Migration of Cytotoxic T Lymphocytes in 3D Collagen Matrices

Sadjadi, Zeinab; Zhao, Renping; Hoth, Markus; Qu, Bin; Rieger, Heiko

doi:10.1016/j.bpj.2020.10.020

Cited by 48 publications

(45 citation statements)

References 49 publications

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“…Keeping the concentration of collagen constant, lowering polymerization temperature increases the pore size of the fibrillar matrix, whereas pretreatment of collagen with ribose enhances the stiffness of collagen fibrils. We show that speed and persistence of human CTL migration in 3D are distinctively regulated: the speed strongly correlated with the pore size, in good agreement with previous reports (51,52); while the persistence is mainly determined by the stiffness, in good agreement with a recent report for ovarian cancer cells (53).…”

Section: Discussionsupporting

confidence: 91%

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

et al. 2021

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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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Section: Discussionsupporting

confidence: 91%

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

et al. 2021

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“…T-lymphocyte migration is characterized by the stop and go manner they display to survey the environment, which makes speed measurements challenging (Dupré et al ., 2015; Jerison and Quake, 2020). Sadjadi and colleagues investigated the migration speed of T-cells in different collagen concentrations (Sadjadi et al ., 2020). They tested 2, 4 and 5 mg/mL.…”

Section: Discussionmentioning

confidence: 99%

Transendothelial migration induces differential migration dynamics of leukocytes in tissue matrix

Steen

Kempers

Schoppmeyer

et al. 2021

Preprint

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Leukocyte extravasation into inflamed tissue is a complex process that is difficult to capture as a whole in vitro. We employed a blood-vessel-on-a-chip model in which endothelial cells were cultured in a tube-like lumen in a collagen-1 matrix. The vessels are leak-tight, creating a barrier for molecules and leukocytes. Addition of inflammatory cytokine TNF-α caused vasoconstriction, actin remodelling and upregulation of ICAM-1. Introducing leukocytes into the vessels allowed real-time visualisation of leukocyte migration across the vessel wall, into the extracellular matrix. Individual cell tracking over time distinguished striking differences in migratory behaviour between T-cells and neutrophils. Neutrophils cross the endothelial layer more efficiently than T-cells, but upon entering the matrix, neutrophils display high speed but low persistence, whereas T-cells migrate with low speed and rather linear migration. In conclusion, 3D imaging in real-time of leukocyte extravasation in a vessel-on-a-chip enables detailed qualitative and quantitative analysis of different stages of the full leukocyte extravasation process in a single assay.

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“…Another example of 1D migration in vivo is during cell movement along ECM fibers, which depends on the local density and alignment of the collagen around the tissue or tumor boundaries (Yamada and Sixt 2019 ). A recent in vitro study shows that primary human CD8 + T cells preferably migrate through the channels formed in collagen matrix (Sadjadi et al 2020 ), suggesting another possible 1D scenario for immune cell migration in vivo. Thus, 3D, 2D, and 1D environments are all physiologically relevant conditions, whereby each requires the use of a different migratory mechanism by the immune cells.…”

Section: Migration Of Immune Cells Is Central For Immune Surveillancementioning

confidence: 99%

Characterization of immune cell migration using microfabrication

Vesperini

Montalvo

et al. 2021

Biophys Rev

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The immune system provides our defense against pathogens and aberrant cells, including tumorigenic and infected cells. Motility is one of the fundamental characteristics that enable immune cells to find invading pathogens, control tissue damage, and eliminate primary developing tumors, even in the absence of external treatments. These processes are termed “immune surveillance.” Migration disorders of immune cells are related to autoimmune diseases, chronic inflammation, and tumor evasion. It is therefore essential to characterize immune cell motility in different physiologically and pathologically relevant scenarios to understand the regulatory mechanisms of functionality of immune responses. This review is focused on immune cell migration, to define the underlying mechanisms and the corresponding investigative approaches. We highlight the challenges that immune cells encounter in vivo, and the microfabrication methods to mimic particular aspects of their microenvironment. We discuss the advantages and disadvantages of the proposed tools, and provide information on how to access them. Furthermore, we summarize the directional cues that regulate individual immune cell migration, and discuss the behavior of immune cells in a complex environment composed of multiple directional cues.

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Migration of Cytotoxic T Lymphocytes in 3D Collagen Matrices

Cited by 48 publications

References 49 publications

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

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

Transendothelial migration induces differential migration dynamics of leukocytes in tissue matrix

Characterization of immune cell migration using microfabrication

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