Cell Softness Prevents Cytolytic T-cell Killing of Tumor-Repopulating Cells
Cell Softness Prevents Cytolytic T-cell Killing of Tumor-Repopulating Cells
复制标题
细胞柔软度可防止溶细胞 T 细胞杀死肿瘤再生细胞
DOI：
10.1158/0008-5472.can-20-2569
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发表时间：
2021-01-15
期刊：
影响因子：
11.2
通讯作者：
Huang, Bo
中科院分区：
文献类型：
--
作者：
Liu, Yuying;Zhang, Tianzhen;Huang, Bo
生物力学是细胞的基本特征。然而，actomysin张力影响肿瘤免疫逃避的方式仍不清楚。在这里，我们表明，虽然细胞毒性T淋巴细胞（CTL）可以有效地摧毁僵硬的分化肿瘤细胞，他们不能杀死软肿瘤重建细胞（TRC）。TRC柔软性防止由CU释放的穿孔素引起的膜孔形成。穿孔蛋白与非肌肉肌球蛋白重链9相互作用，将力传递给软TRC中较少的F-肌动蛋白，从而产生不足以形成穿孔蛋白孔的收缩力。硬化TRC允许穿孔素钻穿膜的能力，导致CTL介导的TRC杀伤。重要的是，克服人TRC中的机械柔软性也增强了由人CTL引起的TRC细胞死亡，增强了基于机械的免疫策略。这些发现揭示了一种机械介导的肿瘤免疫逃避，从而为肿瘤免疫治疗提供了一种潜在的替代方法。意义肿瘤重建细胞通过机械柔软机制逃避CD 8（+）细胞溶解性T细胞的杀伤，这是免疫突触部位穿孔形成障碍的基础。
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 CU-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 perform pore formation at the immune synapse site.