Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy
Kewen Lei, Armand Kurum, Murat Kaynak, Lucia Bonati, Yulong Han, Veronika Cencen, Min Gao, Yu-Qing Xie, Yugang Guo, Mélanie T M Hannebelle, Yangping Wu, Guanyu Zhou, Ming Guo, Georg E Fantner, Mahmut Selman Sakar, Li Tang, Kewen Lei, Armand Kurum, Murat Kaynak, Lucia Bonati, Yulong Han, Veronika Cencen, Min Gao, Yu-Qing Xie, Yugang Guo, Mélanie T M Hannebelle, Yangping Wu, Guanyu Zhou, Ming Guo, Georg E Fantner, Mahmut Selman Sakar, Li Tang
Abstract
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.
Conflict of interest statement
Competing interests
The authors declare no competing interests.
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
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References
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