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Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices

Efficacy of cytotoxic T lymphocyte (CTL)-based immunotherapy is still unsatisfactory against solid tumors, which are frequently characterized by condensed extracellular matrix. Here, using a unique 3D killing assay, we identify that the killing efficiency of primary human CTLs is substantially impai...

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Autores principales: Zhao, Renping, Zhou, Xiangda, Khan, Essak S., Alansary, Dalia, Friedmann, Kim S., Yang, Wenjuan, Schwarz, Eva C., del Campo, Aránzazu, Hoth, Markus, Qu, Bin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416057/
https://www.ncbi.nlm.nih.gov/pubmed/34484240
http://dx.doi.org/10.3389/fimmu.2021.729820
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author Zhao, Renping
Zhou, Xiangda
Khan, Essak S.
Alansary, Dalia
Friedmann, Kim S.
Yang, Wenjuan
Schwarz, Eva C.
del Campo, Aránzazu
Hoth, Markus
Qu, Bin
author_facet Zhao, Renping
Zhou, Xiangda
Khan, Essak S.
Alansary, Dalia
Friedmann, Kim S.
Yang, Wenjuan
Schwarz, Eva C.
del Campo, Aránzazu
Hoth, Markus
Qu, Bin
author_sort Zhao, Renping
collection PubMed
description Efficacy of cytotoxic T lymphocyte (CTL)-based immunotherapy is still unsatisfactory against solid tumors, which are frequently characterized by condensed extracellular matrix. Here, using a unique 3D killing assay, we identify that the killing efficiency of primary human CTLs is substantially impaired in dense collagen matrices. Although the expression of cytotoxic proteins in CTLs remained intact in dense collagen, CTL motility was largely compromised. Using light-sheet microscopy, we found that persistence and velocity of CTL migration was influenced by the stiffness and porosity of the 3D matrix. Notably, 3D CTL velocity was strongly correlated with their nuclear deformability, which was enhanced by disruption of the microtubule network especially in dense matrices. Concomitantly, CTL migration, search efficiency, and killing efficiency in dense collagen were significantly increased in microtubule-perturbed CTLs. In addition, the chemotherapeutically used microtubule inhibitor vinblastine drastically enhanced CTL killing efficiency in dense collagen. Together, our findings suggest targeting the microtubule network as a promising strategy to enhance efficacy of CTL-based immunotherapy against solid tumors, especially stiff solid tumors.
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spelling pubmed-84160572021-09-04 Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices Zhao, Renping Zhou, Xiangda Khan, Essak S. Alansary, Dalia Friedmann, Kim S. Yang, Wenjuan Schwarz, Eva C. del Campo, Aránzazu Hoth, Markus Qu, Bin Front Immunol Immunology Efficacy of cytotoxic T lymphocyte (CTL)-based immunotherapy is still unsatisfactory against solid tumors, which are frequently characterized by condensed extracellular matrix. Here, using a unique 3D killing assay, we identify that the killing efficiency of primary human CTLs is substantially impaired in dense collagen matrices. Although the expression of cytotoxic proteins in CTLs remained intact in dense collagen, CTL motility was largely compromised. Using light-sheet microscopy, we found that persistence and velocity of CTL migration was influenced by the stiffness and porosity of the 3D matrix. Notably, 3D CTL velocity was strongly correlated with their nuclear deformability, which was enhanced by disruption of the microtubule network especially in dense matrices. Concomitantly, CTL migration, search efficiency, and killing efficiency in dense collagen were significantly increased in microtubule-perturbed CTLs. In addition, the chemotherapeutically used microtubule inhibitor vinblastine drastically enhanced CTL killing efficiency in dense collagen. Together, our findings suggest targeting the microtubule network as a promising strategy to enhance efficacy of CTL-based immunotherapy against solid tumors, especially stiff solid tumors. Frontiers Media S.A. 2021-08-17 /pmc/articles/PMC8416057/ /pubmed/34484240 http://dx.doi.org/10.3389/fimmu.2021.729820 Text en Copyright © 2021 Zhao, Zhou, Khan, Alansary, Friedmann, Yang, Schwarz, del Campo, Hoth and Qu https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Zhao, Renping
Zhou, Xiangda
Khan, Essak S.
Alansary, Dalia
Friedmann, Kim S.
Yang, Wenjuan
Schwarz, Eva C.
del Campo, Aránzazu
Hoth, Markus
Qu, Bin
Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices
title Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices
title_full Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices
title_fullStr Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices
title_full_unstemmed Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices
title_short Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices
title_sort targeting the microtubule-network rescues ctl killing efficiency in dense 3d matrices
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416057/
https://www.ncbi.nlm.nih.gov/pubmed/34484240
http://dx.doi.org/10.3389/fimmu.2021.729820
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