Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma
Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma
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DOI：
10.1016/j.intimp.2015.09.017
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发表时间：
2015-12-01
影响因子：
5.6
通讯作者：
Zhang, Yongkui
中科院分区：
文献类型：
--
作者：
Xu, Liyun;Huang, Yanyan;Zhang, Yongkui
T细胞免疫球蛋白和粘蛋白结构域包含分子-3(Tim-3)在人类疾病中发挥重要作用。然而，自然杀伤(NK)细胞中TIM-3的表达与人肺腺癌的关系尚不清楚。因此，我们研究了TIM-3在NK细胞中的表达，并探讨了TIM-3阻断对人肺腺癌NK细胞介导的活性的影响。用流式细胞仪检测肺腺癌患者CD3-CD56+细胞(P<；0.05)和CD3-CD56(DIM)细胞(P<；0.05)上TIM-3的表达。此外，CD3-CD56+NK细胞中TIM-3的表达在有淋巴结转移(LNM)的肺腺癌患者(P<；0.05)或肿瘤分期为T3-T4的患者(P<；0.05)中也较高。CD56(Dim)NK细胞亚群中Tim-3的表达在肿瘤大小<3 cm(P<；0.05)、淋巴结转移(P<；0.05)或肿瘤分期为T3-T4(P<；0.05)的患者中较高。进一步分析显示，CD3CD56+NK细胞和CD56(Dim)NK细胞亚群上TIM-3的高表达与肺腺癌患者总生存期的缩短独立相关(LOG-RANK检验，P分别为0.0418和0.0406)。重要的是，用抗TIM-3抗体阻断TIM-3信号转导导致肺腺癌患者外周血NK细胞的细胞毒作用和干扰素-γ的产生增加。我们的数据表明，NK细胞中TIM-3的表达可以作为判断人肺腺癌预后的生物标志物，并支持TIM-3可能成为免疫治疗策略的新靶点。(C)2015爱思唯尔B.V.保留所有权利。
T cell immunoglobulin- and mucin-domain-containing molecule-3 (Tim-3) has been shown to play an important role in mediating NK-cell function in human diseases. However, the relationship between Tim-3 expression in natural killer (NK) cells and human lung adenocarcinoma remains unclear. We therefore investigated the expression of Tim-3 in NK cells and explored the effect of Tim-3 blockade on NK cell-mediated activity in human lung adenocarcinoma. Upregulated expression of Tim-3 on CD3-CD56 + cells (P < 0.05) and CD3-CD56(dim) cells (P < 0.05) of patients with lung adenocarcinoma was detected by flow cytometry. Moreover, Tim-3 expression in CD3-CD56+ NK cells was higher in patients with lung adenocarcinoma with lymph node metastasis (LNM) (P < 0.05) or with tumor stage T3-T4 (P < 0.05). Tim-3 expression in CD56(dim) NK-cell subset was higher in patients with tumor size >= 3 cm (P < 0.05), or LNM (P < 0.05) or with tumor stage T3-T4 (P < 0.05). Further analysis showed that higher expressions of Tim-3 on both CD3-CD56 + NK cells and CD56(dim) NK-cell subset were independently correlated with shorter overall survival of patients with lung adenocarcinoma (log-rank test, P = 0.0418, 0.0406, respectively). Importantly, blockade of Tim-3 signaling with anti-Tim-3 antibodies resulted in the increased cytotoxicity and IFN-gamma production of peripheral NK cells from patients with lung adenocarcinoma. Our data indicate that Tim-3 expression in NK cells can function as a prognostic biomarker in human lung adenocarcinoma and support that Tim-3 could be a new target for an immunotherapeutic strategy. (C) 2015 Elsevier B.V. All rights reserved.