Institute of Materials Science and Engineering, École polytechnique fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Institute of Mechanical Engineering, EPFL, Lausanne, Switzerland.
Nat Biomed Eng. 2021 Dec;5(12):1411-1425. doi: 10.1038/s41551-021-00826-6. Epub 2021 Dec 6.
Malignant transformation and tumour progression are associated with cancer-cell softening. Yet how the biomechanics of cancer cells affects T-cell-mediated cytotoxicity and thus the outcomes of adoptive T-cell immunotherapies is unknown. Here we show that T-cell-mediated cancer-cell killing is hampered for cortically soft cancer cells, which have plasma membranes enriched in cholesterol, and that cancer-cell stiffening via cholesterol depletion augments T-cell cytotoxicity and enhances the efficacy of adoptive T-cell therapy against solid tumours in mice. We also show that the enhanced cytotoxicity against stiffened cancer cells is mediated by augmented T-cell forces arising from an increased accumulation of filamentous actin at the immunological synapse, and that cancer-cell stiffening has negligible influence on: T-cell-receptor signalling, production of cytolytic proteins such as granzyme B, secretion of interferon gamma and tumour necrosis factor alpha, and Fas-receptor-Fas-ligand interactions. Our findings reveal a mechanical immune checkpoint that could be targeted therapeutically to improve the effectiveness of cancer immunotherapies.
恶性转化和肿瘤进展与癌细胞的软化有关。然而，癌细胞的生物力学如何影响 T 细胞介导的细胞毒性，从而影响过继性 T 细胞免疫疗法的结果，目前尚不清楚。在这里，我们表明，T 细胞介导的癌细胞杀伤受到皮质软癌细胞的阻碍，这些癌细胞的质膜富含胆固醇，而通过胆固醇耗竭使癌细胞变硬会增强 T 细胞的细胞毒性，并增强过继性 T 细胞疗法对小鼠实体瘤的疗效。我们还表明，针对变硬的癌细胞的增强的细胞毒性是通过免疫突触处丝状肌动蛋白的积累增加而导致的 T 细胞力的增强来介导的，并且癌细胞变硬对：T 细胞受体信号传导、细胞毒性蛋白如颗粒酶 B 的产生、干扰素 γ 和肿瘤坏死因子 α 的分泌以及 Fas 受体-Fas 配体相互作用几乎没有影响。我们的研究结果揭示了一种机械免疫检查点，可通过靶向治疗来提高癌症免疫疗法的有效性。
