Trastuzumab (Herceptin) enhances class I-restricted antigen presentation recognized by HER-2/neu-specific T cytotoxic lymphocytes
Trastuzumab (Herceptin) enhances class I-restricted antigen presentation recognized by HER-2/neu-specific T cytotoxic lymphocytes
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DOI：
10.1158/1078-0432.ccr-03-0424
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发表时间：
2004-04-01
影响因子：
11.5
通讯作者：
Fujii, H
中科院分区：
文献类型：
--
作者：
Kono, K;Sato, E;Fujii, H
目的：来自动物模型和临床试验的大量例子表明，HER-2衍生肽被自然加工为CTL表位，并且可以被几种HER-2过表达肿瘤的肿瘤特异性CTL识别。人源化抗HER-2单克隆抗体赫赛汀（Herceptin）已被设计用于通过靶向HER-2蛋白的细胞外结构域特异性拮抗HER-2功能。赫赛汀的作用之一包括HER-2的内化和降解，这可能会增加可用于加载到MHC i类的HER-2衍生肽的数量。实验设计：在本研究中，我们研究了赫赛汀治疗HER-2过表达靶点如何影响HER-2特异性ctl的裂解。结果：我们发现赫赛汀使her -2过表达的肿瘤对hla - a2限制性或hla - a24限制性ctl的溶解敏感，而对MHC 1类、共刺激分子、粘附分子或TAP-1在靶标上的表达没有任何影响。此外，赫赛汀增强的细胞溶解活性被添加一种特定的蛋白酶体抑制剂乳酸蛋白酶抑制。结论：这些结果表明，赫赛汀治疗可能通过蛋白酶体步骤增强内源性HER-2抗原的i类限制性呈递，导致HER-2过表达肿瘤对HER-2特异性ctl溶解的敏感性更高。
Purpose: Numerous examples from animal models and clinical trials showed that HER-2-derived peptides are naturally processed as a CTL epitope and can be recognized by tumor-specific CTLs in several tumors with HER-2 overexpression. The humanized anti-HER-2 monoclonal antibody, Herceptin, has been designed to specifically antagonize the HER-2 function by directing against the extracellular domain of the HER-2 protein. One of the actions of Herceptin includes the internalization and degradation of HER-2, which might increase the amount of HER-2-derived peptides available for loading to MHC class I.Experimental Design: In the present study, we investigated how Herceptin treatment of HER-2-overexpressing targets affects lysis by HER-2-specific CTLs.Results: We showed that Herceptin sensitized HER-2-overexpressing tumors to lysis by HLA-A2-restricted or HLA-A24-restricted CTLs, without any effect of the expression of MHC class 1, costimulatory molecules, adhesion molecules, or TAP-1 on the targets. Furthermore, the enhancement of cytolytic activity with Herceptin was inhibited by addition of a specific proteasome inhibitor, lactacystin.Conclusions: These results suggested that Herceptin treatment might enhance the class I-restricted presentation of endogenous HER-2 antigen via the proteasome step, resulting in higher susceptibility of HER-2-overexpressing tumors to lysis by the HER-2-specific CTLs.