Sorafenib inhibits activation of human peripheral blood T cells by targeting LCK phosphorylation
Sorafenib inhibits activation of human peripheral blood T cells by targeting LCK phosphorylation
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DOI：
10.1038/leu.2008.58
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发表时间：
2008-06-01
期刊：
影响因子：
11.4
通讯作者：
Xu, Q.
中科院分区：
文献类型：
--
作者：
Zhao, W.;Gu, Y. H.;Xu, Q.
索拉非尼是一种治疗转移性肾癌的新药，对多种酪氨酸激酶具有广谱活性，包括Raf-1、血管内皮生长因子受体和血小板衍生生长因子受体。然而，人们对其对免疫系统的影响知之甚少。在这份报告中，我们研究了索拉非尼对人外周血T细胞增殖和活化的影响，以及对小鼠T细胞介导的免疫应答的影响。在与患者使用的浓度相似的浓度下，索拉非尼在体外抑制原代人T细胞的增殖。当浓度超过10 μ M时，索拉非尼甚至在停药后也引起不可恢复的增殖抑制。此外，索拉非尼在高于10 μ M的浓度下诱导T细胞凋亡。索拉非尼还引起T细胞G（0）/G（1）期阻滞、CD 25和CD 69表达抑制、白细胞介素-2产生和LCK磷酸化;所有这些作用均表现出剂量和时间依赖性。当对小鼠接触性皮炎进行测试时，索拉非尼显著降低了苦基氯诱导的耳肿胀。这些结果表明，索拉非尼可能通过诱导细胞凋亡和靶向LCK导致T细胞免疫应答的丧失。这可能会导致癌症患者的免疫抑制。
Sorafenib, a novel drug for metastatic renal cancer, has broad-spectrum activity against multiple tyrosine kinases, including Raf-1, vascular endothelial growth factor receptor and platelet-derived growth factor receptor. However, little is known about its effects on the immune system. In this report, we examine the effects of sorafenib on the proliferation and activation of human peripheral blood T cells, as well as its effects on T-cell-mediated immune response in mice. At concentrations similar to those used in patients, sorafenib inhibited the proliferation of primary human T cells in vitro. At more than 10 mu M, sorafenib caused an irrecoverable inhibition of proliferation, even after drug withdrawal. In addition, sorafenib induced T-cell apoptosis at concentrations higher than 10 mu M. sorafenib also caused G(0)/G(1) phase arrest, inhibition of CD25 and CD69 expression, interleukin-2 production and LCK phosphorylation in the T cells; all of these effects exhibited dose and time dependence. When tested against contact dermatitis in mice, sorafenib significantly reduced the ear swelling induced by picryl chloride. These findings suggest that sorafenib may cause the loss of T-cell immune response by inducing apoptosis and targeting LCK. This could potentially lead to immunosuppression in patients with cancer.