瑞士生物系统科学与工程系Sai T. Reddy和Rodrigo Vazquez-Lombardi共同合作近期取得重要工作进展，他们通过功能筛选的高通量T细胞受体工程确定了具有增强效力和特异性的候选细胞。相关论文于2022年9月28日在线发表于《免疫》杂志上。

研究人员开发了TCR-Engine，这是一种结合了基因组编辑、计算设计和深度测序的方法，可以在高通量下设计人类T细胞系表面的TCR的功能活性和特异性。研究人员应用TCR-Engine成功设计了合成TCRs，以提高对临床相关的肿瘤相关抗原（MAGE-A3）的效力和特异性，并通过多种体内外相关的安全及疗效评估验证了它们的转化潜力。因此，TCR-Engine代表了一项有价值的技术，可以应用于免疫治疗中安全、有效TCRs的工程化合成。

据介绍，过继T细胞免疫治疗的主要挑战是发现对肿瘤抗原具有高活性和特异性的天然T细胞受体（TCRs）。由于存在引入交叉反应的风险，以及TCRs对抗原（肽-MHC）的结合亲和力和活性之间可能存在较差的相关性，因此，工程化合成TCRs以增加肿瘤抗原识别是复杂的。

附：英文原文

Title: High-throughput T cell receptor engineering by functional screening identifies candidates with enhanced potency and specificity

Author: Rodrigo Vazquez-Lombardi, Johanna S. Jung, Fabrice S. Schlatter, Anna Mei, Natalia Rodrigues Mantuano, Florian Bieberich, Kai-Lin Hong, Jakub Kucharczyk, Edo Kapetanovic, Erik Aznauryan, Cédric R. Weber, Alfred Zippelius, Heinz Lubli, Sai T. Reddy

Issue&Volume: 2022-09-28

Abstract: A major challenge in adoptive T cell immunotherapy is the discovery of natural T cell receptors (TCRs) with high activity and specificity to tumor antigens. Engineering synthetic TCRs for increased tumor antigen recognition is complicated by the risk of introducing cross-reactivity and by the poor correlation that can exist between binding affinity and activity of TCRs in response to antigen (peptide-MHC). Here, we developed TCR-Engine, a method combining genome editing, computational design, and deep sequencing to engineer the functional activity and specificity of TCRs on the surface of a human T cell line at high throughput. We applied TCR-Engine to successfully engineer synthetic TCRs for increased potency and specificity to a clinically relevant tumor-associated antigen (MAGE-A3) and validated their translational potential through multiple in vitro and in vivo assessments of safety and efficacy. Thus, TCR-Engine represents a valuable technology for engineering of safe and potent synthetic TCRs for immunotherapy applications.

DOI: 10.1016/j.immuni.2022.09.004

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00498-8