确定互补性的区域聚类可能会导致CAR-T细胞功能障碍
Tina Sarén1, Giulia Saronio1, Paula Marti Torrell1
1Uppsala University, Dept Immunology, Genetics, Pathology, Science for Life Laboratory, Uppsala, Sweden.
Nature communications
|August 10, 2023
概括
CAR-T细胞治疗设计受到CDR循环的挑战,导致CAR集群. 这导致抗原独立的T细胞激活和功能障碍,影响癌症治疗的疗效.
科学领域:
- 免疫学 免疫学 免疫学
- 癌症生物学 癌症生物学
- 生物技术是生物技术.
背景情况:
- 化学抗原受体 (CAR) -T细胞疗法在癌症治疗方面表现有前途.
- 设计最佳的CAR是复杂的,单链变量片段 (scFvs) 通过互补性确定区域 (CDR) 定义特异性.
研究的目的:
- 研究CDR循环对CAR集群和T细胞功能的影响.
- 为了确定抗原独立的CAR-T细胞激活和功能障碍的机制.
主要方法:
- 具有相同框架但不同的CDR序列的工程CAR.
- 评估了T细胞表面上的CAR集群.
- 测量了抗原独立的T细胞激活标志物 (细胞大小,IFN-γ分泌).
- 评估了CAR-T细胞耗尽,细胞死亡和瘤细胞响应能力.
主要成果:
- 发现CDR循环在T细胞表面中介于CAR集群.
- CAR聚类诱导了抗原独立的T细胞激活,由细胞大小增加和IFN-γ分泌物证明.
- 这种增强信号导致CAR-T细胞耗尽,激活诱导的细胞死亡和减少抗瘤活性.
结论:
- 抗原独立的增强信号可以通过CDR介导的CAR集群触发.
- 这种现象仅仅通过scFv序列无法预测,但会影响CAR-T细胞的疗效.
- 评估未刺激的CAR-T细胞活动对于预测治疗结果至关重要.
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