CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape Journal Article
| Authors: | Hamieh, M.; Dobrin, A.; Cabriolu, A.; van der Stegen, S. J. C.; Giavridis, T.; Mansilla-Soto, J.; Eyquem, J.; Zhao, Z.; Whitlock, B. M.; Miele, M. M.; Li, Z.; Cunanan, K. M.; Huse, M.; Hendrickson, R. C.; Wang, X.; Rivière, I.; Sadelain, M. |
| Article Title: | CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape |
| Abstract: | Chimeric antigen receptors (CARs) are synthetic antigen receptors that reprogram T cell specificity, function and persistence 1 . Patient-derived CAR T cells have demonstrated remarkable efficacy against a range of B-cell malignancies 1–3 , and the results of early clinical trials suggest activity in multiple myeloma 4 . Despite high complete response rates, relapses occur in a large fraction of patients; some of these are antigen-negative and others are antigen-low 1,2,4–9 . Unlike the mechanisms that result in complete and permanent antigen loss 6,8,9 , 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. © 2019, The Author(s), under exclusive licence to Springer Nature Limited. |
| Keywords: | controlled study; protein expression; unclassified drug; nonhuman; letter; protein localization; animal cell; mouse; cell death; cell survival; cell protein; animal experiment; animal model; tumor antigen; granzyme b; regulatory mechanism; gamma interferon; cell damage; tumor cell; chimeric antigen receptor; cytokine production; density; leukemia relapse; cell activity; cell expansion; cd19 antigen; cd28 antigen; cell killing; mesothelin; cd22 antigen; programmed death 1 receptor; tumor escape; antigen density; male; female; priority journal; b cell maturation antigen; lag 3 protein; trogocytosis; cell exhaustion; hepatitis a virus cellular receptor 2; tumor necrosis factor receptor superfamily member 9; cd19 gene; phenomena and functions of biological membrane |
| Journal Title: | Nature |
| Volume: | 568 |
| Issue: | 7750 |
| ISSN: | 0028-0836 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2019-04-04 |
| Start Page: | 112 |
| End Page: | 116 |
| Language: | English |
| DOI: | 10.1038/s41586-019-1054-1 |
| PUBMED: | 30918399 |
| PROVIDER: | scopus |
| PMCID: | PMC6707377 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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