Combined blockade of Tim-3 and MEK inhibitor enhances the efficacy against melanoma
Combined blockade of Tim-3 and MEK inhibitor enhances the efficacy against melanoma
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Tim-3 和 MEK 抑制剂联合阻断可增强抗黑色素瘤的功效
DOI：
10.1016/j.bbrc.2017.01.128
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发表时间：
2017-03-04
影响因子：
3.1
通讯作者：
Hu, Lihua
中科院分区：
文献类型：
--
作者：
Liu, Yang;Cai, Pengcheng;Hu, Lihua
对丝裂原激活蛋白激酶 (MAPK) 通路和免疫检查点作用的深入了解使靶向治疗和免疫治疗联合成为一种有前途的治疗方案。 Trametinib 是一种丝裂原激活的细胞外信号调节激酶 (MEK) 抑制剂，已证明对晚期黑色素瘤患者有效。 T细胞免疫球蛋白和粘蛋白结构域分子3（Tim-3）是一种免疫检查点分子，参与抗肿瘤免疫的多重负调节。据我们所知，我们首次报道了曲美替尼和抗 Tim-3 单克隆抗体 (mAb) 联合治疗 B16-F10 黑色素瘤小鼠。我们发现曲美替尼显着促进细胞凋亡并抑制细胞增殖，而抑制MEK则提高Tim-3的表达并导致CD8(+) T细胞减少；相反，抗Tim-3 mAb通过刺激CD8(+) T细胞增强抗肿瘤免疫，因此联合治疗协同产生了有效的抗肿瘤作用。总而言之，我们的研究为曲美替尼和抗 Tim-3 mAb 联合作为治疗黑色素瘤的潜在有价值的方案提供了令人信服的证据。 (C) 2017 Elsevier Inc. 保留所有权利。
Insights into the role of the mitogen-activated protein kinase (MAPK) pathway and immune checkpoints have led combined targeted therapy and immunotherapy to be a promising regimen. Trametinib, as a mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, has demonstrated effectiveness in patients with advanced melanoma. T cell immunoglobulin-and mucin-domain-containing molecule-3 (Tim-3), an immune checkpoint molecule, participates in multiple negative regulation of antitumor immunity. We for the first time to our knowledge reported the combination of trametinib and anti-Tim-3 monoclonal antibody (mAb) in treating B16-F10 melanoma mice. We discovered that trametinib remarkably promoted apoptosis and inhibited cell proliferation while inhibition of MEK improved the expression of Tim-3 and caused the decrease of CD8(+) T cells; to the contrary, anti-Tim-3 mAb enhanced antitumor immunity by stimulating CD8(+) T cells, thus the combined therapy produced potent antitumor effect cooperatively. Taken together, our study provides compelling evidence for combining trametinib and anti-Tim-3 mAb as a potential valuable regimen in treating melanoma. (C) 2017 Elsevier Inc. All rights reserved.