Heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin enhances EphA2+ tumor cell recognition by specific CD8+ T cells.
Heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin enhances EphA2+ tumor cell recognition by specific CD8+ T cells.
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DOI：
10.1158/0008-5472.can-08-4511
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发表时间：
2009-09-01
期刊：
影响因子：
11.2
通讯作者：
Storkus WJ
中科院分区：
文献类型：
--
作者：
Kawabe M;Mandic M;Taylor JL;Vasquez CA;Wesa AK;Neckers LM;Storkus WJ
EphA 2是受体酪氨酸激酶（RTK）家族的成员，通常由广泛的癌症类型表达，其中其（过）表达水平与不良临床结果相关。由于肿瘤细胞表达的EphA 2是非突变的“自身”蛋白，特异性CD 8 + T细胞受到自身耐受机制的影响，并且通常仅表现出中等至低的功能亲合力，使得它们勉强能够在体外或体内识别EphA 2+肿瘤细胞。我们最近报道，在用EphA 2激动剂预处理癌细胞后，特异性CD 8 + T细胞识别EphA 2+肿瘤细胞的能力可以增强，所述EphA 2激动剂促进蛋白酶体降解并上调肿瘤细胞膜上EphA 2/I类复合物的表达（Wesa等人，2008;181：7721-7）。在目前的研究中，我们表明，治疗EphA 2+肿瘤细胞与不可逆的HSP 90抑制剂，17-DMAG，类似地增强其识别EphA 2特异性的CD 8 + T细胞系和克隆在体外通过一种机制，这是依赖于蛋白酶体和TAP功能，以及EphA 2到肿瘤细胞质的逆转录。当17-DMAG和激动剂抗EphA 2 mAb共同应用时，肿瘤细胞的T细胞识别进一步增加，超过单独使用任一试剂所观察到的。这些研究表明EphA 2代表一种新的HSP 90客户蛋白，并且用基于17-DMA的“脉冲”疗法治疗癌症患者可以改善对EphA 2衍生表位具有反应性的CD 8 + T效应细胞的抗肿瘤功效。
EphA2, a member of the receptor tyrosine kinase (RTK) family, is commonly expressed by a broad range of cancer types, where its level of (over)expression correlates with poor clinical outcome. Since tumor cell expressed EphA2 is a non-mutated “self” protein, specific CD8+ T cells are subject to self-tolerance mechanisms and typically exhibit only moderate-to-low functional avidity, rendering them marginally competent to recognize EphA2+ tumor cells in vitro or in vivo. We have recently reported that the ability of specific CD8+ T cells to recognize EphA2+ tumor cells can be augmented after the cancer cells are pretreated with EphA2 agonists that promote proteasomal degradation and upregulated expression of EphA2/class I complexes on the tumor cell membrane (Wesa et al., J. Immunol. 2008;181:7721-7). In the current study we show that treatment of EphA2+ tumor cells with the irreversible HSP90 inhibitor, 17-DMAG, similarly enhances their recognition by EphA2-specific CD8+ T cell lines and clones in vitro via a mechanism that is dependent on proteasome and TAP function, as well as, the retrotranslocation of EphA2 into the tumor cytoplasm. When 17-DMAG and agonist anti-EphA2 mAb are co-applied, T cell recognition of tumor cells is further increased over that observed for either agent alone. These studies suggest that EphA2 represents a novel HSP90 client protein and that the treatment of cancer patients with 17-DMAG-based “pulse” therapy may improve the anti-tumor efficacy of CD8+ T effector cells reactive against EphA2-derived epitopes.