厦门大学周大旺等研究人员合作发现，Osr2发挥生物力学检查点的功能来加剧肿瘤中CD8⁺ T细胞的衰竭。相关论文于2024年5月13日在线发表在《细胞》杂志上。

研究人员发现转录因子（TF）Osr2整合了生物力学信号，并促进了肿瘤反应性CD8⁺ T细胞的终末衰竭。通过T细胞受体（TCR）信号转导和Piezo1/钙/CREB轴介导的生物力学应激，Osr2在终末衰竭的肿瘤特异性CD8⁺ T细胞亚群中被选择性诱导表达。一致的是，在实体瘤模型中，Osr2的耗竭会缓解肿瘤特异性CD8⁺ T细胞或CAR-T细胞的衰竭，而强迫Osr2表达则会加剧它们的衰竭。

从机理上讲，Osr2会招募HDAC3重新连接表观遗传程序，抑制细胞毒性基因的表达，并促进CD8⁺ T细胞衰竭。因此，这些研究结果揭示了Osr2作为一种生物力学检查点加剧CD8⁺ T细胞衰竭的功能，可以作为靶点来增强癌症免疫疗法。

据介绍，细胞外基质（ECM）结构和硬度的改变是癌症的标志。ECM的生物力学特性是否会影响肿瘤反应性CD8⁺ T细胞的功能在很大程度上仍是未知数。

附：英文原文

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

Author: Jinjia Zhang, Junhong Li, Yongqiang Hou, Yao Lin, Hao Zhao, Yiran Shi, Kaiyun Chen, Cheng Nian, Jiayu Tang, Lei Pan, Yunzhi Xing, Huan Gao, Bingying Yang, Zengfang Song, Yao Cheng, Yue Liu, Min Sun, Yueyue Linghu, Jiaxin Li, Haitao Huang, Zhangjian Lai, Zhien Zhou, Zifeng Li, Xiufeng Sun, Qinghua Chen, Dongxue Su, Wengang Li, Zhihai Peng, Pingguo Liu, Wei Chen, Hongling Huang, Yixin Chen, Bailong Xiao, Lilin Ye, Lanfen Chen, Dawang Zhou

Issue&Volume: 2024-05-13

Abstract: Alterations in extracellular matrix (ECM) architecture and stiffness represent hallmarksof cancer. Whether the biomechanical property of ECM impacts the functionality oftumor-reactive CD8+ T cells remains largely unknown. Here, we reveal that the transcription factor (TF)Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion oftumor-reactive CD8+ T cells. Osr2 expression is selectively induced in the terminally exhausted tumor-specificCD8+ T cell subset by coupled T cell receptor (TCR) signaling and biomechanical stressmediated by the Piezo1/calcium/CREB axis. Consistently, depletion of Osr2 alleviatesthe exhaustion of tumor-specific CD8+ T cells or CAR-T cells, whereas forced Osr2 expression aggravates their exhaustionin solid tumor models. Mechanistically, Osr2 recruits HDAC3 to rewire the epigeneticprogram for suppressing cytotoxic gene expression and promoting CD8+ T cell exhaustion. Thus, our results unravel Osr2 functions as a biomechanical checkpointto exacerbate CD8+ T cell exhaustion and could be targeted to potentiate cancer immunotherapy.

DOI: 10.1016/j.cell.2024.04.023

Source: https://www.cell.com/cell/abstract/S0092-8674(24)00448-3