Heat Shock Protein 70, Released from Heat-Stressed Tumor Cells, Initiates Antitumor Immunity by Inducing Tumor Cell Chemokine Production and Activating Dendritic Cells via TLR4 Pathway
Heat Shock Protein 70, Released from Heat-Stressed Tumor Cells, Initiates Antitumor Immunity by Inducing Tumor Cell Chemokine Production and Activating Dendritic Cells via TLR4 Pathway
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DOI：
10.4049/jimmunol.182.3.1449
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发表时间：
2009-02-01
影响因子：
4.4
通讯作者：
Cao, Xuetao
中科院分区：
文献类型：
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作者：
Chen, Taoyong;Guo, Jun;Cao, Xuetao
细胞外热休克蛋白（Extracellular Heat Shock Proteins，HSP）可激活树突状细胞（Dendritic Cell，DC）和单核/巨噬细胞（monocytes/macrophages），而来源于肿瘤细胞的HSP被认为是一种有效的佐剂，可促进肿瘤抗原的提呈和诱导抗肿瘤免疫。然而，可释放HSP在诱导抗肿瘤免疫中的作用及其机制尚未完全阐明。在这项研究中，我们报告热应激可以诱导肿瘤细胞释放各种HSP，从而激活肿瘤细胞产生趋化因子，通过TI.R4信号通路对DC和T细胞进行化学吸引。在体内，我们发现局部热疗后肿瘤内DC和T细胞的浸润和功能显著增加。我们还提供了证据表明，由肿瘤细胞释放的HSP 70蛋白和由肿瘤细胞/DC表达的TLR 4对于DC/T细胞的化学吸引和随后的肿瘤特异性抗肿瘤免疫的诱导是必不可少的。因此，我们的研究表明，热应激诱导的肿瘤细胞释放的HSP 70蛋白通过诱导肿瘤细胞产生趋化因子和通过TLR 4途径激活化学吸引的DC在启动抗肿瘤免疫中起重要作用。免疫学杂志，2009，182：1449-1459.
Extracellular heat shock proteins (HSP) can activate dendritic cells (DC) and monocytes/macrophages, and HSP derived from tumor cells have been regarded as potent adjuvant facilitating presentation of tumor Ags and induction of antitumor immunity. However, the roles and the underlying mechanisms of releasable HSP in the induction of antitumor immunity have not been fully elucidated. In this study, we report that heat stress can induce the release of various HSP from tumor cells, which, in turn, activate tumor cells to produce chemokines for chemoattraction of DC and T cells via TI.R4 signaling pathway. In vivo, we find that the infiltration and function of DC and T cells within tumor after local hyperthermia are increased significantly. We also provide evidence that HSP70 proteins released by tumor cells and TLR4 expressed by tumor cells/DC are essential for the chemoattraction of DC/T cells and for the subsequent induction of tumor-specific antitumor immunity. Therefore, our study suggests that heat stress-induced releasable HSP70 proteins from tumor cells play important roles in the initiation of antitumor immunity by inducing tumor cell production of chemokines and by activating the chemoattracted DC via TLR4 pathway. The Journal of Immunology, 2009, 182: 1449-1459.