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Cancer-cell stiffening via cholesterol depletion enhances adoptive T-cell immunotherapy

2021; Nature Portfolio; Volume: 5; Issue: 12 Linguagem: Inglês

10.1038/s41551-021-00826-6

2157-846X

Kewen Lei, Armand Kurum, Murat Kaynak, Lucia Bonati, Yulong Han, Veronika Cencen, Min Gao, Yuqing Xie, Yugang Guo, Mélanie T. M. Hannebelle, Yangping Wu, Guanyu Zhou, Ming Guo, Georg E. Fantner, Mahmut Selman Sakar, Li Tang,

CAR-T cell therapy research

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. Cancer cells enriched in cholesterol in their plasma membrane impair T-cell-mediated cytotoxicity, which can be augmented by stiffening the cancer cells via cholesterol depletion, as shown in mouse models of adoptive T-cell immunotherapy.