Laboratory of Molecular Immunology, Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia.
Front Immunol. 2024 Oct 10;15:1470130. doi: 10.3389/fimmu.2024.1470130. eCollection 2024.
Adoptive cell therapy using TCR-engineered T-cells is one of the most effective strategies against tumor cells. The TCR T-cell approach has been well tested against a variety of blood neoplasms but is yet to be deeply tested against solid tumors. Among solid tumors, cancer-testis antigens are the most prominent targets for tumor-specific therapy, as they are usually found on cells that lie behind blood-tissue barriers.
We have employed a novel efficient protocol for MAGE-A3-specific T-cell clonal expansion, performed single-cell multi-omic analysis of the expanded T-cells via BD Rhapsody, engineered a selected T-cell receptor into a lentiviral construct, and tested it in an LDH-cytotoxicity test.
We have observed a 191-fold increase in the MAGE-A3-specific T-cell abundance, obtained a dominant T-cell receptor via single-cell multi-omic BD Rhapsody data analysis in the TCRscape bioinformatics tool, and observed potent cytotoxicity of the dominant-clonotype transduced TCR T-cells against a MAGE-A3-positive tumor. We have demonstrated the efficiency of our T-cell enrichment protocol in obtaining potent anti-tumor T-cells and their T-cell receptors, especially when paired with the modern single-cell analysis methods.
利用 TCR 工程化 T 细胞的过继细胞疗法是对抗肿瘤细胞最有效的策略之一。TCR T 细胞的方法已经在各种血液肿瘤中得到了很好的测试，但尚未在实体肿瘤中进行深入测试。在实体肿瘤中，癌症睾丸抗原是肿瘤特异性治疗的最主要靶点，因为它们通常存在于血组织屏障后面的细胞上。
我们采用了一种新的有效 MAGE-A3 特异性 T 细胞克隆扩增方案，通过 BD Rhapsody 对扩增的 T 细胞进行单细胞多组学分析，将选定的 T 细胞受体工程化到慢病毒构建体中，并在 LDH 细胞毒性试验中进行测试。
我们观察到 MAGE-A3 特异性 T 细胞的丰度增加了 191 倍，通过 TCRscape 生物信息学工具中的单细胞多组学 BD Rhapsody 数据分析获得了主导性 T 细胞受体，并观察到转导了主导型克隆型 TCR 的 T 细胞对 MAGE-A3 阳性肿瘤具有强大的细胞毒性。我们证明了我们的 T 细胞富集方案在获得有效抗肿瘤 T 细胞及其 T 细胞受体方面的效率，尤其是与现代单细胞分析方法结合使用时。
