Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma
Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma
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Tim-3/galectin-9信号通路介导T细胞功能障碍并预测乙型肝炎病毒相关性肝细胞癌患者的不良预后
DOI：
10.1002/hep.25777
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发表时间：
2012-10-01
期刊：
影响因子：
13.5
通讯作者：
Zou, Weiping
中科院分区：
文献类型：
--
作者：
Li, Hang;Wu, Ke;Zou, Weiping
T辅助细胞1 （Th1）上表达的T细胞免疫球蛋白和粘蛋白结构域分子（Tim-3）及其配体半乳糖凝集素-9之间的相互作用负性调节Th1介导的免疫反应。然而，Tim-3/半乳糖凝集素-9信号通路是否以及如何参与肝细胞癌（HCC）患者的免疫逃逸尚不清楚。在此，我们研究了Tim-3/半乳糖凝集素-9通路在乙型肝炎病毒（HBV）相关性HCC患者中的表达、功能和调控。我们检测了不同水平的半凝集素-9在HCC中抗原呈递细胞（APC）亚群中的表达，包括库普弗细胞（KCs）、髓样树突状细胞（DCs）和浆细胞样dc。半凝集素-9在肝细胞癌胰岛的KCs中表达最高，而在邻近组织中表达最高。与癌旁组织相比，肝癌组织中CD4+和CD8+ T细胞中Tim-3的表达增加，Tim-3+ T细胞是复制性衰老细胞，表达衰老的表面和遗传标记。有趣的是，肿瘤浸润性t细胞衍生干扰素(IFN)-？在HCC微环境中刺激apc上半乳糖凝集素-9的表达。免疫荧光染色显示Tim-3+ T细胞和半凝集素-9+ KCs在HCC中共定位。功能研究表明，阻断Tim-3/半乳糖凝集素-9信号通路可以显著提高肿瘤浸润Tim-3+ T细胞的功能，这可以通过增加T细胞增殖和效应细胞因子的产生来证明。最后，我们发现Tim-3+肿瘤浸润细胞的数量与患者生存率呈负相关。结论：我们的工作表明Tim-3/半乳糖凝集素-9信号通路介导hbv相关性HCC的t细胞衰老。数据表明，该途径可能是hbv相关HCC患者的免疫治疗靶点。(肝脏病学2012)
The interaction between T cell immunoglobulin- and mucin-domain-containing molecule (Tim-3) expressed on T helper 1 (Th1) cells, and its ligand, galectin-9, negatively regulates Th1-mediated immune responses. However, it is poorly understood if and how the Tim-3/galectin-9 signaling pathway is involved in immune escape in patients with hepatocellular carcinoma (HCC). Here we studied the expression, function, and regulation of the Tim-3/galectin-9 pathway in patients with hepatitis B virus (HBV)-associated HCC. We detected different levels of galectin-9 expression on antigen-presenting cell (APC) subsets including Kupffer cells (KCs), myeloid dendritic cells (DCs), and plasmacytoid DCs in HCC. The highest galectin-9 expression was on KCs in HCC islets, not in the adjacent tissues. Furthermore, Tim-3 expression was increased on CD4+ and CD8+ T cells in HCC as compared to the adjacent tissues, and Tim-3+ T cells were replicative senescent and expressed surface and genetic markers for senescence. Interestingly, tumor-infiltrating T-cell-derived interferon (IFN)-? stimulated the expression of galectin-9 on APCs in the HCC microenvironment. Immunofluorescence staining revealed a colocalization of Tim-3+ T cells and galectin-9+ KCs in HCC. Functional studies demonstrated that blockade of the Tim-3/galectin-9 signaling pathway importantly increased the functionality of tumor-infiltrating Tim-3+ T cells as shown by increased T-cell proliferation and effector cytokine production. Finally, we show that the numbers of Tim-3+ tumor-infiltrating cells were negatively associated with patient survival. Conclusion: Our work demonstrates that the Tim-3/galectin-9 signaling pathway mediates T-cell senescence in HBV-associated HCC. The data suggest that this pathway could be an immunotherapeutic target in patients with HBV-associated HCC. (HEPATOLOGY 2012)