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Rewiring T-cell responses to soluble factors with chimeric antigen receptors.
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2018-01-29 , DOI: 10.1038/nchembio.2565
ZeNan L Chang 1, 2 , Michael H Lorenzini 3 , Ximin Chen 1 , Uyen Tran 4 , Nathanael J Bangayan 5 , Yvonne Y Chen 1
Affiliation  

Chimeric antigen receptor (CAR)-expressing T cells targeting surface-bound tumor antigens have yielded promising clinical outcomes, with two CD19 CAR-T cell therapies recently receiving FDA approval for the treatment of B-cell malignancies. The adoption of CARs for the recognition of soluble ligands, a distinct class of biomarkers in physiology and disease, could considerably broaden the utility of CARs in disease treatment. In this study, we demonstrate that CAR-T cells can be engineered to respond robustly to diverse soluble ligands, including the CD19 ectodomain, GFP variants, and transforming growth factor beta (TGF-β). We additionally show that CAR signaling in response to soluble ligands relies on ligand-mediated CAR dimerization and that CAR responsiveness to soluble ligands can be fine-tuned by adjusting the mechanical coupling between the CAR's ligand-binding and signaling domains. Our results support a role for mechanotransduction in CAR signaling and demonstrate an approach for systematically engineering immune-cell responses to soluble, extracellular ligands.

中文翻译:

用嵌合抗原受体重新排列T细胞对可溶性因子的反应。

靶向表面结合的肿瘤抗原的表达嵌合抗原受体(CAR)的T细胞已经取得了可喜的临床结果,最近有两种CD19 CAR-T细胞疗法获得FDA批准用于治疗B细胞恶性肿瘤。采用CARs识别可溶性配体是生理和疾病中的一类独特的生物标志物,可以大大扩展CARs在疾病治疗中的应用。在这项研究中,我们证明了可以对CAR-T细胞进行改造,使其对各种可溶性配体(包括CD19胞外域,GFP变体和转化生长因子β(TGF-β))产生强烈的反应。我们还显示,响应可溶性配体的CAR信号依赖配体介导的CAR二聚化,并且通过调节CAR的配体结合和信号域之间的机械偶联,可以微调CAR对可溶性配体的响应性。我们的结果支持机械转导在CAR信号传导中的作用,并证明了系统工程化免疫细胞对可溶性细胞外配体的反应的方法。
更新日期:2018-01-30
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