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Nature. 2019 Apr;568(7750):112-116. doi: 10.1038/s41586-019-1054-1. Epub 2019 Mar 27.

CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape.

Author information

1
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
2
Immunology Program, Sloan Kettering Institute, New York, NY, USA.
3
Microchemistry and Proteomics Core Laboratory, Sloan Kettering Institute, New York, NY, USA.
4
Quantitative Sciences Unit, Stanford University School of Medicine, Palo Alto, CA, USA.
5
Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USA.
6
Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA. m-sadelain@ski.mskcc.org.
7
Immunology Program, Sloan Kettering Institute, New York, NY, USA. m-sadelain@ski.mskcc.org.

Abstract

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.

PMID:
30918399
DOI:
10.1038/s41586-019-1054-1

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