1. Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity
- Author
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Philippe Bousso, Richard J Beck, Idan Milo, Joost B. Beltman, Capucine L. Grandjean, Jérémy Postat, Fabrice Lemaître, Zacarias Garcia, Marine Cazaux, Eleanor J. Cheadle, Dynamiques des Réponses immunes - Dynamics of Immune Responses, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Universiteit Leiden [Leiden], University of Manchester [Manchester], This work was supported by Institut Pasteur, INSERM, the European Research Council (starting [Lymphocytecontact] and advanced grants [ENLIGHTEN] to P. Bousso), and the NWO (Vidi grant 864.12.013 to J.B. Beltman). M. Cazaux received financial support from ITMO Cancer Alliance Nationale pour les Sciences de la Vie et de la Santé within the framework of the Cancer Plan., HUGOT, Bérengère, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Universiteit Leiden
- Subjects
0301 basic medicine ,Intravital Microscopy ,T-Lymphocytes ,[SDV]Life Sciences [q-bio] ,Cell ,Apoptosis ,Immunotherapy, Adoptive ,Mice ,0302 clinical medicine ,Recurrence ,Immunology and Allergy ,Cytotoxic T cell ,Lung ,Research Articles ,Mice, Knockout ,Receptors, Chimeric Antigen ,Manchester Cancer Research Centre ,hemic and immune systems ,[SDV] Life Sciences [q-bio] ,Lymphatic system ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Models, Animal ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy ,Single-Cell Analysis ,Lymphoma, B-Cell ,[SDV.IMM] Life Sciences [q-bio]/Immunology ,T cell ,Immunology ,Antigens, CD19 ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,03 medical and health sciences ,[SDV.CAN] Life Sciences [q-bio]/Cancer ,In vivo ,Cell Line, Tumor ,medicine ,Animals ,B cell ,ResearchInstitutes_Networks_Beacons/mcrc ,Brief Definitive Report ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,Models, Theoretical ,Mice, Inbred C57BL ,030104 developmental biology ,Cancer research ,Bone marrow ,human activities - Abstract
Cazaux et al. use intravital imaging to dissect anti-CD19 CAR T cell activity. This study uncovers both anatomical and functional diversity in the outcome of anti-CD19 CAR T cell interactions with tumor cells impacting engraftment, killing dynamics, and tumor immunoediting., CAR T cells represent a potentially curative strategy for B cell malignancies. However, the outcome and dynamics of CAR T cell interactions in distinct anatomical sites are poorly understood. Using intravital imaging, we tracked interactions established by anti-CD19 CAR T cells in B cell lymphoma–bearing mice. Circulating targets trapped CAR T cells in the lungs, reducing their access to lymphoid organs. In the bone marrow, tumor apoptosis was largely due to CAR T cells that engaged, killed, and detached from their targets within 25 min. Notably, not all CAR T cell contacts elicited calcium signaling or killing while interacting with tumors, uncovering extensive functional heterogeneity. Mathematical modeling revealed that direct killing was sufficient for tumor regression. Finally, antigen-loss variants emerged in the bone marrow, but not in lymph nodes, where CAR T cell cytotoxic activity was reduced. Our results identify a previously unappreciated level of diversity in the outcomes of CAR T cell interactions in vivo, with important clinical implications., Graphical Abstract
- Published
- 2019