Cell Softness Prevents Cytolytic T-cell Killing of Tumor-Repopulating Cells

Yuying Liu # 1 2, Tianzhen Zhang # 3, Haizeng Zhang # 4, Jiping Li 5, Nannan Zhou 3, Roland Fiskesund 3 6, Junwei Chen 7, Jiadi Lv 3, Jingwei Ma 8, Huafeng Zhang 8, Ke Tang 8, Feiran Cheng 3, Yabo Zhou 3, Xiaohui Zhang 9, Ning Wang 10, Bo Huang 1 2 8

Cancer Res. 2021 Jan 15;81(2):476-488. doi: 10.1158/0008-5472.CAN-20-2569. Epub 2020 Nov 9.

PMID: 33168645

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.