Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells
Survivin is a shared tumor-associated antigen expressed in a broad variety of malignancies and recognized by specific cytotoxic T cells
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DOI：
10.1182/blood-2002-08-2554
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发表时间：
2003-07-15
期刊：
影响因子：
20.3
通讯作者：
Brossart, P
中科院分区：
文献类型：
--
作者：
Schmidt, SM;Schag, K;Brossart, P
Survivin是凋亡抑制蛋白家族的一员，几乎在所有类型的恶性肿瘤中表达，使得该蛋白成为开发广泛适用的疫苗治疗的有用工具。我们使用最近鉴定的HLA-A2结合肽和来自健康供体的树突状细胞（DCs）在体外诱导存活素特异性细胞毒性T淋巴细胞（CTL）。这些T细胞有效地裂解用同源肽脉冲的靶细胞。此外，生存素特异性CTL以抗原特异性和HLA限制性方式识别HLA-A2匹配的肿瘤细胞系和来自白血病患者的原发性恶性细胞，如使用冷靶抑制测定和阻断抗体所证明的。为了验证存活素的免疫原性，我们在自体环境中进行实验，并使用单核细胞衍生的DC作为靶。有趣的是，我们发现DCS在肿瘤坏死因子α（TNF-α）刺激下上调生存素表达。然而，这些成熟DC不被存活素特异性CTL识别，而它们裂解用抗原肽脉冲或用从存活素表达细胞系纯化的全肿瘤RNA转染的自体成熟DC。为了进一步分析存活素特异性CTL在癌症治疗中的可能用途，我们使用来自慢性淋巴细胞白血病（CLL）患者的外周血单核细胞（PBMNCs）和DC诱导存活素特异性CTL。体外产生的T细胞有效地识别自体恶性CLL细胞，而它们避开自体纯化的非恶性B细胞或DC。我们的研究结果表明，生存素表位上提出了各种恶性肿瘤，并可应用于疫苗接种治疗。(C)2003年，美国血液学会。
Survivin, a member of the inhibitor of apoptosis protein family, is expressed in almost all types of malignancies, making this protein a useful tool for the development of broadly applicable vaccination therapies. We used a recently identified HLA-A2 binding peptide and dendritic cells (DCs) from healthy donors to induce survivin-specific cytotoxic T lymphocytes (CTLs) in vitro. These T cells efficientily lysed target cells pulsed with the cognate peptide. Furthermore, survivin-specific CTLs recognized HLA-A2-matched tumor cell lines and primary malignant cells from patients with leukemia in an antigen-specific and HLA-restricted manner as demonstrated with the use of cold target inhibition assays and blocking antibodies. To validate the immunogenicity of survivin we performed the experiments in an autologous setting and used monocyte-derived DCs as targets. Interestingly, we found that DCS up-regulate survivin expression on stimulation with tumor necrosis factor alpha (TNF-alpha). However, these mature DCs were not recognized by survivin-specific CTLs, whereas they lysed autologous mature DCs pulsed with the antigenic peptide or transfected with whole tumor RNA purified from a survivin-expressing cell line. To further analyze the possible use of survivin-specific CTLs in cancer therapies, we induced survivin-specific CTLs using peripheral blood mononuclear cells (PBMNCs) and DCs from a patient with chronic lymphocytic leukemia (CLL). The in vitro-generated T cells efficiently recognized autologous malignant CLL cells, whereas they spared autologous-purified nonmalignant B cells or DCs. Our results demonstrate that survivin epitopes are presented on a broad variety of malignancies and can be applied in vaccination therapies. (C) 2003 by The American Society of Hematology.