Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells
Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells
复制标题
DOI：
10.1002/ijc.26297
复制
发表时间：
2012-06-01
影响因子：
6.4
通讯作者：
Speiser, Daniel E.
中科院分区：
文献类型：
--
作者：
Baumgaertner, Petra;Jandus, Camilla;Speiser, Daniel E.
对外来（例如病毒）抗原特异性的 T 细胞可以产生强烈的保护性免疫反应，而自身/肿瘤抗原特异性 T 细胞被认为不太强大。然而，由Melan-A/MART-1肽、CpG和IFA组成的合成T细胞疫苗可以在黑色素瘤患者的PBMC中诱导高频率的肿瘤特异性CD8 T细胞。在这里，我们通过多参数流式细胞术直接离体分析了这些 T 细胞的功能。肿瘤 (Melan-A/MART-1) 特异性 T 细胞产生多种细胞因子 (IFN?、TNFa、IL-2) 和上调 LAMP-1 (CD107a) 与病毒 (EBV-BMLF1) 特异性 CD8 T 细胞相当。此外，肿瘤和病毒特异性 T 细胞中 STAT1、STAT5 和 ERK1/2 的磷酸化以及 CD3 zeta 链的表达相似，证明了功能性信号通路。有趣的是，无论患者的年龄或性别如何，都会诱导出高频率的功能性 T 细胞。最后，CD8 T 细胞功能与无病生存相关。然而，这一结果是初步的，因为该研究是 I 期临床试验。我们得出的结论是，人类肿瘤特异性 CD8 T 细胞可以在体内达到功能能力，从而鼓励进一步开发和评估稳健疫苗接种策略临床疗效的 III 期试验。
T-cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen-specific T-cells are thought to be less powerful. However, synthetic T-cell vaccines composed of Melan-A/MART-1 peptide, CpG and IFA can induce high frequencies of tumor-specific CD8 T-cells in PBMC of melanoma patients. Here we analyzed the functionality of these T-cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFN?, TNFa, IL-2) and upregulation of LAMP-1 (CD107a) by tumor (Melan-A/MART-1) specific T-cells was comparable to virus (EBV-BMLF1) specific CD8 T-cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor- and virus-specific T-cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T-cells were induced irrespective of patient's age or gender. Finally, CD8 T-cell function correlated with disease-free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor-specific CD8 T-cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies.