Liver Transplantation Center of the First Affiliated Hospital and State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu Province, China.
Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
Cell Death Dis. 2018 May 1;9(5):478. doi: 10.1038/s41419-018-0528-7.
Although one of the first comprehensive examinations of long non-coding RNA (lncRNA) expression was performed in human CD8 T lymphocytes, little is known about their roles in CD8 T cells functions during the progression of hepatocellular carcinoma (HCC). Here, we show that Lnc-Tim3 is upregulated and negatively correlates with IFN-γ and IL-2 production in tumor-infiltrating CD8 T cells of HCC patients. Lnc-Tim3 plays a pivotal role in stimulating CD8 T exhaustion and the survival of the exhausted CD8 T cells. Mechanistically, Lnc-Tim3 specifically binds to Tim-3 and blocks its interaction with Bat3, thus suppressing downstream Lck/ NFAT1/AP-1 signaling, leading to nuclear localization of Bat3, and enhancing p300-dependent p53 and RelA transcriptional activation of anti-apoptosis genes including MDM2 and Bcl-2. In summary, Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity, suggesting that Lnc-Tim3 and its associated signaling pathways may influence the outcome of cancer therapies aimed at modulating the acquired immune system.
尽管最早对长非编码 RNA (lncRNA) 表达的全面研究之一是在人类 CD8 T 淋巴细胞中进行的，但对于它们在肝癌 (HCC) 进展过程中 CD8 T 细胞功能中的作用知之甚少。在这里，我们表明 Lnc-Tim3 在 HCC 患者肿瘤浸润性 CD8 T 细胞中上调，并与 IFN-γ 和 IL-2 的产生呈负相关。Lnc-Tim3 在刺激 CD8 T 耗竭和耗竭的 CD8 T 细胞的存活中起着关键作用。在机制上，Lnc-Tim3 特异性结合 Tim-3 并阻断其与 Bat3 的相互作用，从而抑制下游 Lck/NFAT1/AP-1 信号传导，导致 Bat3 的核定位，并增强 p300 依赖性 p53 和 RelA 转录激活包括 MDM2 和 Bcl-2 在内的抗凋亡基因。总之，Lnc-Tim3 促进了 T 细胞耗竭，这种表型与抗肿瘤免疫受损相关，表明 Lnc-Tim3 及其相关信号通路可能影响旨在调节获得性免疫系统的癌症治疗的结果。
