Kawabe Mayumi, Mandic Maja, Taylor Jennifer L, Vasquez Cecilia A, Wesa Amy K, Neckers Leonard M, Storkus Walter J
Department of Immunology, University of Pittsburgh School of Medicine, PA 15213, USA.
Cancer Res. 2009 Sep 1;69(17):6995-7003. doi: 10.1158/0008-5472.CAN-08-4511. Epub 2009 Aug 18.
EphA2, a member of the receptor tyrosine kinase family, is commonly expressed by a broad range of cancer types, where its level of (over)expression correlates with poor clinical outcome. Because tumor cell expressed EphA2 is a nonmutated "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 up-regulated expression of EphA2/class I complexes on the tumor cell membrane. In the current study, we show that treatment of EphA2(+) tumor cells with the irreversible heat shock protein 90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (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 transporter-associated protein function as well as the retrotranslocation of EphA2 into the tumor cytoplasm. When 17-DMAG and agonist anti-EphA2 monoclonal antibodies are coapplied, T-cell recognition of tumor cells is further increased over that observed for either agent alone. These studies suggest that EphA2 represents a novel heat shock protein 90 client protein and that the treatment of cancer patients with 17-DMAG-based "pulse" therapy may improve the antitumor efficacy of CD8(+) T effector cells reactive against EphA2-derived epitopes.
EphA2是受体酪氨酸激酶家族的一员，在多种癌症类型中普遍表达，其（过）表达水平与不良临床预后相关。由于肿瘤细胞表达的EphA2是一种未发生突变的“自身”蛋白，特异性CD8(+) T细胞会受到自身耐受机制的影响，通常仅表现出中低水平的功能亲和力，这使得它们在体外或体内识别EphA2(+)肿瘤细胞的能力有限。我们最近报道，在用促进蛋白酶体降解并上调肿瘤细胞膜上EphA2/Ⅰ类复合物表达的EphA2激动剂预处理癌细胞后，特异性CD8(+) T细胞识别EphA2(+)肿瘤细胞的能力可以增强。在本研究中，我们发现用不可逆的热休克蛋白90抑制剂17-二甲基氨基乙基氨基-17-去甲氧基格尔德霉素（17-DMAG）处理EphA2(+)肿瘤细胞，同样能在体外通过一种依赖蛋白酶体和转运相关蛋白功能以及EphA2向肿瘤细胞质逆向转运的机制，增强EphA2特异性CD8(+) T细胞系和克隆对它们的识别。当联合应用17-DMAG和激动剂抗EphA2单克隆抗体时，T细胞对肿瘤细胞的识别比单独使用任何一种试剂时进一步增加。这些研究表明，EphA2是一种新型的热休克蛋白90客户蛋白，用基于17-DMAG的“脉冲”疗法治疗癌症患者可能会提高针对EphA2衍生表位的CD8(+) T效应细胞的抗肿瘤疗效。
