High-throughput identification of antigen-specific TCRs by TCR gene capture
High-throughput identification of antigen-specific TCRs by TCR gene capture
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DOI：
10.1038/nm.3359
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发表时间：
2013-11-01
期刊：
影响因子：
82.9
通讯作者：
Schumacher, Ton N. M.
中科院分区：
文献类型：
--
作者：
Linnemann, Carsten;Heemskerk, Bianca;Schumacher, Ton N. M.
将T细胞受体（TCR）基因转移到患者T细胞中是治疗病毒感染和癌症的一种有前途的方法。虽然存在有效的方法来鉴定用于治疗这些疾病的抗体，但缺乏鉴定TCR的可比策略。我们已经开发了一种基于DNA的高通量策略，通过捕获和测序编码TCR基因的基因组DNA片段来鉴定TCR序列。我们通过组装一个大型的癌症生殖系肿瘤抗原反应性TCR文库来确定这种方法的价值。此外，通过利用TCR基因捕获的定量性质，我们显示了在来自人材料或TCR人源化小鼠的寡克隆T细胞群中鉴定抗原特异性TCR的可行性。最后，我们证明了在不了解抗原特异性的情况下识别肿瘤内T细胞亚群中的肿瘤反应性TCR的能力，这可能是发展自体TCR基因治疗以靶向人类癌症中患者特异性新抗原的第一步。
The transfer of T cell receptor (TCR) genes into patient T cells is a promising approach for the treatment of both viral infections and cancer. Although efficient methods exist to identify antibodies for the treatment of these diseases, comparable strategies to identify TCRs have been lacking. We have developed a high-throughput DNA-based strategy to identify TCR sequences by the capture and sequencing of genomic DNA fragments encoding the TCR genes. We establish the value of this approach by assembling a large library of cancer germline tumor antigen-reactive TCRs. Furthermore, by exploiting the quantitative nature of TCR gene capture, we show the feasibility of identifying antigen-specific TCRs in oligoclonal T cell populations from either human material or TCR-humanized mice. Finally, we demonstrate the ability to identify tumor-reactive TCRs within intratumoral T cell subsets without knowledge of antigen specificities, which may be the first step toward the development of autologous TCR gene therapy to target patient-specific neoantigens in human cancer.