor antigen-specific T cells and long-lasting antitumor immunity. A critical role of Stat3 in mediating immunosuppression by certain cytokines and growth factors in the tumor microenvironment has been recently documented. By demonstrating direct and rapid activation of Stat3 by TLR agonists, we identify a second level of Stat3-mediated immunosuppression. Our results further suggest that targeting Stat3 can drastically improve CpG-based immunotherapeutic approaches.