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search.filters.applied.f.access: openAccess × Type: Text × search.filters.applied.f.series: Frontiers in immunology 12 (2021) × WGL Institute: INM ×

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    Targeting the Microtubule-Network Rescues CTL Killing Efficiency in Dense 3D Matrices
    (Lausanne : Frontiers Media, 2021) Zhao, Renping; Zhou, Xiangda; Khan, Essak S.; Alansary, Dalia; Friedmann, Kim S.; Yang, Wenjuan; Schwarz, Eva C.; Del Campo, Aránzazu; Hoth, Markus; Qu, Bin
    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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    High Glucose Enhances Cytotoxic T Lymphocyte-Mediated Cytotoxicity
    (Lausanne : Frontiers Media, 2021) Zhu, Jie; Yang, Wenjuan; Zhou, Xiangda; Zöphel, Dorina; Soriano-Baguet, Leticia; Dolgener, Denise; Carlein, Christopher; Hof, Chantal; Zhao, Renping; Ye, Shandong; Schwarz, Eva C.; Brenner, Dirk; Prates Roma, Leticia; Qu, Bin
    Cytotoxic T lymphocytes (CTLs) are key players to eliminate tumorigenic or pathogen-infected cells using lytic granules (LG) and Fas ligand (FasL) pathways. Depletion of glucose leads to severely impaired cytotoxic function of CTLs. However, the impact of excessive glucose on CTL functions still remains largely unknown. Here we used primary human CD8+ T cells, which were stimulated by CD3/CD28 beads and cultured in medium either containing high glucose (HG, 25 mM) or normal glucose (NG, 5.6 mM). We found that in HG-CTLs, glucose uptake and glycolysis were enhanced, whereas proliferation remained unaltered. Furthermore, CTLs cultured in HG exhibited an enhanced CTL killing efficiency compared to their counterparts in NG. Unexpectedly, expression of cytotoxic proteins (perforin, granzyme A, granzyme B and FasL), LG release, cytokine/cytotoxic protein release and CTL migration remained unchanged in HG-cultured CTLs. Interestingly, additional extracellular Ca2+ diminished HG-enhanced CTL killing function. Our findings suggest that in an environment with excessive glucose, CTLs could eliminate target cells more efficiently, at least for a certain period of time, in a Ca2+-dependent manner.