Tumor-specific killer cells in paraneoplastic cerebellar degeneration
Tumor-specific killer cells in paraneoplastic cerebellar degeneration
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DOI：
10.1038/3315
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发表时间：
1998-11-01
期刊：
影响因子：
82.9
通讯作者：
Darnell, RB
中科院分区：
文献类型：
--
作者：
Albert, ML;Darnell, JC;Darnell, RB
小鼠免疫介导的肿瘤消退模型已经确定了细胞毒性 T 淋巴细胞 (CTL) 的重要作用；然而，人们对人类自然发生的肿瘤免疫知之甚少(1)。副肿瘤性小脑变性（PCD）患者为探索乳腺癌和卵巢癌的肿瘤免疫机制提供了机会。尽管 PCD 中的肿瘤免疫和自身免疫性神经元变性与针对肿瘤和脑抗原 cdr2(2,3) 的特异性抗体反应相关，但这种体液反应尚未被证明具有致病性(3,4)。在这里，我们提供了 PCD 患者特定细胞免疫反应的证据。我们在 3/3 HLA-A2.1(+) PCD 患者的血液中检测到 MHC I 类限制性 cdr2 特异性 CTL 群体的扩大，据我们所知，在简单的回忆测定中使用原代人类细胞提供了对肿瘤特异性 CTL 的首次描述。树突状细胞对凋亡细胞的交叉呈递也导致了有效的 CTL 反应。这些结果表明，吞噬凋亡肿瘤细胞的未成熟树突状细胞可以成熟并迁移到引流淋巴器官，在那里它们可以诱导对组织限制性抗原的 CTL 反应。在 PCD 中，cdr2 特异性 CTL 的外周激活可能有助于自身免疫性神经元变性的后续发展。
Models for immune-mediated tumor regression in mice have defined an essential role for cytotoxic T lymphocytes (CTLs); however, naturally occurring tumor immunity in humans is poorly understood(1). Patients with paraneoplastic cerebellar degeneration (PCD) provide an opportunity to explore the mechanisms underlying tumor immunity to breast and ovarian cancer. Although tumor immunity and autoimmune neuronal degeneration in PCD correlates with a specific antibody response to the tumor and brain antigen cdr2(2,3), this humoral response has not been shown to be pathogenic(3,4). Here we present evidence for a specific cellular immune response in PCD patients. We have detected expanded populations of MHC class I-restricted cdr2-specific CTLs in the blood of 3/3 HLA-A2.1(+) PCD patients, providing the first description, to our knowledge, of tumor-specific CTLs using primary human cells in a simple recall assay. Cross-presentation of apoptotic cells by dendritic cells also led to a potent CTL response. These results indicate a model whereby immature dendritic cells that engulf apoptotic tumor cells can mature and migrate to draining lymph organs where they could induce a CTL response to tissue-restricted antigens. In PCD, peripheral activation of cdr2-specific CTLs is likely to contribute to the subsequent development of the autoimmune neuronal degeneration.