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Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity
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–be...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504219/ https://www.ncbi.nlm.nih.gov/pubmed/30936262 http://dx.doi.org/10.1084/jem.20182375 |
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author | Cazaux, Marine Grandjean, Capucine L. Lemaître, Fabrice Garcia, Zacarias Beck, Richard J. Milo, Idan Postat, Jérémy Beltman, Joost B. Cheadle, Eleanor J. Bousso, Philippe |
author_facet | Cazaux, Marine Grandjean, Capucine L. Lemaître, Fabrice Garcia, Zacarias Beck, Richard J. Milo, Idan Postat, Jérémy Beltman, Joost B. Cheadle, Eleanor J. Bousso, Philippe |
author_sort | Cazaux, Marine |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6504219 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-65042192019-11-06 Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity Cazaux, Marine Grandjean, Capucine L. Lemaître, Fabrice Garcia, Zacarias Beck, Richard J. Milo, Idan Postat, Jérémy Beltman, Joost B. Cheadle, Eleanor J. Bousso, Philippe J Exp Med Research Articles 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. Rockefeller University Press 2019-05-06 2019-04-01 /pmc/articles/PMC6504219/ /pubmed/30936262 http://dx.doi.org/10.1084/jem.20182375 Text en © 2019 Cazaux et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Cazaux, Marine Grandjean, Capucine L. Lemaître, Fabrice Garcia, Zacarias Beck, Richard J. Milo, Idan Postat, Jérémy Beltman, Joost B. Cheadle, Eleanor J. Bousso, Philippe Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity |
title | Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity |
title_full | Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity |
title_fullStr | Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity |
title_full_unstemmed | Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity |
title_short | Single-cell imaging of CAR T cell activity in vivo reveals extensive functional and anatomical heterogeneity |
title_sort | single-cell imaging of car t cell activity in vivo reveals extensive functional and anatomical heterogeneity |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504219/ https://www.ncbi.nlm.nih.gov/pubmed/30936262 http://dx.doi.org/10.1084/jem.20182375 |
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