HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses
HER-2/neu antigen loss and relapse of mammary carcinoma are actively induced by T cell-mediated anti-tumor immune responses
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DOI：
10.1002/eji.200636639
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发表时间：
2007-03-01
影响因子：
5.4
通讯作者：
Manjili, Masoud H.
中科院分区：
文献类型：
--
作者：
Kmieciak, Maciej;Knutson, Keith L.;Manjili, Masoud H.
诱导肿瘤特异性免疫反应导致抑制肿瘤发展。然而，由于肿瘤免疫编辑过程促进了肿瘤逃逸机制的发展，肿瘤会复发。目前尚不清楚肿瘤逃逸是否是一个主动过程，抗肿瘤免疫反应会诱导抗原阳性克隆中靶抗原的丢失或下调。为了解决这个问题，我们使用了大鼠 neu 过表达的小鼠乳腺癌 (MMC) 及其复发性 neu 抗原阴性变体 (ANV)。 ANV 在体内 neu 特异性 T 细胞反应的压力下从 MMC 中出现。然后，我们克隆了来自 MMC 的残留 neu 抗原阴性细胞和来自 ANV 的残留 neu 抗原阳性细胞。我们发现这些neu阴性克隆和ANV之间存在显着差异，表明残留的neu阴性克隆可能不是ANV的起源。由于 MMC 的初始排斥与分泌 IFN-γ 的 T 细胞的存在有关，因此我们用 IFN-γ 处理 MMC，结果表明 IFN-γ 可以诱导 MMC 中 neu 表达的下调。这似乎是由于 neu 启动子的甲基化所致。总之，这些数据表明，由于 neu 靶向抗肿瘤免疫反应，neu 抗原丢失是原发性肿瘤中发生的一个活跃过程。
induction of tumor-specific immune responses results in the inhibition of tumor development. However, tumors recur because of the tumor immunoediting process that facilitates development of escape mechanisms in tumors. it is not known whether tumor escape is an active process whereby anti-tumor immune responses induce loss or downregulation of the target antigen in the antigen-positive clones. To address this question, we used rat neu-overexpressing mouse mammary carcinoma (MMC) and its relapsed neu antigen-negative variant (ANV). ANV emerged from MMC under pressure from neu-specific T cell responses in vivo. We then cloned residual neu antigen-negative cells from MMC and residual neu antigen-positive cells from ANV. We found marked differences between these neu-negative clones and ANV, demonstrating that the residual neu-negative clones are probably not the origin of ANV. Since initial rejection of MMC was associated with the presence of IFN-gamma-secreting T cells, we treated MMC with IFN-gamma and showed that IFN-gamma could induce downregulation of neu expression in MMC. This appears to be due to methylation of the neu promoter. Together, these data suggest that neu antigen loss is an active process that occurs in primary tumors due to the neu-targeted anti-tumor immune responses.