c-Jun overexpression in CART cells induces exhaustion resistance

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

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c-Jun overexpression in CART cells induces exhaustion resistance

机译：CART细胞中c-Jun的过度表达诱导精疲力竭

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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.

机译：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细胞衰竭所致的功能障碍是进展的重要障碍（4-6）。为了研究表达CAR受体的人类T细胞衰竭的生物学特性，我们使用了具有声调信号CAR的模型系统，该系统诱导了疲劳的标志性特征（6）。精疲力竭与IL-2产生中的一个严重缺陷有关，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与介导精疲力竭的T细胞功能障碍有关（7- 10）。在这里，我们显示工程化过表达典型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能，增加的功能能力，减少的终末分化和提高的抗肿瘤效力。我们得出的结论是，c-Jun的功能缺陷介导了精疲力竭的人类T细胞的功能障碍，而工程CAR T细胞过度表达c-Jun使其抵抗力衰竭，从而解决了这一新兴治疗药物类别的主要障碍。

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来源
《Nature》 |2019年第7786期|293-300|共8页
作者
Lynn Rachel C.; Weber Evan W.; Sotillo Elena; Gennert David; Xu Peng; Good Zinaida; Anbunathan Hima; Lattin John; Jones Robert; Tieu Victor; Nagaraja Surya; Granja Jeffrey; de Bourcy Charles F. A.; Majzner Robbie; Satpathy Ansuman T.; Quake Stephen R.; Monje Michelle; Chang Howard Y.; Mackall Crystal L.;
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作者单位

Stanford Univ Sch Med Stanford Canc Inst Stanford CA 94305 USA|Lyell Immunopharma San Francisco CA USA;

Stanford Univ Sch Med Stanford Canc Inst Stanford CA 94305 USA;

Stanford Univ Ctr Personal Dynam Regulomes Stanford CA 94305 USA;

Stanford Univ Sch Med Stanford Canc Inst Stanford CA 94305 USA|Stanford Univ Dept Biomed Data Sci Stanford CA 94305 USA|Parker Inst Canc Immunotherapy San Francisco CA 94129 USA;

Stanford Univ Dept Neurol Stanford CA 94305 USA;

Stanford Univ Dept Bioengn Stanford CA 94305 USA|Stanford Univ Dept Appl Phys Stanford CA 94305 USA|Chan Zuckerberg Initiat San Francisco CA USA;

Stanford Univ Dept Pediat Sch Med Stanford CA 94305 USA;

Stanford Univ Ctr Personal Dynam Regulomes Stanford CA 94305 USA|Parker Inst Canc Immunotherapy San Francisco CA 94129 USA;

Stanford Univ Dept Bioengn Stanford CA 94305 USA|Stanford Univ Dept Appl Phys Stanford CA 94305 USA|Chan Zuckerberg Biohub San Francisco CA USA;

Stanford Univ Sch Med Stanford Canc Inst Stanford CA 94305 USA|Stanford Univ Dept Neurol Stanford CA 94305 USA|Stanford Univ Dept Pediat Sch Med Stanford CA 94305 USA;

Stanford Univ Ctr Personal Dynam Regulomes Stanford CA 94305 USA|Parker Inst Canc Immunotherapy San Francisco CA 94129 USA|Stanford Univ Howard Hughes Med Inst Stanford CA 94305 USA;

Stanford Univ Sch Med Stanford Canc Inst Stanford CA 94305 USA|Parker Inst Canc Immunotherapy San Francisco CA 94129 USA|Stanford Univ Dept Pediat Sch Med Stanford CA 94305 USA|Stanford Univ Dept Med Sch Med Stanford CA 94305 USA;

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收录信息美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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专利

1. Inducible overexpression of c-Jun in MCF7 cells causes resistance to vinblastine via inhibition of drug-induced apoptosis and senescence at a step subsequent to mitotic arrest. [J] . Duan L, Sterba K, Kolomeichuk S, Biochemical Pharmacology . 2007,第4期

机译：MCF7细胞中c-Jun的诱导型过表达在有丝分裂停滞后的一个步骤中通过抑制药物诱导的凋亡和衰老而引起对长春碱的抗性。
2. c-jun and multistage carcinogenesis: association of overexpression of introduced c-jun with progression toward a neoplastic endpoint in mouse JB6 cells sensitive to tumor promoter-induced transformation. [J] . Watts RG, Ben Ari ET, Bernstein LR, Molecular Carcinogenesis . 1995,第1期

机译：c-jun和多阶段癌变：在对肿瘤启动子诱导的转化敏感的小鼠JB6细胞中，引入的c-jun的过度表达与向肿瘤终点的进展有关。
3. Doxorubicin-induced alterations of c-myc and c-jun gene expression in rat glioblastoma cells: role of c-jun in drug resistance and cell death. [J] . Pourquier P, Montaudon D, Huet S, Biochemical Pharmacology . 1998,第12期

机译：阿霉素诱导的大鼠胶质母细胞瘤细胞中c-myc和c-jun基因表达的改变：c-jun在耐药性和细胞死亡中的作用。
4. Particulate Joint Replacement Materials Induce Apoptosis of Rabbit Synoviocytes Cell Line HIG-82 through c-Jun N-Terminal Kinase (JNK) Pathway [C] . Chu Feng-Min, Lian Shuang-Shii, Sung Yen-Jen International Conference on Biomedical Engineering and Informatics;BMEI '09 . 2009

机译：颗粒关节替代材料通过c-Jun N末端激酶（JNK）途径诱导兔滑膜细胞HIG-82细胞凋亡
5. The role of c-jun/AP-1 in cholecystokinin induced pancreatic acinar cell growth in vivo and in vitro [D] . Guo, Lili 2008

机译：c-jun / AP-1在胆囊收缩素诱导的胰腺腺泡细胞体内外生长中的作用
6. Inducible overexpression of c-Jun in MCF7 cells causes resistance to vinblastine via inhibition of drug-induced apoptosis and senescence at a step subsequent to mitotic arrest [O] . Lingling Duan, Kristen Sterba, Sergey Kolomeichuk, -1

机译：MCF7细胞中c-Jun的诱导型过表达通过抑制药物诱导的有丝分裂阻滞后的细胞凋亡和衰老而导致对长春碱的抗性
7. Faculty Opinions recommendation of c-Jun overexpression in CAR T cells induces exhaustion resistance. [O] . Graham Pawelec 2020

机译：C-Jun过表达在汽车T细胞中的教师意见推荐诱导耗尽耐耐力。

c-Jun overexpression in CART cells induces exhaustion resistance

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