Liver disease causes two million deaths annually and represents a significant and growing public health burden, with cirrhosis and primary liver cancer accounting for the majority of these deaths. Liver cirrhosis, resulting from chronic inflammation and fibrosis of the liver, is a significant risk factor for the most prevalent type of primary liver cancer, hepatocellular carcinoma. The pleiotropic chemokine (C-X-C motif) ligand 12 (CXCL12) has been implicated in both liver fibrosis and primary liver cancer. By signaling through its two cognate receptors, C-X-C motif receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3), CXCL12 may promote both liver fibrosis and tumor growth, progression, and metastasis. In addition, CXCL12 can also control immune cell egress from the bone marrow and their recruitment to the tumor, which may shape a pro-tumorigenic tumor microenvironment. In this study, the role of CXCL12 on liver fibrosis and primary liver cancer was further investigated, using experimental settings intended to explore CXCL12 inhibition as a potential target for novel interventions in these disease conditions. To address this in liver fibrosis, NOX-A12, a CXCL12-neutralizing RNA oligomer, was applied in two experimental mouse models, induced either by chronic carbon tetrachloride (CCl4) injections or by feeding a high fat methionine-choline deficient (MCD) diet. To explore the impact of CXCL12 on primary liver cancer, NOX-A12 was used in a model of diethylnitrosamine (DEN) induced liver cancer combined with either CCl4 to create a fibrotic environment or with a high-fat, high-sugar, and high-cholesterol Western diet (WD) to induce non-alcoholic fatty liver disease (NAFLD). CXCL12 inhibition with NOX-A12 had no impact on liver fibrosis but led to a prolonged inflammation after injury cessation. Furthermore, NOX-A12 increased chemokine levels in blood plasma, which was accompanied by an increase of peripheral blood myeloid cells. In the liver, CXCL12 inhibition provoked changes in hepatic monocyte-derived macrophage (MoMF) populations characterized by a decrease of CD11c+MHC-II+ MoMF and a relative increase of immature Ly6C+ MoMF. In addition, CXCL12 inhibition drastically reduced eosinophils in the liver of CCl4-treated, but not in NAFLD livers. Intriguingly, NOX-A12 promoted tumor growth both in the fibrosis- and in the NAFLD-associated model of DEN-induced liver cancer, despite reducing tumor-infiltrating MoMF and increasing cytotoxic CD8+ T cells in tumor lesions. Moreover, CXCL12 inhibition activated vascular remodeling in tumor microvessels, evident by an upregulation of CXCR4 on endothelial cells and increased expression of angiogenic and anti-angiogenic genes, particularly pronounced in NASH-HCC after therapeutic treatment with NOX-A12. Taken together, these data suggest a role for CXCL12 in chronic inflammation resolution, and in limiting primary liver cancer, mediated by a multi-faceted re-shaping of the tumor microenvironment.
