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Alterations in the structure and stiffness of the extracellular matrix (ECM) are hallmarks of cancer. Whether the biomechanical properties of the ECM affect the function of tumor-responsive CD8+ T cells remains unknown.
2024年5月13日，厦门大学周大旺、陈兰芬及陆军军医大学叶丽林共同通讯在Cell 在线发表题为“Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor”的研究论文，该研究发现转录因子(TF) Osr2整合了生物力学信号并促进肿瘤反应性CD8+ T细胞的最终衰竭。 通过偶联T细胞受体(TCR)信号传导和Piezo1/钙/CREB轴介导的生物力学应力，在终末衰竭的肿瘤特异性CD8+ T细胞亚群中选择性地诱导Osr2表达。
Consistently, in solid tumor models, deletion of Osr2 attenuates tumor-specific CD8+ T cell or CAR-T cell exhaustion, while forced Osr2 expression exacerbates their exhaustion. Mechanistically, Osr2 recruits HDAC3 to reconnect epigenetic programs, inhibit cytotoxic gene expression and promote CD8+ T cell exhaustion. Therefore, the results of this study reveal the function of Osr2 as a biomechanical checkpoint, which can exacerbate the exhaustion of CD8+ T cells and can target enhanced cancer immunotherapy.
Alterations in the structure and stiffness of the extracellular matrix (ECM) become one of the hallmarks of cancer. ECM components secreted by tumor-associated fibroblasts (CAFs) are organized and remodeled through a complex signal input network of tumor and stromal cells. In general, solid tumors exhibit greater ECM stiffness compared to healthy tissues. The spatial distribution of immune cells in the tumor microenvironment (TME) and surrounding stroma strongly influences prognosis and response to cancer treatment. Reducing ECM stiffness improves T cell migration and increases the efficacy of tumor immune checkpoint blockade (ICB). Mechanosensitive ion channels (MSICs), such as degenerin/epithelial sodium channels (DEG/ENaC), transient receptor potential (TRP), TWIK-associated K+ channel 1 (TREK1), transmembrane channel-like (TMC), and piezoelectric channels, as well as cell adhesion molecules such as integrins, selectins, and cadherins, have been shown to sense external biomechanical signals and convert them into molecular signals.
模式图（Credit: Cell）
Piezo1 and Piezo2 are newly discovered MSICs with high calcium affinity, which are evolutionarily conserved and involved in the development and differentiation of a variety of tissues, triggered by a series of mechanical stimuli. Many factors that are markers of cancer contribute to tumor-specific CD8+ T cell dysfunction in the TME. However, the exact effects of ECM stiffness and extracellular biomechanical cues on tumor-specific CD8+ T cells within TME in solid tumors remain largely elusive. The study found that a transcription factor (TF), Odd-skipped-associated 2 (Osr2), previously thought to be involved in palate development, synovial joints, and bone formation, can be selectively and significantly induced in tumor-specific CD8+ T cells subjected to biomechanical stress. Osr2 is not only necessary but sufficient to program the key features of depleted T cells in response to biomechanical stress. Thus, the study confirmed that Osr2 is a mechanoreactive TF that can aggravate the exhaustion of CD8+ T cells in the TME, and suggests that interfering with Osr2 signaling in adoptive-cell-treated engineered T cells may improve its therapeutic efficacy in solid tumors.
Original link https://doi.org/10.1016/j.cell.2024.04.023
Editor-in-charge|Explore Jun
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文章来源|“ iNature”
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