Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients
Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients
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DOI：
10.1172/jci46102
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发表时间：
2011-06-01
影响因子：
15.9
通讯作者：
Speiser, Daniel E.
中科院分区：
文献类型：
--
作者：
Baitsch, Lukas;Baumgaertner, Petra;Speiser, Daniel E.
在慢性病毒感染中，CD8(+) T细胞功能缺失，并表现出多种分子改变。相比之下，对于小鼠和人类自身特异性及肿瘤特异性CD8(+) T细胞却知之甚少。在此，我们测定了黑色素瘤患者肿瘤特异性CD8(+) T细胞的分子图谱。在接种了CpG和黑色素瘤抗原Melan - A/MART - 1肽的患者外周血中，我们发现了功能性效应T细胞群，在针对持续性疱疹病毒（EBV和CMV）的特异性T细胞中仅有微小但显著的差异。相反，从黑色素瘤患者转移灶中分离出的Melan - A/MART - 1特异性T细胞表达了大量与T细胞耗竭相关的基因。所确定的耗竭图谱揭示了广泛的分子改变。我们的数据表明，循环中的效应细胞与肿瘤环境中的耗竭细胞显著共存。功能性T细胞损伤是由抑制性受体及其他分子通路介导的，这些是癌症治疗的潜在靶点。
In chronic viral infections, CD8(+) T cells become functionally deficient and display multiple molecular alterations. In contrast, only little is known of self- and tumor-specific CD8(+) T cells from mice and humans. Here we determined molecular profiles of tumor-specific CD8(+) T cells from melanoma patients. In peripheral blood from patients vaccinated with CpG and the melanoma antigen Melan-A/MART-1 peptide, we found functional effector T cell populations, with only small but nevertheless significant differences in T cells specific for persistent herpesviruses (EBV and CMV). In contrast, Melan-A/MART-1-specific T cells isolated from metastases from patients with melanoma expressed a large variety of genes associated with T cell exhaustion. The identified exhaustion profile revealed extended molecular alterations. Our data demonstrate a remarkable coexistence of effector cells in circulation and exhausted cells in the tumor environment. Functional T cell impairment is mediated by inhibitory receptors and further molecular pathways, which represent potential targets for cancer therapy.