Li Rutao, Zhang Yijian, Wang Anpeng, Feng Yipeng, Zhang Te, Wang Hui, Chen Yuzhong, Yu Xinnian, Song Xuming, Ding HanLin, Xu Lin, Dong Gaochao, Jiang Feng
Department of Thoracic Surgery, Nanjing Medical University Affiliated Cancer Hospital & Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research, Nanjing, China.
Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Cancer Institute of Jiangsu Province, Nanjing, China.
Cell Death Discov. 2024 Jul 23;10(1):334. doi: 10.1038/s41420-024-02102-3.
Previous studies revealed that MIR155HG possessed an oncogenic role in many types of tumors including lung adenocarcinoma (LUAD), along with higher expression in tumors. However, in our study, we observed a positive correlation between MIR155HG expression and overall survival across different cohorts. The transferred PBMC on the NCG mouse model abrogated the tumor intrinsic oncogenic role of MIR155HG in LUAD. Upregulation of MIR155HG positively correlated with CD8 T cell infiltration both in vitro and in vivo, as well as LUAD tissues. Mechanistically, we revealed that MIR155HG increased the cytokine CCL5 expression at the transcriptional level, which depended on the interaction between MIR155HG and YBX1 protein, a novel transcription factor of CCL5, resulting in the more protein stability of YBX1 through dampening ubiquitination. Additionally, we also observed that MIR155 could increase PD-L1 expression to hamper the activity of recruited CD8 T cells, which could be rescued through PD-L1 mAb addition. Finally, we uncovered that patients with high MIR155HG expression had a higher response rate to immunotherapy, and the combination of MIR155HG overexpression and PD-L1 mAb increased the efficacy of PD-L1 mAb. Together, our study provides a novel biomarker and potential combination treatment strategy for patients who received immunotherapy.
先前的研究表明，MIR155HG在包括肺腺癌（LUAD）在内的多种肿瘤中具有致癌作用，且在肿瘤中表达较高。然而，在我们的研究中，我们观察到不同队列中MIR155HG表达与总生存期呈正相关。在NCG小鼠模型上移植外周血单核细胞消除了MIR155HG在LUAD中的肿瘤内在致癌作用。MIR155HG的上调在体外和体内以及LUAD组织中均与CD8 T细胞浸润呈正相关。从机制上讲，我们发现MIR155HG在转录水平上增加了细胞因子CCL5的表达，这依赖于MIR155HG与YBX1蛋白（CCL5的一种新型转录因子）之间的相互作用，通过抑制泛素化导致YBX1的蛋白稳定性更高。此外，我们还观察到MIR155可以增加PD-L1的表达以阻碍募集的CD8 T细胞的活性，这可以通过添加PD-L1单克隆抗体来挽救。最后，我们发现MIR155HG高表达的患者对免疫治疗的反应率更高，MIR155HG过表达与PD-L1单克隆抗体的联合使用提高了PD-L1单克隆抗体的疗效。总之，我们的研究为接受免疫治疗的患者提供了一种新的生物标志物和潜在的联合治疗策略。
