1. Lipid droplet accumulation mediates macrophage survival and Treg recruitment via the CCL20/CCR6 axis in human hepatocellular carcinoma.
- Author
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Wang Y, Chen W, Qiao S, Zou H, Yu XJ, Yang Y, Li Z, Wang J, Chen MS, Xu J, and Zheng L
- Subjects
- Humans, Animals, Mice, Mice, Inbred C57BL, Cell Line, Tumor, Cell Survival, Male, Carcinoma, Hepatocellular pathology, Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular metabolism, Liver Neoplasms pathology, Liver Neoplasms immunology, Liver Neoplasms metabolism, Lipid Droplets metabolism, Macrophages metabolism, Macrophages immunology, Chemokine CCL20 metabolism, T-Lymphocytes, Regulatory immunology, Receptors, CCR6 metabolism
- Abstract
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., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)- Published
- 2024
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