Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Eur J Immunol. 2021 Jun;51(6):1505-1518. doi: 10.1002/eji.202049007. Epub 2021 May 5.
A T-cell receptor (TCR) with optimal avidity to a tumor antigen can be used to redirect T cells to eradicate cancer cells via adoptive cell transfer. Cancer testis antigens (CTAs) are attractive targets because they are expressed in the testis, which is immune-privileged, and in the tumor. However, CTAs are self-antigens and natural TCRs to CTAs have low affinity/avidity due to central tolerance. We previously described a method of directed evolution of TCR avidity using somatic hypermutation. In this study, we made several improvements to this method and enhanced the avidity of the hT27 TCR, which is specific for the cancer testis antigen HLA-A2-MAGE-A1 . We identified eight point mutations with varying degrees of improved avidity. Human T cells transduced with TCRs containing these mutations displayed enhanced tetramer binding, IFN-γ and IL2 production, and cytotoxicity. Most of the mutations have retained specificity, except for one mutant with extremely high avidity. We demonstrate that somatic hypermutation is capable of optimizing avidity of clinically relevant TCRs for immunotherapy.
T 细胞受体 (TCR) 对肿瘤抗原具有最佳亲和力，可以通过过继细胞转移将 T 细胞重新定向以消灭癌细胞。癌症睾丸抗原 (CTA) 是很有吸引力的靶标，因为它们在睾丸（免疫特惠）和肿瘤中表达。然而，CTA 是自身抗原，由于中枢耐受，天然 TCR 对 CTA 的亲和力/亲合力较低。我们之前描述了一种使用体细胞超突变定向进化 TCR 亲和力的方法。在这项研究中，我们对该方法进行了一些改进，并增强了 hT27 TCR 的亲和力，该 TCR 特异性针对癌症睾丸抗原 HLA-A2-MAGE-A1。我们鉴定了具有不同程度增强亲和力的 8 个点突变。转导了这些突变 TCR 的人 T 细胞显示出增强的四聚体结合、IFN-γ 和 IL2 产生以及细胞毒性。除了一个具有极高亲和力的突变体外，大多数突变体都保留了特异性。我们证明体细胞超突变能够优化免疫治疗中临床相关 TCR 的亲和力。
