Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor

• Published in: Cell Vol. 187; no. 13; pp. 3409 - 3426.e24
• Main Authors: Zhang, Jinjia, Li, Junhong, Hou, Yongqiang, Lin, Yao, Zhao, Hao, Shi, Yiran, Chen, Kaiyun, Nian, Cheng, Tang, Jiayu, Pan, Lei, Xing, Yunzhi, Gao, Huan, Yang, Bingying, Song, Zengfang, Cheng, Yao, Liu, Yue, Sun, Min, Linghu, Yueyue, Li, Jiaxin, Huang, Haitao, Lai, Zhangjian, Zhou, Zhien, Li, Zifeng, Sun, Xiufeng, Chen, Qinghua, Su, Dongxue, Li, Wengang, Peng, Zhihai, Liu, Pingguo, Chen, Wei, Huang, Hongling, Chen, Yixin, Xiao, Bailong, Ye, Lilin, Chen, Lanfen, Zhou, Dawang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.06.2024
• Subjects: biomechanical stress; cancer immunotherapy; Osr2; Piezo1; T cell exhaustion; T cell exhaustion; Osr2; Piezo1; biomechanical stress; cancer immunotherapy
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2024.04.023

Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarks of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor-reactive CD8+ T cells remains largely unknown. Here, we reveal that the transcription factor (TF) Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor-reactive CD8+ T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specific CD8+ T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stress mediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviates the exhaustion of tumor-specific CD8+ T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustion in solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigenetic program for suppressing cytotoxic gene expression and promoting CD8+ T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8+ T cell exhaustion and could be targeted to potentiate cancer immunotherapy. [Display omitted] •Osr2 is selectively induced in activated CD8+ T cells in response to mechanical stress•Mechanical stress augments CD8+ T cell exhaustion via the Piezo1/CaMKII/CREB/Osr2 axis•Osr2 specifically attenuates the functionality of terminally exhausted CD8+ T cells•Targeting Osr2 signaling enhances T cell-mediated immunotherapies against solid tumors Biomechanical stress drives CD8+ T cell exhaustion program in solid tumors via a signaling cascade centered on the transcription factor Osr2. Intervention in this signaling pathway reverses CD8+ T cell exhaustion and enhances their anti-tumor efficacy.