Immunosurveillance and survivin-specific T-cell immunity in children with high-risk neuroblastoma
Immunosurveillance and survivin-specific T-cell immunity in children with high-risk neuroblastoma
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DOI：
10.1200/jco.2005.05.3314
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发表时间：
2006-12-20
影响因子：
45.3
通讯作者：
Vonderheide, Robert H.
中科院分区：
文献类型：
--
作者：
Coughlin, Christina M.;Fleming, Mark D.;Vonderheide, Robert H.
目的 肿瘤免疫监视影响肿瘤发生和肿瘤生长，但临床免疫监视失败是否是淋巴细胞功能障碍或肿瘤逃逸的结果仍存在争议。在本研究中，我们的目标是描述高危神经母细胞瘤 (HR-NBL) 儿童肿瘤免疫监视的生理学特征。患者和方法 对来自费城儿童医院 2003 年 5 月至 2005 年 5 月期间在费城儿童医院诊断的 HR-NBL 患者队列中的 26 个肿瘤样本进行了免疫组织病理学研究。对该队列中 9 名 HLA-A2(+) 患者的血液进行了 T 细胞特异性分析抗凋亡蛋白survivin。结果26个肿瘤中有26个表达Survivin蛋白。在 HLA-A2(+) 患者中，通过肽/主要组织相容性复合物四聚体分析，在诊断时 9 名 HR-NBL 儿童中的 8 名患者的血液中检测到了对生存素具有特异性的循环细胞毒性 T 淋巴细胞 (CTL)。九名患者中的六名患者的细胞毒性和干扰素γ酶联免疫斑点测定表明，循环中的生存素特异性CTL并没有在体内选择性地呈现无反应性，而是具有高度功能。在 5 名患者中，有 5 名发现了 T 细胞对生存素特异性 CD107a 的动员。通过免疫组织化学分析，26 个肿瘤中的 26 个肿瘤中肿瘤浸润 T 细胞很少或不存在。结论 HR-NBL 儿童在诊断时对通用肿瘤抗原生存素具有强烈的细胞免疫反应，但肿瘤内 T 细胞却极其罕见，表明细胞免疫监视失败。有必要努力开发新的疗法来增加 T 细胞向肿瘤巢的运输。
Purpose Tumor immunosurveillance influences oncogenesis and tumor growth, but it remains controversial whether clinical failure of immunosurveillance is a result of lymphocyte dysfunction or tumor escape. In this study, our goal was to characterize the physiology of tumor immunosurveillance in children with high-risk neuroblastoma (HR-NBL).Patients and Methods Immunohistopathologic studies were carried out on 26 tumor samples from a cohort of HR-NBL patients diagnosed at Children's Hospital of Philadelphia for the 2-year period from May 2003 to May 2005. Blood from nine HLA-A2(+) patients in this cohort was analyzed for T cells specific for the antiapoptotic protein survivin.Results Survivin protein was expressed by 26 of 26 tumors. In HLA-A2(+) patients, circulating cytotoxic T lymphocytes (CTLs) specific for survivin were detected by peptide/major histocompatibility complex tetramer analysis in the blood of eight of nine children with HR-NBL at the time of diagnosis. Rather than being selectively rendered anergic in vivo, circulating survivin-specific CTLs were highly functional as shown by cytotoxicity and interferon gamma enzyme-linked immunospot assays in six of nine patients. Survivin-specific CD107a mobilization by T cells was found in five of five patients. By immunohistochemistry, tumor-infiltrating T cells were few or absent in 26 of 26 tumors.Conclusion Children with HR-NBL harbor robust cellular immune responses to the universal tumor antigen survivin at the time of diagnosis, but intratumoral T cells are strikingly rare, suggesting a failure of cellular immunosurveillance. Efforts to develop novel therapies that increase T-cell trafficking into tumor nests are warranted.