| First Author | Zhang J | Year | 2024 |
| Journal | Cell | Volume | 187 |
| Issue | 13 | Pages | 3409-3426.e24 |
| PubMed ID | 38744281 | Mgi Jnum | J:349110 |
| Mgi Id | MGI:7646773 | Doi | 10.1016/j.cell.2024.04.023 |
| Citation | Zhang J, et al. (2024) Osr2 functions as a biomechanical checkpoint to aggravate CD8(+) T cell exhaustion in tumor. Cell |
| abstractText | 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. |
