人乳头瘤病毒 (HPV) 的致癌蛋白 E7 在 HPV 相关肿瘤中表达，有可能成为基于 T 细胞受体 (TCR) 的免疫治疗的靶点。 TCR 工程 T (TCR-T) 细胞的过继转移已显示出作为 HPV 诱导肿瘤的治疗方法的前景。本研究旨在通过 E789-97/HLA-A11:01 四聚体促进的单细胞分选和测序，从 HLA-A11:01 转基因小鼠中鉴定 HPV-E7 特异性 TCR。鉴定出两个显性 TCR，它们与 HLA-A*11:01 背景下的 E789-97 表现出特异性结合。 TCR-T细胞是通过用含有TCR基因的慢病毒感染原代T细胞来制备的，两种TCR表现出显着的反应性并表现出CD8依赖性细胞因子分泌特征。对细胞因子谱的进一步分析表明，这两种 TCR 能够在特定刺激下发挥多功能反应。这些发现表明，这两种 TCR 代表了未来在 HLA-A*11:01 肿瘤免疫治疗背景下开发针对 HPV-E7 的治疗药物的有前途的候选药物。版权所有 © 2024 Elsevier Ltd. 保留所有权利。

The oncogenic protein E7 of the Human Papillomavirus (HPV) is constitutionally expressed in HPV-associated tumors and has the potential to be targeted in T cell receptor (TCR)-based immunotherapy. Adoptive transfer of TCR-engineered T (TCR-T) cells has shown promise as a therapeutic approach for HPV-induced tumors. This study aimed to identify HPV-E7 specific TCRs from HLA-A11:01 transgenic mice through single-cell sorting and sequencing facilitated by E789-97/HLA-A11:01 tetramer. Two dominant TCRs were identified, which exhibited specific binding to E789-97 presented in the context of HLA-A*11:01. TCR-T cells were prepared by infecting primary T cells with lentiviruses containing the TCR genes, and the two TCRs demonstrated substantial responsiveness and showed CD8+ dependent cytokine secretion characteristics. Further analyses of the cytokine profiles revealed that the two TCRs were capable of exerting polyfunctional responses upon specific stimulation. These findings suggest that the two TCRs represent promising candidates for the development of future therapeutic drugs targeting HPV-E7 in the context of HLA-A*11:01 for tumor immunotherapy.Copyright © 2024 Elsevier Ltd. All rights reserved.