荷兰癌症研究所Wouter Scheper等人通过大量平行文库合成和筛选，发现肿瘤反应性T细胞受体（TCR）。该研究于2024年4月23日发表于国际学术期刊《自然-生物技术》杂志。

研究人员研发了一种高通量、个性化TCR生产途径，它能在一次反应中组装复杂的TCR合成文库，然后在报告T细胞中集中表达，能针对患者来源的肿瘤或抗原递呈细胞进行功能基因筛选。研究人员利用该方法筛选了多名患者的数千个肿瘤浸润淋巴细胞（TIL）衍生的TCR，发现了数十个具有强肿瘤反应性CD4⁺和CD8⁺ T细胞衍生的TCR，包括能识别患者特异性新抗原的TCR。

据了解，T细胞受体基因疗法是一种有效的细胞免疫疗法，通过基因工程改造患者T细胞，使其表达具有明确肿瘤反应性的TCR。然而，由于患者T细胞库中肿瘤特异性T细胞稀缺，而肿瘤上表达的T细胞表位又具有患者特异性，因此分离治疗用TCRs变得非常复杂。

附：英文原文

Title: Discovery of tumor-reactive T cell receptors by massively parallel library synthesis and screening

Author: Moravec, Ziva, Zhao, Yue, Voogd, Rhianne, Cook, Danielle R., Kinrot, Seon, Capra, Benjamin, Yang, Haiyan, Raud, Brenda, Ou, Jiayu, Xuan, Jiekun, Wei, Teng, Ren, Lili, Hu, Dandan, Wang, Jun, Haanen, John B.A.G., Schumacher, Ton N., Chen, Xi, Porter, Ely, Scheper, Wouter

Issue&Volume: 2024-04-23

Abstract: T cell receptor (TCR) gene therapy is a potent form of cellular immunotherapy in which patient T cells are genetically engineered to express TCRs with defined tumor reactivity. However, the isolation of therapeutic TCRs is complicated by both the general scarcity of tumor-specific T cells among patient T cell repertoires and the patient-specific nature of T cell epitopes expressed on tumors. Here we describe a high-throughput, personalized TCR discovery pipeline that enables the assembly of complex synthetic TCR libraries in a one-pot reaction, followed by pooled expression in reporter T cells and functional genetic screening against patient-derived tumor or antigen-presenting cells. We applied the method to screen thousands of tumor-infiltrating lymphocyte (TIL)-derived TCRs from multiple patients and identified dozens of CD4+ and CD8+ T-cell-derived TCRs with potent tumor reactivity, including TCRs that recognized patient-specific neoantigens.

DOI: 10.1038/s41587-024-02210-6

Source: https://www.nature.com/articles/s41587-024-02210-6