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, Xiao-Hui Zhang, Ning Wang, Bo Huang

Research output: Contribution to journalArticlepeer-review

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 þ cytolytic T-cell killing through a mechanical softness mechanism, underlying the impediment of perforin pore formation at the immune synapse site.

Original languageEnglish (US)
Pages (from-to)476-488
Number of pages13
JournalCancer Research
Volume81
Issue number2
Early online dateNov 9 2020
DOIs
StatePublished - Jan 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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