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.
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不清楚。在这项研究中，我们发现转录因子（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耗竭。机制上，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，促进CD8+ T细胞耗竭。因此，我们的研究结果揭示了Osr2作为一种生物力学检查点加剧CD8+ T细胞耗竭竭，可以作为靶点来增强癌症免疫疗法。
参考文献
Zhang J, Li J, Hou Y, Lin Y, Zhao H, Shi Y, Chen K, Nian C, Tang J, Pan L, Xing Y, Gao H, Yang B, Song Z, Cheng Y, Liu Y, Sun M, Linghu Y, Li J, Huang H, Lai Z, Zhou Z, Li Z, Sun X, Chen Q, Su D, Li W, Peng Z, Liu P, Chen W, Huang H, Chen Y, Xiao B, Ye L, Chen L, Zhou D. 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.
