HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway
HER-2/neu-mediated regulation of components of the MHC class I antigen-processing pathway
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DOI：
10.1158/0008-5472.can-2522-2
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发表时间：
2004-01-01
期刊：
影响因子：
11.2
通讯作者：
Seliger, B
中科院分区：
文献类型：
--
作者：
Herrmann, F;Lehr, HA;Seliger, B
由于其在许多人类肿瘤中的扩增和/或过表达，HER-2/neu原癌基因代表了T细胞介导的疫苗接种策略的有吸引力的靶标。然而，癌基因的过表达通常与MHC I类抗原加工机制（APM）的组分的表达缺陷相关，从而导致癌基因转化细胞的免疫逃逸表型。为了确定HER-2/neu是否影响MHC I类抗原加工途径，在组成型和四环素控制的HER 2/neu表达的鼠体外模型中检查了不同APM组分的表达模式。与HER-2/neu（-）对照细胞相比，HER-2/ neu（+）成纤维细胞表现出降低水平的MHC I类表面抗原，其与抗原加工相关的肽转运蛋白、蛋白酶体亚基低分子量蛋白2和低分子量蛋白10、蛋白酶体激活剂PA 28 α和PA 28 β以及tapasin的表达和/或功能受损相关。这些APM异常导致对CTL裂解的敏感性降低。HER-2/neu介导的免疫逃逸表型可以通过IFN-γ治疗来纠正。通过对一系列HER-2/neu-和HER-2/neu（+）乳腺癌标本的免疫组化分析，HER-2/neu和与抗原加工蛋白表达相关的肽转运蛋白之间的负相关性支持了这一发现的临床相关性。因此，缺乏APM组件的表达和HER-2/neu过表达之间的功能联系，提出可能会影响HER-2/neu靶向T细胞的免疫策略的设计。
Because of its amplification and/or overexpression in many human tumors, the HER-2/neu proto-oncogene represents an attractive target for T-cell-mediated vaccination strategies. However, overexpression of oncogenes is often associated with defective expression of components of the MHC class I antigen-processing machinery (APM), thereby resulting in an immune escape phenotype of oncogene-transformed cells. To determine whether HER-2/neu influences the MHC class I antigen-processing pathway, the expression pattern of different APM components was examined in murine in vitro models of constitutive and tetracycline-controlled HER2/neu expression. In comparison with HER-2/neu(-) control cells, HER-2/ neu(+) fibroblasts exhibit reduced levels of MHC class I surface antigens that were associated with impaired expression and/or function of the peptide transporter associated with antigen processing, the proteasome subunits low molecular weight protein 2 and low molecular weight protein 10, the proteasome activators PA28alpha and PA28beta, and tapasin. These APM abnormalities resulted in reduced sensitivity to lysis by CTLs. The HER-2/neu-mediated immune escape phenotype could be corrected by IFN-gamma treatment. The clinical relevance of this finding was supported by an inverse correlation between HER-2/neu and the peptide transporter associated with antigen-processing protein expression as determined by immunhistochemical analysis of a series of HER-2/neu- and HER-2/neu(+) breast cancer specimens. Thus, a functional link between deficient APM component expression and HER-2/neu overexpression is proposed that might influence the design of HER-2/neu-targeted T-cell-based immunotherapeutic strategies.