Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, Los Angeles, California, USA.
Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA.
Nat Chem Biol. 2018 Mar;14(3):317-324. doi: 10.1038/nchembio.2565. Epub 2018 Jan 29.
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.
嵌合抗原受体 (CAR)-表达 T 细胞靶向表面结合的肿瘤抗原已产生有希望的临床结果，最近有两种针对 CD19 的 CAR-T 细胞疗法获得 FDA 批准用于治疗 B 细胞恶性肿瘤。CAR 用于识别可溶性配体（生理和疾病中一类独特的生物标志物）的采用，可以极大地扩展 CAR 在疾病治疗中的应用。在这项研究中，我们证明可以对 CAR-T 细胞进行工程改造，使其对多种可溶性配体（包括 CD19 胞外结构域、GFP 变体和转化生长因子-β (TGF-β)）产生强烈反应。我们还表明，CAR 信号响应可溶性配体依赖于配体介导的 CAR 二聚化，并且可以通过调整 CAR 的配体结合和信号结构域之间的机械偶联来微调 CAR 对可溶性配体的响应。我们的结果支持机械转导在 CAR 信号中的作用，并证明了一种系统地工程化免疫细胞对可溶性细胞外配体的反应的方法。
