| 项目编号 | PRJCA030194 | ||||||||||||
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| 项目标题 | LARP4-mediated translation remodeling drives T cell exhaustion in tumor | ||||||||||||
| 涉及领域 | Medical | ||||||||||||
| 数据类型 |
Transcriptome or Gene expression
Single cell sequencing mRNA translation |
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| 物种名称 | Mus musculus | ||||||||||||
| 描述信息 | Using low-input ribosome sequencing (RPLace-seq), we uncover that intratumoral T cells undergo translatome remodeling and shift into a hyper-translation state as they acquire dysfunctional and exhaustion traits. We identify the RNA-binding protein LARP4 as a translation regulator mediating this hypertranslation state in exhausted T cells within tumors. LARP4 directly recognizes and increases the translation efficiency of a group of nuclear-encoded oxidative phosphorylation (OXPHOS) mRNAs in exhausted T cells while not affecting that of mitochondria-encoded mRNAs, thereby leading to an imbalance in OXPHOS subunits synthesis and mitochondrial dysfunction. Knockout of Larp4 in tumor-specific CD8+ T cells attenuates hyper-translation of intratumor T cells, restores their mitochondrial fitness, and enhances effector T cell differentiation with improved persistence within tumors, ultimately resulting in a superior antitumor response. Moreover, LARP4 knockdown in chimeric antigen receptor (CAR) T cells prevents terminal exhaustion differentiation of CAR T cells and improves their anti-tumor potency in both leukemia and solid tumors. Our study unveils the involvement of translation regulation in fine-tuning T cell fitness within tumors and identifies LARP4 as a potential target for enhancing the effectiveness of adoptive T cell therapies against solid tumors. | ||||||||||||
| 样品范围 | Monoisolate | ||||||||||||
| 发布日期 | 2025-05-29 | ||||||||||||
| 项目资金来源 |
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| 提交者 | Dali Han (handl@big.ac.cn) | ||||||||||||
| 提交单位 | Beijing Institute of Genomics, Chinese Academy of Sciences | ||||||||||||
| 提交日期 | 2024-09-14 |