CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape

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


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.

MeSH terms

  • 4-1BB Ligand / immunology
  • Animals
  • Antigens, Neoplasm / immunology*
  • Antigens, Neoplasm / metabolism*
  • CD28 Antigens / immunology
  • Cytotoxicity, Immunologic
  • Female
  • Immunotherapy, Adoptive
  • Leukemia / immunology*
  • Leukemia / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Neoplasm Recurrence, Local / immunology
  • Receptors, Chimeric Antigen / immunology*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Tumor Escape / immunology*


  • 4-1BB Ligand
  • Antigens, Neoplasm
  • CD28 Antigens
  • Receptors, Chimeric Antigen