Cell Softness Prevents Cytolytic T-cell Killing of Tumor-Repopulating Cells
Yuying Liu, Tianzhen Zhang, Haizeng Zhang, Jiping Li, Nannan Zhou, Roland Fiskesund, Junwei Chen, Jiadi Lv, Jingwei Ma, Huafeng Zhang, Ke Tang, Feiran Cheng, Yabo Zhou, Xiaohui Zhang, Ning Wang, Bo Huang
Abstract
Abstract Biomechanics is a fundamental feature of a cell. However, the manner by which actomysin tension affects tumor immune evasion remains unclear. Here we show that although cytotoxic T lymphocytes (CTL) can effectively destroy stiff differentiated tumor cells, they fail to kill soft tumor-repopulating cells (TRC). TRC softness prevented membrane pore formation caused by CTL-released perforin. Perforin interacting with nonmuscle myosin heavy-chain 9 transmitted forces to less F-actins in soft TRC, thus generating an inadequate contractile force for perforin pore formation. Stiffening TRC allowed perforin the ability to drill through the membrane, leading to CTL-mediated killing of TRC. Importantly, overcoming mechanical softness in human TRC also enhanced TRC cell death caused by human CTL, potentiating a mechanics-based immunotherapeutic strategy. These findings reveal a mechanics-mediated tumor immune evasion, thus potentially providing an alternative approach for tumor immunotherapy. Significance: Tumor-repopulating cells evade CD8+ cytolytic T-cell killing through a mechanical softness mechanism, underlying the impediment of perforin pore formation at the immune synapse site.