Hepatic stellate cells shape the ECM-disorganized and immunosuppressive microenvironment via CCL11/CCR3 axis in lenvatinib-treated hepatocellular carcinoma

作者：Na Qiang, Lan Cheng, Lin An, Hiroaki Kanzaki, Masanori Inoue, Naoya Kanogawa, Takayuki Kondo, Sadahisa Ogasawara, Masato Nakamura, Shingo Nakamoto, Dawei Cui, Hang Lv, Qiuran Xu, Guiping Chen, Junjie Ao · 发表于：Cellular Signalling · 年份：2025 · DOI：10.1016/j.cellsig.2025.112263 · 被引用次数：1 · 研究领域：Immune cells in cancer、Chemokine receptors and signaling、Liver physiology and pathology

Hepatic stellate cell (HSC) activation plays a crucial role in the progression from chronic liver disease to hepatocellular carcinoma (HCC) by establishing disorganized extracellular matrix (ECM) and facilitating immune evasion. However, the effects of HSC on the tumor microenvironment (TME) in lenvatinib (LEN)-treated HCC have not been well explored. In the present study, CCL11 secretory levels elevated in both the serum of HCC patients and the supernatant of HSCs following LEN treatment. In HSCs, CCL11 protein increased, while a CCR3 inhibitor decreased, expression of CCL11- and ECM-related genes: Col3a1 and Col16a1. Based on the expression of Ccl11 and its top 10 related genes, TCGA HCC samples (n = 371) were stratified into high- (n = 175) and low-expression (n = 196) groups. The pathways related to ECM and cell chemotaxis were upregulated in the high-expression group through GO and KEGG analyses. Tumor-associated- macrophages (TAMs) and neutrophils (TANs) and their marker genes (Cd206 and S100a9) were also enriched in this group. Mechanically, the over-production of CCL11 activates HSCs through the CCL11/CCR3 signaling pathway, resulting in the augmented CCL26 secretion to promote the infiltration of TAMs and TANs. In mice, LEN showed weaker tumor control and increased COL3A1, CD206, and S100A9 expression in tumors co-transplanted with HSCs versus tumor cells alone. Combining a CCR3 inhibitor with LEN reversed these effects. In conclusion, CCL11 over-production drives HS...