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

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

  • Cell. 2024 May 9:S0092-8674(24)00448-3. doi: 10.1016/j.cell.2024.04.023.
Jinjia Zhang 1,  Junhong Li 1,  Yongqiang Hou 1,  Yao Lin 2,  Hao Zhao 1,  Yiran Shi 1,  Kaiyun Chen 3,  Cheng Nian 1,  Jiayu Tang 1,  Lei Pan 4,  Yunzhi Xing 1,  Huan Gao 1,  Bingying Yang 1,  Zengfang Song 1,  Yao Cheng 1,  Yue Liu 1,  Min Sun 1,  Yueyue Linghu 1,  Jiaxin Li 1,  Haitao Huang 1,  Zhangjian Lai 1,  Zhien Zhou 1,  Zifeng Li 1,  Xiufeng Sun 1,  Qinghua Chen 1,  Dongxue Su 1,  Wengang Li 5,  Zhihai Peng 5,  Pingguo Liu 6,  Wei Chen 7,  Hongling Huang 1,  Yixin Chen 3,  Bailong Xiao 8,  Lilin Ye 9,  Lanfen Chen 10,  Dawang Zhou 11
Affiliations

Affiliations

  • 1 State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
  • 2 Institute of Immunology, Third Military Medical University, Chongqing 400038, China; Changping Laboratory, 102206 Beijing, China.
  • 3 Fujian State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, School of Life Sciences, Xiamen University, Xiamen 361102, China.
  • 4 State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, Institute of Neuroscience, School of Medicine, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, China.
  • 5 Department of Hepatobiliary and Pancreatic & Organ Transplantation Surgery, Xiang'an Hospital, School of Medicine, Xiamen University, Xiamen, Fujian 361102, China.
  • 6 Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Department of Hepatobiliary Surgery, Zhongshan Hospital, School of Medicine, Xiamen University, Xiamen, Fujian 361004, China.
  • 7 Department of Cell Biology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310058, China.
  • 8 State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, IDG/McGovern Institute for Brain Research, Beijing Frontier Research Center for Biological Structure, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China.
  • 9 Institute of Immunology, Third Military Medical University, Chongqing 400038, China; Changping Laboratory, 102206 Beijing, China. Electronic address: yelilinlcmv@tmmu.edu.cn.
  • 10 State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: chenlanfen@xmu.edu.cn.
  • 11 State Key Laboratory of Cellular Stress Biology, Xiang'an Hospital, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: dwzhou@xmu.edu.cn.
PMID: 38744281 DOI: 10.1016/j.cell.2024.04.023
Abstract

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.

Keywords

Osr2; Piezo1; T cell exhaustion; biomechanical stress; cancer immunotherapy.

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