Cell softness renders cytotoxic T lymphocytes and T leukemic cells resistant to perforin-mediated killing

Yabo Zhou, Dianheng Wang, Li Zhou, Nannan Zhou, Zhenfeng Wang, Jie Chen, Ruiyang Pang, Haixia Fu, Qiusha Huang, Fang Dong, Hui Cheng, Huafeng Zhang, Ke Tang, Jingwei Ma, Jiadi Lv, Tao Cheng, Roland Fiskesund, Xiaohui Zhang () and Bo Huang ()
Additional contact information
Yabo Zhou: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College
Dianheng Wang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College
Li Zhou: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College
Nannan Zhou: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College
Zhenfeng Wang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College
Jie Chen: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College
Ruiyang Pang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College
Haixia Fu: Peking University Institute of Hematology
Qiusha Huang: Peking University Institute of Hematology
Fang Dong: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Hui Cheng: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Huafeng Zhang: School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology
Ke Tang: Tongji Medical College, Huazhong University of Science and Technology
Jingwei Ma: School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology
Jiadi Lv: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College
Tao Cheng: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Roland Fiskesund: Karolinska University Hospital
Xiaohui Zhang: Peking University Institute of Hematology
Bo Huang: Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the cytotoxic T lymphocytes (CTL)-mediated killing of tumor cells in a unidirectional fashion. How such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. Here we show that activated CTLs use their softness to evade perforin-mediated autolysis, which, however, is shared by T leukemic cells to evade CTL killing. Downregulation of filamin A is identified to induce softness via ZAP70-mediated YAP Y357 phosphorylation and activation. Despite the requirements of YAP in both cell types for softness induction, CTLs are more resistant to YAP inhibitors than malignant T cells, potentially due to the higher expression of the drug-resistant transporter, MDR1, in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but spares CTLs, thus allowing CTLs to cytolyze malignant cells without autolysis. Our findings thus hint a mechanical force-based immunotherapeutic strategy against T cell leukemia.

Date: 2024
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DOI: 10.1038/s41467-024-45750-w

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