AFM data of Cell softness renders CTLs and T-leukemic cells resistant to perforin-mediated killing

Mechanical force contributes to perforin pore formation at immune synapses, thus facilitating the CTL killing of tumor cells in a unidirectional fashion. Whether and how such mechanical cues affect CTL evasion of perforin-mediated autolysis remains unclear. In this study, 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, which is mediated by activated YAP. This YAP activation is caused by Y357 phosphorylation by ZAP70. Despite both requirements of YAP, we found that CTLs are more resistant to YAP inhibitors than malignant T cells because of the high expression of the drug-resistant transporter MDR1 in CTLs. As a result, moderate inhibition of YAP stiffens malignant T cells but not CTLs, thus enhancing CTLs to cytolyze malignant cells without autolysis. These findings provide a mechanics-based immunotherapeutic strategy against T cell leukemia.