嵌合抗原受体
抗原
生物
CD28
免疫学
免疫疗法
T细胞
细胞毒性T细胞
抗原提呈细胞
免疫系统
细胞生物学
癌症研究
体外
生物化学
作者
Mohamad Hamieh,Anton Dobrin,Annalisa Cabriolu,Sjoukje J. C. van der Stegen,Theodoros Giavridis,Jorge Mansilla-Soto,Justin Eyquem,Zeguo Zhao,Benjamin M. Whitlock,Matthew M. Miele,Zhuoning Li,Kristen Cunanan,Morgan Huse,Ronald C. Hendrickson,Xiuyan Wang,Isabelle Rivière,Michel Sadelain
出处
期刊:Nature
[Springer Nature]
日期:2019-03-27
卷期号:568 (7750): 112-116
被引量:417
标识
DOI:10.1038/s41586-019-1054-1
摘要
Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence1. Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies1–3, and the results of early clinical trials suggest activity in multiple myeloma4. Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low1,2,4–9. Unlike the mechanisms that result in complete and permanent antigen loss6,8,9, those that lead to escape of antigen-low tumours remain unclear. Here, using mouse models of leukaemia, we show that CARs provoke reversible antigen loss through trogocytosis, an active process in which the target antigen is transferred to T cells, thereby decreasing target density on tumour cells and abating T cell activity by promoting fratricide T cell killing and T cell exhaustion. These mechanisms affect both CD28- and 4-1BB-based CARs, albeit differentially, depending on antigen density. These dynamic features can be offset by cooperative killing and combinatorial targeting to augment tumour responses to immunotherapy. Chimeric antigen receptors (CARs) promote antigen loss in tumour cells by trogocytosis, which results in T cell fratricide killing and exhaustion but can be counteracted by cooperative killing and combinatorial targeting.
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