c-Jun過表達可以抵抗CAR T細胞衰竭
作者：
小柯機器人發布時間：2019/12/6 11:00:44
美國史丹福大學醫學院Crystal L. Mackall研究組的最新研究，揭示了嵌合抗原受體（CAR）T細胞中c-Jun過表達誘導衰竭抵抗。該項研究成果在線發表在2019年12月4日的《自然》上。
為了研究CAR T細胞衰竭的生物學特性，研究人員利用可調節性表達CAR信號模擬系統，該系統可以誘導產生T細胞衰竭的標誌性特徵。T細胞衰竭與IL-2產生過程中的一個嚴重缺陷有關，同時AP-1轉錄因子基序染色質的可及性增加以及bZIP和IRF轉錄因子過表達也與衰竭T細胞功能障礙有關。研究人員發現工程化過表達經典AP-1因子c-Jun的CAR T細胞在五個不同的小鼠體內腫瘤模型中具有增強擴增潛能、功能發揮，減少終末分化和提高抗腫瘤效力。因此，研究人員介紹，c-Jun的功能缺陷介導了人衰竭T細胞的功能障礙，通過過度表達c-Jun改造的CAR T細胞增強了其抗衰竭能力，從而解決了這一新興治療方式的主要障礙。
據了解，CAR T細胞在極少部分癌症患者中發揮抗腫瘤作用，但T細胞衰竭導致的功能障礙阻礙了CAR-T治療的進展。
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