Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer
Spontaneous and vaccine induced AFP-specific T cell phenotypes in subjects with AFP-positive hepatocellular cancer
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DOI：
10.1007/s00262-007-0337-9
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发表时间：
2007-12-01
影响因子：
5.8
通讯作者：
Economou, James S.
中科院分区：
文献类型：
--
作者：
Butterfield, Lisa H.;Ribas, Antoni;Economou, James S.
我们正在研究使用甲胎蛋白（AFP）作为肝细胞癌（HCC）的肿瘤排斥抗原。我们最近完成了10例AFP+/HLA-A2.1+ HCC受试者的AFP肽致敏自体树突状细胞（DC）疫苗接种。接种后，循环AFP特异性T细胞和产生IFN γ的AFP特异性T细胞的频率增加。为了更好地了解免疫应答和临床应答之间缺乏相关性，我们研究了患者AFP免疫应答的其他方面。在这里，我们的特点是循环AFP四聚体阳性CD 8 T细胞的细胞表面表型和评估AFP特异性CD 4功能。在接种疫苗之前，HCC受试者循环AFP特异性CD 8 T细胞的频率增加，具有一系列幼稚、效应、中枢和效应记忆表型。一些患者有上调的激活标志物。评估了一部分患者在接种疫苗前后的表型变化，缺乏完全分化为效应或记忆表型的证据。CD 8表型和细胞因子应答与患者血清AFP抗原水平（74 - 463，040 ng/ml）无关。通过ELISPOT和多细胞因子测定法评估的CD 4 + T细胞应答未鉴定出对该分泌蛋白的任何自发性CD 4 T细胞应答。这些数据表明，有一个扩大池的部分分化的AFP特异性CD 8 T细胞在许多这些HCC受试者，但这些细胞在很大程度上是非功能性的，和可检测的CD 4 T细胞对这种分泌的癌胚抗原的反应是缺乏。
We are investigating the use of Alpha Fetoprotein (AFP) as a tumor rejection antigen for hepatocellular carcinoma (HCC). We recently completed vaccination of 10 AFP+/HLA-A2.1+ HCC subjects with AFP peptide-pulsed autologous dendritic cells (DC). There were increased frequencies of circulating AFP-specific T cells and of IFN gamma-producing AFP-specific T cells after vaccination. In order to better understand the lack of association between immune response and clinical response, we have examined additional aspects of the AFP immune response in patients. Here, we have characterized the cell surface phenotype of circulating AFP tetramer-positive CD8 T cells and assessed AFP-specific CD4 function. Before vaccination, HCC subjects had increased frequencies of circulating AFP-specific CD8 T cells with a range of naive, effector, central and effector memory phenotypes. Several patients had up-regulated activation markers. A subset of patients was assessed for phenotypic changes pre- and post-vaccination, and evidence for complete differentiation to effector or memory phenotype was lacking. CD8 phenotypic and cytokine responses did not correlate with level of patient serum AFP antigen (between 74 and 463,040 ng/ml). Assessment of CD4+ T cell responses by ELISPOT and multi-cytokine assay did not identify any spontaneous CD4 T cell responses to this secreted protein. These data indicate that there is an expanded pool of partially differentiated AFP-specific CD8 T cells in many of these HCC subjects, but that these cells are largely non-functional, and that a detectable CD4 T cell response to this secreted oncofetal antigen is lacking.