Blocking the CCL2-CCR2 axis using CCL2 neutralizing antibody is an effective therapy for hepatocellular cancer in a mouse model

Abstract

Hepatocellular carcinoma (HCC), a deadly disease, commonly arises in the setting of chronic inflammation. C-C motif chemokine ligand2 (CCL2/MCP1), a chemokine that recruits CCR2-positive immune cells to promote inflammation, is highly upregulated in HCC patients. Here, we examined the therapeutic efficacy of CCL2-CCR2 axis inhibitors against hepatitis and HCC in the miR-122 knockout (aka KO) mouse model. This mouse model displays upregulation of hepatic CCL2 expression, which correlates with hepatitis that progress to HCC with age. Therapeutic potential of CCL2-CCR2 axis blockade was determined by treating KO mice with a CCL2 neutralizing antibody (nab). This immunotherapy suppressed chronic liver inflammation in these mice by reducing the population of CD11 ^highGr1 ⁺ inflammatory myeloid cells, and inhibiting expression of IL-6 and TNF-α in KO livers. Furthermore, treatment of tumor-bearing KO mice with CCL2 nab for 8 weeks significantly reduced liver damage, HCC incidence and, tumor burden. Phospho-STAT3 (Y705) and c-MYC, the downstream targets of IL-6, as well as NF-κB, the downstream target of TNF-α, were downregulated upon CCL2 inhibition, which correlated with suppression of tumor growth. Additionally, CCL2 nab enhanced hepatic NK cell cytotoxicity and IFN-γ production, which is likely to contribute to the inhibition of tumorigenesis. Collectively, these results demonstrate that CCL2 immunotherapy could be an effective therapeutic approach against inflammatory liver disease and HCC.