A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells.
A novel phosphorylated STAT3 inhibitor enhances T cell cytotoxicity against melanoma through inhibition of regulatory T cells.
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DOI：
10.1007/s00262-008-0618-y
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发表时间：
2009-07
期刊：
影响因子：
--
通讯作者：
Heimberger AB
中科院分区：
文献类型：
--
作者：
Kong LY;Wei J;Sharma AK;Barr J;Abou-Ghazal MK;Fokt I;Weinberg J;Rao G;Grimm E;Priebe W;Heimberger AB
信号转导子和转录激活子 3 (STAT3) 的激活已被确定为驱动黑色素瘤恶性肿瘤基本组成部分的关键介质，包括黑色素瘤患者的免疫抑制。越来越多的证据还表明，调节性 T 细胞 (Treg) 在抑制抗肿瘤免疫方面发挥着重要作用，并在否定有效的免疫治疗方法方面发挥着主导作用。我们假设 WP1066 是一种新型 STAT3 信号传导抑制剂，通过抑制 Tregs 逆转免疫抑制，这有助于这些药物对抗黑色素瘤脑转移的抗肿瘤活性。我们发现，与健康供体相比，黑色素瘤脑转移患者的样本中表达磷酸化 STAT3 (p-STAT3) 的外周血单核细胞的平均百分比显着升高，分别为 16.13% ± 2.48% 和 4.17% ± 1.79%。 p-STAT3 抑制剂 WP1066 增强 CD3+（含有 Tregs）但不增强 CD8+ T 细胞对人 A375 黑色素瘤细胞的细胞毒性，表明这种 p-STAT3 阻断剂不会直接激活 CD8+ T 细胞。此外，p-STAT3抑制剂不会增强CD3+CD25-T细胞（其中不包括Tregs）的细胞毒性，表明WP1066增强的细胞毒性是其对Tregs的抑制继发的。通过证明 WP1066 以剂量依赖性方式抑制 FoxP3+ Treg 诱导，证实了这一点。此外，暴露于 WP1066 后，CD3+ T 细胞表现出磷酸化 ZAP-70 的水平显着增强，ZAP-70 是 T 细胞激活的关键近端信号。在 Treg 耗尽的 CD3+CD25-T 细胞群中没有观察到类似的效果，这证实了 WP 化合物对 T 细胞的激活是继发于它们对 Tregs 的抑制。这些结果表明 WP1066 通过抑制 Tregs 增强 T 细胞对黑色素瘤的细胞毒性。
The activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients. Increasing evidence also suggests that regulatory T cells (Tregs) are important in suppressing anti-tumor immunity and play a dominant role in negating efficacious immunotherapy approaches. We hypothesized that WP1066, a novel inhibitor of STAT3 signaling, reverses immune suppression through the inhibition of Tregs and that this contributes to the antitumor activity of these agents against melanoma brain metastases. We found that the mean percentage of peripheral blood mononuclear cells expressing phosphorylated STAT3 (p-STAT3) was significantly elevated in samples from patients with melanoma brain metastases compared to healthy donors, 16.13% ± 2.48% vs 4.17% ± 1.79%. The p-STAT3 inhibitor WP1066 enhanced CD3+ (which contained Tregs) but not CD8+ T cell cytotoxicity against human A375 melanoma cells, indicating that this p-STAT3 blockade agent did not directly activate CD8+ T cells. Furthermore, the p-STAT3 inhibitor did not enhance the cytotoxicity of CD3+CD25- T cells (from which Tregs were excluded), indicating that the enhanced cytotoxicity of WP1066 is secondary to its inhibition of Tregs. This was confirmed by demonstrating that WP1066 inhibited FoxP3+ Treg induction in a dose-dependent manner. Moreover, CD3+ T cells exhibited markedly enhanced levels of phosphorylated ZAP-70, a critical proximal signal in T cell activation, after exposure to WP1066. Similar effects were not observed in Treg-depleted CD3+CD25- T cell populations, confirming that the T cell activation by WP compounds is secondary to their inhibition of the Tregs. These results suggest that WP1066 enhances T cell cytotoxicity against melanoma through inhibition of Tregs.
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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：
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作者：
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影响因子：
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作者：
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