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PIEZO1-mediated mechanosensing governs NK cell killing efficiency in 3D

  • Natural killer (NK) cells play a vital role in eliminating tumorigenic cells. Efficient locating and killing of target cells in complex three-dimensional (3D) environments is critical for their functions under physiological conditions. Recent studies have shown that NK cell activation is regulated by substrate stiffness. However, the role of mechanosensing in regulating NK cell killing efficiency in physiologically relevant scenarios is poorly understood. In this study, we report that the responsiveness of NK cells is regulated by tumor cell stiffness. NK cell killing efficiency in 3D is impaired against softened tumor cells, while it is enhanced against stiffened tumor cells. Notably, the durations required for NK cell killing and detachment are significantly shortened for stiffened tumor cells. Furthermore, we have identified PIEZO1 as the predominantly expressed mechanosensitive ion channel in NK cells. Perturbation of PIEZO1 by GsMTx4 abolishes stiffness-dependent NK cell responsiveness, significantly impairs the killing efficiency of NK cells in 3D, and substantially reduces NK cell infiltration into 3D collagen matrices. Conversely, PIEZO1 activation enhances NK killing efficiency as well as infiltration. In conclusion, our findings demonstrate that PIEZO1-mediated mechanosensing is crucial for NK killing functions, highlighting the role of mechanosensing in NK cell killing efficiency under physiological conditions and the influence of environmental physical cues on NK cell functions.

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Document Type:Preprint
Author:Archana K. YanamandraORCiD, Jingnan Zhang, Galia MontalvoORCiD, Doreen BiedenwegORCiD, Markus HothORCiD, Franziska LautenschlägerORCiD, Oliver OttoORCiD, Aránzazu del Campo BécaresORCiD, Bin QuORCiD
Parent Title (English):BioRxiv
First Page:1
Last Page:25
Year of Completion:2023
Date of first Publication:2023/03/29
Release Date:2023/05/31
Funding Information:Deutsche Forschungsgemeinschaft (SFB 1027)
Groups:Dynamische Biomaterialien
DDC classes:500 Naturwissenschaften und Mathematik / 570 Biowissenschaften, Biologie
Open Access:Open Access
Signature:INM 2023/066_preprint
Licence (German):License LogoCreative Commons - CC BY-NC-ND - Namensnennung - Nicht kommerziell - Keine Bearbeitungen 4.0 International