小柯机器人

美国斯坦福大学医学院Crystal L. Mackall研究组的最新研究，揭示了嵌合抗原受体（CAR）T细胞中c-Jun过表达诱导衰竭抵抗。该项研究成果在线发表在2019年12月4日的《自然》上。

为了研究CAR T细胞衰竭的生物学特性，研究人员利用可调节性表达CAR信号模拟系统，该系统可以诱导产生T细胞衰竭的标志性特征。T细胞衰竭与IL-2产生过程中的一个严重缺陷有关，同时AP-1转录因子基序染色质的可及性增加以及bZIP和IRF转录因子过表达也与衰竭T细胞功能障碍有关。研究人员发现工程化过表达经典AP-1因子c-Jun的CAR T细胞在五个不同的小鼠体内肿瘤模型中具有增强扩增潜能、功能发挥，减少终末分化和提高抗肿瘤效力。因此，研究人员介绍，c-Jun的功能缺陷介导了人衰竭T细胞的功能障碍，通过过度表达c-Jun改造的CAR T细胞增强了其抗衰竭能力，从而解决了这一新兴治疗方式的主要障碍。

据了解，CAR T细胞在极少部分癌症患者中发挥抗肿瘤作用，但T细胞衰竭导致的功能障碍阻碍了CAR-T治疗的进展。

附：英文原文

Title: c-Jun overexpression in CAR T cells induces exhaustion resistance

Author: Rachel C. Lynn, Evan W. Weber, Elena Sotillo, David Gennert, Peng Xu, Zinaida Good, Hima Anbunathan, John Lattin, Robert Jones, Victor Tieu, Surya Nagaraja, Jeffrey Granja, Charles F. A. de Bourcy, Robbie Majzner, Ansuman T. Satpathy, Stephen R. Quake, Michelle Monje, Howard Y. Chang, Crystal L. Mackall

Issue&Volume: 2019-12-04

Abstract: Chimeric antigen receptor (CAR) T cells mediate anti-tumour effects in a small subset of patients with cancer13, but dysfunction due to T cell exhaustion is an important barrier to progress46. 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 exhaustion6. 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 cells710. 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. Chimeric antigen receptor (CAR) T cells engineered to overexpress the canonical AP-1 transcription factor c-Jun are resistant to T cell exhaustion, and provide enhanced therapeutic benefit in mouse tumour models.

DOI: 10.1038/s41586-019-1805-z

Source: https://www.nature.com/articles/s41586-019-1805-z

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