Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Lyell Immunopharma, South San Francisco, CA, USA.
Nature. 2019 Dec;576(7786):293-300. doi: 10.1038/s41586-019-1805-z. Epub 2019 Dec 4.
Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer, but dysfunction due to T cell exhaustion is an important barrier to progress. To investigate the biology of exhaustion in human T cells expressing CAR receptors, we used a model system with a tonically signaling CAR, which induces hallmark features of exhaustion. Exhaustion was associated with a profound defect in the production of IL-2, along with increased chromatin accessibility of AP-1 transcription factor motifs and overexpression of the bZIP and IRF transcription factors that have been implicated in mediating dysfunction in exhausted T cells. Here we show that CAR T cells engineered to overexpress the canonical AP-1 factor c-Jun have enhanced expansion potential, increased functional capacity, diminished terminal differentiation and improved anti-tumour potency in five different mouse tumour models in vivo. We conclude that a functional deficiency in c-Jun mediates dysfunction in exhausted human T cells, and that engineering CAR T cells to overexpress c-Jun renders them resistant to exhaustion, thereby addressing a major barrier to progress for this emerging class of therapeutic agents.
嵌合抗原受体 (CAR) T 细胞在一小部分癌症患者中介导抗肿瘤作用，但由于 T 细胞耗竭导致的功能障碍是进展的重要障碍。为了研究表达 CAR 受体的人类 T 细胞耗竭的生物学特性，我们使用了一种持续信号 CAR 的模型系统，该系统诱导了耗竭的标志性特征。耗竭与 IL-2 产生的严重缺陷相关，同时 AP-1 转录因子基序的染色质可及性增加，以及 bZIP 和 IRF 转录因子的过度表达，这些转录因子已被牵连介导耗竭 T 细胞的功能障碍。在这里，我们表明，过表达经典 AP-1 因子 c-Jun 的 CAR T 细胞具有增强的扩增潜力、增加的功能能力、减少的终末分化和在五种不同的体内小鼠肿瘤模型中提高的抗肿瘤效力。我们得出的结论是，c-Jun 的功能缺陷介导了耗竭的人类 T 细胞的功能障碍，并且工程 CAR T 细胞过表达 c-Jun 使它们对耗竭具有抗性，从而解决了这一新兴治疗药物类别的主要进展障碍。
