c-Jun overexpression in CAR T cells induces exhaustion resistance
c-Jun overexpression in CAR T cells induces exhaustion resistance
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DOI：
10.1038/s41586-019-1805-z
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发表时间：
2019-12-12
期刊：
影响因子：
64.8
通讯作者：
Mackall, Crystal L.
中科院分区：
文献类型：
--
作者：
Lynn, Rachel C.;Weber, Evan W.;Mackall, Crystal L.
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（1-3），但由于T细胞耗竭导致的功能障碍是进展的重要障碍（4-6）。为了研究表达CAR受体的人T细胞中的耗竭生物学，我们使用了具有紧张性信号传导CAR的模型系统，其诱导耗竭的标志性特征（6）。耗竭与IL-2产生中的严重缺陷相关，沿着AP-1转录因子基序的染色质可及性增加以及bZIP和IRF转录因子的过表达，bZIP和IRF转录因子参与介导耗竭T细胞中的功能障碍（7-10）。在这里，我们表明，工程化以过表达经典AP-1因子c-Jun的CAR T细胞在体内五种不同的小鼠肿瘤模型中具有增强的扩增潜力，增加的功能能力，减少的终末分化和提高的抗肿瘤效力。我们的结论是，c-Jun的功能缺陷介导了耗尽的人类T细胞的功能障碍，并且工程化CAR T细胞以过表达c-Jun使它们对耗尽具有抗性，从而解决了这类新兴治疗药物进展的主要障碍。
Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer(1-3), but dysfunction due to T cell exhaustion is an important barrier to progress(4-6). 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(6). 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(7-10). 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.