PIEZO1 mechanically regulates the antitumour cytotoxicity of T lymphocytes
Ruiyang Pang # 1, Weihao Sun # 2 3, Yingyun
Yang # 4, Dahan Wen # 1, Feng Lin # 3, Dingding Wang 5, Kailong Li 6, Ning
Zhang 7 8, Junbo Liang 9, Chunyang Xiong 10 11, Yuying Liu 12 13
Nat Biomed Eng. 2024 Mar 21. doi:
10.1038/s41551-024-01188-5.
PMID: 38514773
Abstract
The killing function of cytotoxic T cells
can be enhanced biochemically. Here we show that blocking the mechanical sensor
PIEZO1 in T cells strengthens their traction forces and augments their
cytotoxicity against tumour cells. By leveraging cytotoxic T cells collected
from tumour models in mice and from patients with cancers, we show that PIEZO1
upregulates the transcriptional factor GRHL3, which in turn induces the
expression of the E3 ubiquitin ligase RNF114. RNF114 binds to filamentous
actin, causing its downregulation and rearrangement, which depresses traction
forces in the T cells. In mice with tumours, the injection of cytotoxic T cells
collected from the animals and treated with a PIEZO1 antagonist promoted their
infiltration into the tumour and attenuated tumour growth. As an immunomechanical
regulator, PIEZO1 could be targeted to enhance the outcomes of cancer
immunotherapies.