Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma  

作　　者：Yongchun Wang Weibai Chen Shuang Qiao Hao Zou Xing-juan Yu Yanyan Yang Zhixiong Li Junfeng Wang Min-shan Chen Jing Xu Limin Zheng 

机构地区：[1]Collaborative Innovation Center for Cancer Medicine,State Key Laboratory of Oncology in South China,Guangdong Provincial Clinical Research Center for Cancer,Sun Yat-sen University Cancer Center,Guangzhou,510060,PR China [2]Key Laboratory of Gene Function and Regulation of the Ministry of Education,School of Life Sciences,Sun Yat-sen University,Guangzhou,510275,PR China [3]Department of Liver Surgery,Sun Yat-sen University Cancer Center,Guangzhou,PR China

出　　处：《Cellular & Molecular Immunology》2024年第10期1120-1130,共11页中国免疫学杂志（英文版）

基　　金：supported by project grants from the National Key R&D Program of China(2023YFA0915703);the Guangdong Basic and Applied Basic Research Foundation(2022A1515111205);the National Natural Science Foundation of China(32230034,82273296);the Open Fund Project of Guangdong Academy of Medical Sciences(YKY-KF202207).

摘　　要：Metabolic changes play a crucial role in determining the status and function of macrophages,but how lipid reprogramming in macrophages contributes to tumor progression is not yet fully understood.Here,we investigated the phenotype,contribution,and regulatory mechanisms of lipid droplet(LD)-laden macrophages(LLMs)in hepatocellular carcinoma(HCC).Enriched LLMs were found in tumor tissues and were associated with disease progression in HCC patients.The LLMs displayed immunosuppressive phenotypes(with extensive expression of TREM2,PD-L1,CD206,and CD163)and attenuated the antitumor activities of CD8^(+)T cells.Mechanistically,tumor-induced reshuffling of cellular lipids and TNFα-mediated uptake of tumoral fatty acids contribute to the generation of triglycerides and LDs in macrophages.LDs prolong LLM survival and promote CCL20 secretion,which further recruits CCR6^(+)Tregs to HCC tissue.Inhibiting LLM formation by targeting DGAT1 and DGAT2,which catalyze the synthesis of triglycerides,significantly reduced Treg recruitment,and delayed tumor growth in a mouse hepatic tumor model.Our results reveal the suppressive phenotypes and mechanisms of LLM enrichment in HCC and suggest the therapeutic potential of targeting LLMs for HCC patients.

关 键 词：Lipid droplets Macrophage survival CCL20 Treg Hepatocellular carcinoma 

分 类 号：R735.7[医药卫生—肿瘤]