Open AccessCancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy
Author(s) -
Kewen Lei,
Armand Kurum,
Murat Kaynak,
Lucia Bonati,
Yu Han,
Veronika Cencen,
Min Gao,
Yuqing Xie,
Yugang Guo,
Mélanie T. M. Hannebelle,
Yangping Wu,
Guoxiong Zhou,
Ming Guo,
Georg E. Fantner,
Mahmut Selman Sakar,
Li Tang
Publication year - 2021
Publication title -
nature biomedical engineering
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.961
H-Index - 56
ISSN - 2157-846X
DOI - 10.1038/s41551-021-00826-6
Subject(s) - cancer cell , cancer immunotherapy , cancer research , adoptive cell transfer , t cell , cytotoxic t cell , cytotoxicity , immunotherapy , cell , cancer , biology , immunology , microbiology and biotechnology , chemistry , immune system , biochemistry , genetics , in vitro
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.