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Collagen density defines 3D migration of CTLs and their consequent cytotoxicity against tumor cells

  • Solid tumors are often characterized by condensed extracellular matrix (ECM). The impact of dense ECM on cytotoxic T lymphocytes (CTL) function is not fully understood. Here, we report that CTL-mediated cytotoxicity is substantially impaired in dense collagen matrices. Although the intrinsic killing machinery including expression of cytotoxic proteins and degranulation was intact, CTL motility was substantially compromised in dense collagen. We found that for 3D CTL migration, persistence and velocity was regulated by collagen stiffness and the porosity, respectively. Interestingly, 3D CTL velocity is strongly correlated with their nuclear deformability/flexibility during migration, which is regulated by the microtubule network. Moreover, CTL migration was completely abolished by inhibition of actin polymerization and or myosin IIA. Remarkably, disruption of the microtubule-networks significantly improves the impaired migration, search efficiency, and cytotoxicity of CTLs in dense collagen. Our work suggests the microtubule network as a promising target to rescue impaired CTL killing capacity in solid tumor related scenarios.

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Document Type:Preprint
Author:Renping ZhaoORCiD, Xiangda Zhou, Essak S. KhanORCiD, Dalia AlansaryORCiD, Kim S. Friedmann, Wenjuan Yang, Eva C. SchwarzORCiD, Aránzazu del Campo BécaresORCiD, Markus HothORCiD, Bin QuORCiD
Parent Title (English):bioRxiv
Date of first Publication:2021/03/17
Release Date:2022/08/09
Groups:Dynamische Biomaterialien
DDC classes:600 Technik, Medizin, angewandte Wissenschaften / 610 Medizin, Gesundheit
Open Access:Open Access
Signature:INM 2021/032_preprint
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International