Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Cazaux, Marine, Grandjean, Capucine L., Lemaître, Fabrice, Garcia, Zacarias, Beck, Richard J., Milo, Idan, Postat, Jérémy, Beltman, Joost B., Cheadle, Eleanor J., Bousso, Philippe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
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
_version_ 1783416530051006464
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
work_keys_str_mv AT cazauxmarine singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity
AT grandjeancapucinel singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity
AT lemaitrefabrice singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity
AT garciazacarias singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity
AT beckrichardj singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity
AT miloidan singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity
AT postatjeremy singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity
AT beltmanjoostb singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity
AT cheadleeleanorj singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity
AT boussophilippe singlecellimagingofcartcellactivityinvivorevealsextensivefunctionalandanatomicalheterogeneity