PO.IM01.01 · 免疫学
一种产生TNF的中性粒细胞亚群驱动年龄依赖性肝毒性
A TNF-producing neutrophil subset drives age-dependent hepatotoxicity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
衰老加剧癌症治疗有害效应的机制仍知之甚少。本研究中我们发现，合成dsRNA（polyIC）能有效抑制年轻小鼠的肝脏肿瘤，却在老年小鼠中诱发致死性肝坏死。单细胞及功能分析揭示了一个CD14⁺中性粒细胞亚群，其特征为仅在老年肝脏中由polyIC强烈诱导TNFalpha。NR3C1表达受损以及NF-κB和AP-1信号升高，驱动老年肝脏中细胞偏向Tnf⁺而非Saa1⁺中性粒细胞。中和TNF可挽救polyIC诱导的死亡，同时增强其在老年小鼠中的抗肿瘤效应。生物信息学分析显示，Tnf⁺Saa1⁻中性粒细胞基因特征与60岁以上肝癌患者生存率下降显著相关。本研究揭示了老年肝脏中一种此前未知的有害机制，该机制在基础条件下无法检测。我们提供了一种新策略，通过减轻治疗相关毒性来改善老年患者的治疗结局。
查看英文原文 English abstract
The mechanisms by which aging contributes to the detrimental effect of cancer therapy remain poorly understood. Herein we show that while a synthetic dsRNA (polyIC) effectively suppresses liver tumors in young mice, it induces lethal liver necrosis in aged mice. Single-cell and functional analyses unearthed a CD14⁺ neutrophil subset featured by robust TNFalpha induction by polyIC exclusively in the aged liver. Impaired NR3C1 expression and elevated NF-κB and AP-1 signaling drive a skewing toward Tnf⁺ over Saa1⁺ neutrophils in the aged liver. TNF neutralization rescued polyIC-induced mortality, while also enhancing its antitumor effect in aged mice. Bioinformatic analysis revealed significant association of a Tnf⁺Saa1⁻ neutrophil gene signature with reduced survival in liver cancer patients over 60. This study uncovers a previously unknown detrimental mechanism in the aged liver, which is undetectable under basal conditions. We provide a new strategy to improve therapeutic outcomes in elderly patients by mitigating treatment-associated toxicity.
利益披露 Disclosure
J. Lee, None..
Y. Gao, None..
Y. Zhang, None..
A. Havas, None..
P. Adams, None..
G. S. Shadel, None..
S. M. Kaech, None..
G. Feng, None.