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BACKGROUND AND AIMS

HSCs contribute to HCC progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX3CR1+ macrophages to protumorigenic properties in the peritumoral area.

APPROACH AND RESULTS

In single-cell RNA-sequencing analysis of patients with HCC, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14+CD11b+HLA-DR- macrophages with CX3CR1 in the HCC adjacent region where α-smooth muscle actin-expressing activated hepatic stellate cells (aHSCs) showed colocalized expression of CX3CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX3CR1+Ly6C+ macrophages was mostly observed with decreased CD8+ T cells. In adoptive transfer and in vitro coculture of myeloid cells, we demonstrated that CX3CR1+Ly6C+ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or coculturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX3CR1+Ly6C+ macrophages and human blood CD14+ cells, leading to the suppression of CD8+ T-cell proliferation. Moreover, genetic deficiency of CX3CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development.

CONCLUSIONS

We showed that CX3CR1+Ly6C+ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX3CR1+Ly6C+ macrophages, subsequently depriving CD8+ T cells of arginine and promoting HCC.

BACKGROUND AND AIMS

APPROACH AND RESULTS

CONCLUSIONS

背景与目的

肝星状细胞（HSCs）通过调节多种因子促进肝癌进展。然而，HSCs的整体免疫调节功能仍不清楚。在此，我们旨在研究HSCs是否会使肿瘤周围区域的CX3CR1⁺巨噬细胞具有促肿瘤特性。

方法与结果

在肝癌患者的单细胞RNA测序分析中，肿瘤周围区域的一个巨噬细胞亚群特异性表达精氨酸酶1（Arg1）和Cx3cr1，并且富含视黄醇代谢相关基因。流式细胞术分析显示，在肝癌相邻区域，表达α-平滑肌肌动蛋白的活化肝星状细胞（aHSCs）显示CX3CL1共定位表达，其中具有CX3CR1的CD14⁺CD11b⁺HLA-DR⁻巨噬细胞频率显著增加。相应地，在荷瘤小鼠中，相邻肝癌内的aHSCs中Cx3cl1 mRNA表达显著增加，在该区域大多观察到CX3CR1⁺Ly6C⁺巨噬细胞浸润，而CD8⁺T细胞减少。在髓系细胞的过继转移和体外共培养中，我们证明CX3CR1⁺Ly6C⁺巨噬细胞通过与相邻肝癌中富含视黄醇的aHSCs相互作用而迁移并高表达精氨酸酶-1。直接给予视黄醇或与储存视黄醇的小鼠aHSCs或人LX-2细胞共培养显著增加CX3CR1⁺Ly6C⁺巨噬细胞和人血CD14⁺细胞中精氨酸酶-1的表达，导致CD8⁺T细胞增殖受到抑制。此外，髓系细胞中CX3CR1的基因缺陷或视黄醇代谢的药理学抑制显著减弱肝癌发展。