Interferon-γ renders tumors that express low levels of Her-2/neu sensitive to cytotoxic T cells
Interferon-γ renders tumors that express low levels of Her-2/neu sensitive to cytotoxic T cells
复制标题
DOI：
10.1007/s00262-005-0050-5
复制
发表时间：
2006-06-01
影响因子：
5.8
通讯作者：
Nishimura, MI
中科院分区：
文献类型：
--
作者：
Kaplan, BLF;Norell, H;Nishimura, MI
Her-2/neu 是一种肿瘤相关抗原，已被抗体和细胞毒性 T 淋巴细胞 (CTL) 靶向。尽管在接种疫苗的患者中分离出了 Her-2/neu 反应性 CTL，但由于观察到它们通常不能强有力地识别 Her-2neu(+) 肿瘤，因此其治疗用途受到限制。我们试图使用 Ag201P 和 Ag201M 细胞确定这种逃逸的机制，这两种细胞是表达功能性 HLA-A2/K-b 分子的鼠骨肉瘤肿瘤系。我们现在证明 Ag201P 和 Ag201M 表达低水平的鼠 Her-2/neu，并且 Ag201M 被 HLA-A2 限制性、Her-2/neu 反应性人 CTL 克隆适度且不一致地识别。为了确定无效的抗原处理是否可能导致识别较弱，用编码免疫显性 Her-2/neu:369 表位（不需要抗原处理）的短 Her-2/neu 小基因或不需要抗原处理的长 Her-2/neu 小基因转染 COS-A2 细胞。 Her-2/neu 反应性 CTL 克隆仅识别转染有短小基因的 COS-A2 细胞，表明缺乏适当的抗原加工可能是导致靶细胞识别不佳的原因。为了证实这些结果，证明在用干扰素-γ治疗后，Ag201P和Ag201M均强烈且持续地刺激CTL克隆。此外，使用另一种表达低水平 Her-2/neu (B16-A2/K-b) 的小鼠肿瘤系进行干扰素 γ 治疗后，CTL 克隆识别得到增强。在存在干扰素-γ的情况下，Ag201P和Ag201M的识别增强并不是由于Her-2/neu蛋白表达的上调。总的来说，这些结果表明 Her-2/neu 的低效抗原处理可能导致 CTL 缺乏肿瘤识别能力。这些结果还表明，即使是表达低水平 Her-2/neu 的组织，在抗原加工增强的条件下也可能成为 CTL 靶标。
Her-2/neu is a tumor-associated antigen that has been targeted with both antibodies and cytotoxic T lymphocytes (CTL). Despite the isolation of Her-2/neu-reactive CTL in vaccinated patients, their therapeutic use has been limited by the observation that they often do not robustly recognize Her-2neu(+) tumors. We sought to determine the mechanism for this escape using Ag201P and Ag201M cells, which are murine osteosarcoma tumor lines that express a functional HLA-A2/K-b molecule. We now demonstrate that Ag201P and Ag201M express low levels of murine Her-2/neu, and that Ag201M was modestly and inconsistently recognized by an HLA-A2-restricted, Her-2/neu-reactive human CTL clone. In order to determine whether inefficient antigen processing might account for the weak recognition, COS-A2 cells were transfected with a short Her-2/neu minigene coding for the immunodominant Her-2/neu:369 epitope that did not require antigen processing or a long Her-2/neu minigene that did require antigen processing. Her-2/neu-reactive CTL clones only recognized COS-A2 cells transfected with the short minigene, indicating that lack of proper antigen processing could be responsible for the poor recognition of target cells. To confirm these results, it was demonstrated that following treatment with interferon-gamma, both Ag201P and Ag201M robustly and consistently stimulated the CTL clones. Furthermore, CTL clone recognition was enhanced following interferon-gamma treatment using another murine tumor line that expressed low levels of Her-2/neu (B16-A2/K-b). The enhanced recognition of Ag201P and Ag201M in the presence of interferon-gamma was not due to an upregulation of Her-2/neu protein expression. Collectively, these results suggest that inefficient antigen processing of Her-2/neu can contribute to the lack of tumor recognition by CTL. These results also suggest that even tissues that express low levels of Her-2/neu might become CTL targets under conditions in which antigen processing is enhanced.