Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients
Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients
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DOI：
10.1038/9525
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发表时间：
1999-06-01
期刊：
影响因子：
82.9
通讯作者：
Davis, MM
中科院分区：
文献类型：
--
作者：
Lee, PP;Yee, C;Davis, MM
我们使用肽/HLA - A*0201四聚体在11名转移性黑色素瘤患者中的6名患者体内鉴定出了针对肿瘤相关抗原（TAA）MART - 1（27 - 35）或酪氨酸酶（368 - 376）的循环CD8(+) T细胞群。这些TAA特异性细胞群具有两种表型不同的类型：一种是记忆/效应T细胞的典型类型；另一种是此前未被描述的表型，同时表达初始细胞和效应细胞的标志物。后一种类型在一名患者中占总CD8(+) T细胞的2%以上，从而可以进行详细的表型和功能分析。尽管这些细胞具有效应T细胞的许多特征，但它们在功能上无反应，无法直接裂解黑色素瘤靶细胞，也不能对有丝分裂原产生细胞因子。相比之下，来自同一患者的CD8(+) T细胞能够裂解EBV刺激的靶细胞，并表现出强烈的同种异体反应。因此，克隆扩增的TAA特异性细胞群似乎在体内被选择性地诱导为无反应性。对其他患者的TAA特异性T细胞群进行肽刺激未能诱导CD69表达的大幅上调，这表明这些细胞可能也存在功能缺陷，导致激活反应减弱。这些数据表明，癌症患者体内可从头产生全身性的TAA特异性T细胞反应，但抗原特异性无反应性可能解释了为什么这些细胞无法控制肿瘤生长。
We identified circulating CD8(+) T-cell populations specific for the tumor-associated antigens (TAAs) MART-1 (27-35) or tyrosinase (368-376) in six of eleven patients with metastatic melanoma using peptide/HLA-A*0201 tetramers. These TAA-specific populations were of two phenotypically distinct types: one, typical for memory/effector T cells; the other, a previously undescribed phenotype expressing both naive and effector cell markers. This latter type represented more than 2% of the total CD8(+) T cells in one patient, permitting detailed phenotypic and functional analysis. Although these cells have many of the hallmarks of effector T cells, they were functionally unresponsive, unable to directly lyse melanoma target cells or produce cytokines in response to mitogens. In contrast, CD8(+) T cells from the same patient were able to lyse EBV-pulsed target cells and showed robust allogeneic responses. Thus, the clonally expanded TAA-specific population seems to have been selectively rendered anergic in vivo. Peptide stimulation of the TAA-specific T-cell populations in other patients failed to induce substantial upregulation of CD69 expression, indicating that these cells may also have functional defects, leading to blunted activation responses. These data demonstrate that systemic TAA-specific T-cell responses can develop de novo in cancer patients, but that antigen-specific unresponsiveness may explain why such cells are unable to control tumor growth.