嵌合抗原受体
抗原
互补决定区
细胞
细胞生物学
生物
噬菌体展示
计算生物学
化学
T细胞
分子生物学
免疫学
抗体
遗传学
免疫球蛋白轻链
免疫系统
作者
Tina Sarén,Giulia Saronio,Paula Marti Torrell,Xu Zhu,Josefin Thelander,Yasmin Andersson,Camilla Hofström,Marika Nestor,Anna Dimberg,Helena Persson,Mohanraj Ramachandran,Di Yu,Magnus Essand
标识
DOI:10.1038/s41467-023-40303-z
摘要
Chimeric antigen receptor (CAR)-T cell therapy is rapidly advancing as cancer treatment, however, designing an optimal CAR remains challenging. A single-chain variable fragment (scFv) is generally used as CAR targeting moiety, wherein the complementarity-determining regions (CDRs) define its specificity. We report here that the CDR loops can cause CAR clustering, leading to antigen-independent tonic signalling and subsequent CAR-T cell dysfunction. We show via CARs incorporating scFvs with identical framework and varying CDR sequences that CARs may cluster on the T cell surface, which leads to antigen-independent CAR-T cell activation, characterized by increased cell size and interferon (IFN)-γ secretion. This results in CAR-T cell exhaustion, activation-induced cell death and reduced responsiveness to target-antigen-expressing tumour cells. CDR mutagenesis confirms that the CAR-clustering is mediated by CDR-loops. In summary, antigen-independent tonic signalling can be induced by CDR-mediated CAR clustering, which could not be predicted from the scFv sequences, but could be tested for by evaluating the activity of unstimulated CAR-T cells.
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