T cell recognition of HLA-A2 restricted tumor antigens is impaired by the oncogene HER2
T cell recognition of HLA-A2 restricted tumor antigens is impaired by the oncogene HER2
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DOI：
10.1002/ijc.25613
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发表时间：
2011-01-15
影响因子：
6.4
通讯作者：
Kiessling, Rolf
中科院分区：
文献类型：
--
作者：
Mimura, Kousaku;Ando, Takashi;Kiessling, Rolf
HER2癌基因在人类癌症中经常过度表达，是免疫治疗的一个有前途的靶点。以往的研究表明，小鼠或大鼠HER2的过度表达会导致主要组织相容性复合体(MHC)I类分子和抗原处理和提呈机制(APM)分子水平显著降低，从而导致促进肿瘤逃逸免疫系统的表型。本研究旨在分析HER2对HLAA2.1(+)黑色素瘤细胞系MHC-I类抗原提呈及对肿瘤抗原特异性细胞毒性T淋巴细胞(CTL)敏感性的影响。我们发现HER2的表达与总的MHC-I类表面表达以及HER2与人类白细胞抗原A2之间均呈显著的负相关。当黑色素瘤和肿瘤细胞系被转染人HER2基因时，人类白细胞抗原A2的水平显著降低。具有信号活性的HER2分子对于观察到的HLA-A2下调至关重要，因为在酪氨酸信号域高水平表达HER2的转基因细胞没有表现出变化的HLA-A2表达。重要的是，人类黑色素瘤细胞株EST049在HER2转基因后表现出CTL对HER2和黑色素瘤抗原的特异性识别能力降低。此外，HER2的高表达既阻止了干扰素-γ介导的人类白细胞抗原A2的上调，也阻止了处理细胞中人类白细胞抗原A2限制性CTL的识别能力的提高。此外，关键的APM分子被HER2下调。这些发现表明，HER2过表达的肿瘤可能更容易逃脱人类白细胞抗原A2限制的CTL，提示免疫治疗方法诱导整合的体液、细胞和天然免疫反应将是最有效的。
The HER2 oncogene is frequently over-expressed in human cancers and a promising target for immune therapy. Previous studies have shown that over-expression of mouse or rat HER2 leads to markedly reduced levels of major histocompatibility complex (MHC) class I and molecules of the antigen processing and presentation machinery (APM), thus resulting in a phenotype promoting tumor escape from the immune system. Our study focuses on analyzing the effect of HER2 on MHC class I antigen presentation and sensitivity to tumor-antigen specific cytotoxic T lymphocytes (CTLs) in HLA-A2.1(+) melanoma cell lines. We demonstrate significant inverse correlations both between the expression of HER2 and total MHC class I surface expression as well as between HER2 and HLA-A2. A significant reduction of HLA-A2 levels was found when melanoma and carcinoma cell lines were transfected with a human HER2 gene. A signaling-competent HER2 molecule was crucial for the observed HLA-A2 down-regulation, as transfectants expressing high levels of HER2 mutated in the tyrosine signaling domain did not show altered HLA-A2 expression. Importantly, the human melanoma cell line EST049 demonstrated reduced HER2 and melanoma antigen-specific recognition by CTLs upon HER2 transfection. In addition, high expression of HER2 prevented both IFN-gamma mediated HLA-A2 up-regulation and improved recognition by HLA-A2-restricted CTLs in treated cells. Moreover, key APM molecules were down-regulated by HER2. These findings implicate that HER2 over-expressing tumors may be more prone to escape from HLA-A2 restricted CTLs suggesting that immunotherapy approaches inducing an integrated humoral, cellular and innate immune response would be most effective.