CCL11 promotes HCC recurrence after liver surgery via activating immunosuppressive macrophages

Abstract

<p><strong>Background</strong> Surgical stress and chronic inflammation seriously trigger chemokine-mediated dysregulations of the hepatic environment, resulting in tumor progression and recurrence after liver surgery. We aimed to investigate the roles and mechanisms of an inflammation-induced chemokine, C-C motif ligand 11 (CCL11), in regulating the hepatic immune environment in hepatocellular carcinoma (HCC) patients.</p><p><strong>Methods</strong> The circulating and hepatic expression levels of CCL11 and its receptors in HCC patients undergoing liver transplantation (LT) and liver resection were quantified. Clinical relevance and prognostic values of CCL11 in post-surgical HCC recurrence and survival were characterized by statistical analyses. The functions and mechanisms of CCL11 in regulating the recruitment and polarization of macrophages were characterized by a series of in vitro experiments.</p><p><strong>Results</strong> Upregulation of circulating level of post-LT CCL11 was significantly associated with post-LT HCC recurrence and poor overall and disease-free survival. A high level of CCL11 in non-tumor tissues of HCC patients could significantly predict post-resection HCC recurrence and poor survival. Upregulation of the level of CCL11 was significantly associated with elevated inflammation resulting from post-surgical hepatic injury and chronic cirrhosis. The expression level of CCL11 was significantly associated with its receptor CCR5 and CCR5⁺CD206⁺M2-like macrophages, and their co-upregulations were significantly associated with post-surgical recurrence. In vitro functional study showed that CCL11 could enhance the mobilization of CCR5+monocytes and the generation of CCR5+CD206+ M2-like macrophages. Furthermore, CCR5⁺CD206⁺M2-like macrophages were negatively correlated with CD8⁺T cells and also have significant associations with markers of immunosuppressive macrophages, indicating that CCR5⁺CD206⁺M2-like macrophages may induce hepatic immunosuppression microenvironment and subsequently promote HCC recurrence after liver surgery.</p><p><strong>Conclusions</strong> CCL11 could be a potential circulating and tissue prognostic biomarker for HCC patients undergoing LT and hepatectomy. Inflammation-induced upregulation of CCL11 after liver surgery could provide a macrophage-mediated immunosuppressive environment, rendering novel mechanisms of post-surgical HCC recurrence.</p>