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

Yabo Zhou # 1, Dianheng Wang # 1, Li Zhou 1, Nannan Zhou 1, Zhenfeng Wang 1, Jie Chen 1, Ruiyang Pang 1, Haixia Fu 2, Qiusha Huang 2, Fang Dong 3, Hui Cheng 3, Huafeng Zhang 4, Ke Tang 5, Jingwei Ma 6, Jiadi Lv 1, Tao Cheng 3, Roland Fiskesund 7 8, Xiaohui Zhang 9, Bo Huang 10 11

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Nat Commun.2024 Feb 15;15(1):1405. doi: 10.1038/s41467-024-45750-w.

PMID: 38360940

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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.