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Accession PRJCA023484
Title Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor
Relevance Medical
Data types Single cell sequencing
Organisms Homo sapiens
Description The alteration in extracellular matrix (ECM) architecture and stiffness represents a hallmark of cancer. Whether the biomechanical property of ECM impacts the functionality of tumor reactive CD8+ T cells remains largely unknown. Here we reveal that transcription factor Osr2 integrates biomechanical signaling and facilitates the terminal exhaustion of tumor reactive CD8+ T cells in tumor microenvironment. Integrated genetic and multi-omics analyses demonstrate that Osr2 expression is selectively induced in the terminal exhausted tumor specific CD8+ T cell subset by coupled TCR signaling and biomechanical stress mediated by Piezo1/Calcium/CREB axis. Consistently, the depletion of Osr2 alleviates T cell exhaustion, leading to enhanced anti-tumor immunity mediated by tumor specific CD8+ T cells or CAR-T cells in solid tumor models. Moreover, forced Osr2 expression in tumor specific CD8+ T cells aggravates their exhaustion. Mechanistically, Osr2 recruits HDAC3 to rewire epigenetic program for suppressing cytotoxic genes expression and promoting CD8+ T cell exhaustion. In multiple human malignancies, high Osr2 expression is correlated with poor prognosis. Thus, our results unravel Osr2 functions as a biomechanical checkpoint to exacerbate CD8+ T cell exhaustion and could be targeted to potentiate cancer immunotherapy.
Sample scope Single cell
Release date 2024-05-14
Biomaterial provider Lilin Ye
Grants
Agency program Grant ID Grant title
National Natural Science Foundation of China (NSFC) 81925016
Submitter Lanfen Chen (chenlanfen@xmu.edu.cn)
Organization Xiamen University
Submission date 2024-01-29

Project Data

Resource name Description
BioSample (22)  show -