Inhibition of the chemokine CXCL12 promotes liver cancer progression by modulating the inflammatory and angiogenic tumor microenvironment

Background and Aims: The chemokine (C-X-C motif) ligand 12 (CXCL12) and its receptors C-X-C motif receptor 4 (CXCR4) and atypical chemokine receptor 3 (ACKR3, or CXCR7) have been implicated in liver fibrosis progression and tumors in several organs. Moreover, CXCL12 was shown to shape a pro-tumorigenic microenvironment by favoring immunosuppressive immune cell recruitment. This study aims at exploring the therapeutic potential of CXCL12 inhibition for the treatment of primary liver tumors, i.e. hepatocellular carcinoma (HCC), and characterizing its impact on liver inflammation.

Method: The CXCL12-neutralizing Spiegelmer NOX-A12 was used in fibrosis-associated (chronic CCl4 injections), and metabolic dysfunction-associated steatotic liver disease (MASLD) related (Western diet, WD) mouse models combined with diethylnitrosamine (DEN)-induced HCC. Tumor growth, liver injury and liver fibrosis were assessed. Blood and liver immune cell populations were analyzed by flow cytometry and multiplex immunostaining.

Results: CXCL12 inhibition increased tumor growth in both CCl4- and WD-associated HCC models. This was accompanied by reduced monocyte-derived macrophages (MoMF) and increased cytotoxic T cell numbers in tumour lesions. Moreover, NOX-A12 activated tumor microvessels, evidenced by an upregulation of CXCR4 on tumor endothelial cells and increased gene expression of angiogenic (Ang2) and anti-angiogenic (Ang1, Thbs1) genes in tumors. CXCL12 inhibition reduced eosinophils and B cells in the liver of CCl4-treated, but not MASLD livers. Concomitantly, NOX-A12 decreased CD11c+MHC-II+MoMF and increased Ly6C+MoMF accumulation.

Conclusion: This study demonstrates pro-tumorigenic effects of CXCL12 inhibition in mouse models of primary liver cancer and suggests a pivotal role for CXCL12 in modulating the tumor immune microenvironment.

Publication History

Article published online:
20 January 2025