1. Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices.
- Author
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Zhao R, Zhou X, Khan ES, Alansary D, Friedmann KS, Yang W, Schwarz EC, Del Campo A, Hoth M, and Qu B
- Subjects
- Cell Line, Tumor, Coculture Techniques, Elasticity, Extracellular Matrix drug effects, Extracellular Matrix metabolism, Extracellular Matrix pathology, Humans, Hydrogels, Microtubules immunology, Microtubules metabolism, Neoplasms immunology, Neoplasms metabolism, Neoplasms pathology, Porosity, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Cytotoxic metabolism, Cell Movement drug effects, Collagen Type I chemistry, Cytotoxicity, Immunologic, Immunotherapy, Adoptive, Microtubules drug effects, Neoplasms therapy, T-Lymphocytes, Cytotoxic transplantation, Tubulin Modulators pharmacology, Vinblastine pharmacology
- Abstract
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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhao, Zhou, Khan, Alansary, Friedmann, Yang, Schwarz, del Campo, Hoth and Qu.)
- Published
- 2021
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