CD8+ T-cell clones specific for the 5T4 antigen target renal cell carcinoma tumor-initiating cells in a murine xenograft model.
CD8+ T-cell clones specific for the 5T4 antigen target renal cell carcinoma tumor-initiating cells in a murine xenograft model.
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在小鼠异种移植模型中，针对 5T4 抗原特异性的 CD8+ T 细胞克隆靶向肾细胞癌肿瘤起始细胞。
DOI：
10.1097/cji.0b013e318261d630
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发表时间：
2012-09
期刊：
影响因子：
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通讯作者：
Warren EH
中科院分区：
文献类型：
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作者：
Tykodi SS;Satoh S;Deming JD;Chou J;Harrop R;Warren EH
肿瘤抗原5T4在肾细胞癌（RCC）和其他上皮癌中经常高水平表达。正常组织的调查显示胎盘滋养细胞中有丰富的5T4表达，其他地方表达有限。5T4是一种治疗性癌症疫苗（MVA-5T4）的靶标，可引发5T4特异性血清学、增殖和CTL反应。然而，5t4特异性CTL的抗肿瘤活性尚未得到广泛的表征。用HLA-A2结合的非分子肽5T417-25或5T497-105在体外刺激来自HLA-A2+健康供体（n=4）或RCC患者（n=2）的CD8+ T细胞，并用特异性四聚体（TET）流式细胞术筛选。分别从4/6和1/4供体中分离出5T417-25和5T497-105肽特异性CD8+/TET+ T细胞克隆。5T417-25特异性克隆的一个子集对MVA-5T4感染的HLA-A2+ LCL靶细胞和组成性表达HLA-A2和5T4的RCC肿瘤细胞系（包括A498 RCC）具有细胞溶解作用。在异种移植实验中，将具有代表性的5t417 - 25特异性CTL克隆与A498 RCC肿瘤细胞共接种到免疫缺陷小鼠中，完全阻止了A498肿瘤的生长。综上所述，这些数据表明CD8+ CTL能够识别RCC肿瘤细胞上自然处理的5T417-25表位，包括存在于健康供者和RCC患者外周血中的推定肿瘤启动细胞。因此，靶向5T417-25的CD8+ T细胞免疫作为进一步开发疫苗接种或过继细胞免疫疗法的潜在靶点，以及与非特异性免疫疗法相关的免疫监测研究，具有重大意义。
The tumor antigen 5T4 is frequently expressed at high levels on renal cell carcinoma (RCC) and other epithelial carcinomas. Surveys of normal tissues demonstrate abundant 5T4 expression on placental trophoblast cells with limited expression elsewhere. 5T4 is the target for a therapeutic cancer vaccine (MVA-5T4) that elicits 5T4-specific serological, proliferative, and CTL responses. However, the anti-tumor activity of 5T4-specific CTL has not been extensively characterized. CD8+ T cells from HLA-A2+ healthy donors (n=4) or RCC patients (n=2) were stimulated in vitro with the HLA-A2-binding nonamer peptides 5T417–25 or 5T497–105 and screened by flow cytometry with specific tetramers (TET). CD8+/TET+ T cell clones specific for 5T417–25 or 5T497–105 peptide were isolated from 4/6 and 1/4 donors respectively. A subset of clones specific for 5T417–25 was cytolytic for MVA-5T4 infected HLA-A2+ LCL target cells and for constitutively HLA-A2- and 5T4- expressing RCC tumor cell lines (including A498 RCC). In a xenoengraftment assay, the co-inoculation of a representative 5T417–25-specific CTL clone with A498 RCC tumors cells into immune deficient mice completely prevented growth of A498 tumors. Taken together, these data demonstrate high avidity CD8+ CTL able to recognize the naturally-processed 5T417–25 epitope on RCC tumor cells including putative tumor-initiating cells are present in peripheral blood of both healthy donors and RCC patients. CD8+ T cell immunity targeting 5T417–25 is therefore of substantial interest both as a potential target for further development of vaccination or adoptive cellular immunotherapy and for immune monitoring studies in association with nonspecific immunotherapies.