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 CD11highGr1+ 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.

NF-κB RelA Is Required for Hepatoprotection during Pneumonia and Sepsis

“…Curiously, NKT cell blockade actually increased liver injury, possibly owing to the recently described ability of NKT cells to promote resolution and repair, including resolution and repair in the liver (55,56). Similarly, we did not observe changes in liver injury in hepRelA Δ/Δ mice after the reduction of Kupffer cells (using clodronate liposomes), nor was there an effect of CCL2 blockade, which has been shown in some settings to impair monocyte recruitment (27). However, our data suggest that the latter finding is likely due to an absence of CCL2-driven liver monocyte recruitment under the experimental conditions tested, since CCL2 blockade had no effect on this outcome.…”

“…To determine the potential influence of CCL2-dependent monocyte recruitment on hepatotoxicity, WT and hepRelA Δ/Δ mice were administered neutralizing CCL2 antibody and heat-killed S. pneumoniae for 6 h. This approach is well established to block liver monocyte recruitment in other settings, where this event relies on CCL2-CCR2 signaling (27). However, while CCL2 blockade produced pronounced immunologic defects in our preliminary studies using live S. pneumoniae, resulting in mortality (data not shown), this approach had no significant effect on either monocyte recruitment or liver injury in hepRelA Δ/Δ mice ( Fig.…”

Targeting CCR2/5 in the treatment of nonalcoholic steatohepatitis (NASH) and fibrosis: opportunities and challenges

“…Moreover, blocking CCL2/CCR2, genetically or pharmacologically, inhibits tumor growth and metastasis, and enhances survival in an HCC mouse model. This effect was attributed to inhibition of monocyte infiltration and reversal of the immunosuppression status of the tumor microenvironment by activation of a CD8 + T cell response [21,22]. Depletion of CCR5 reduced immune cell infiltration, fibrogenesis and tumor formation in mice [23] and resulted in decreased migration and invasiveness of malignant HCC cells in vitro [24,25].…”

CircRNA hsa_circ_0110102 Function as Anti-Oncogenic Gene in Hepatocellular Carcinoma Through Modulating miR-580-5p/CCL2 Pathway

“…C-C chemokine ligand 2 (CCL2) is overexpressed in HCC and is a prognostic factor for patients [10]. In tumor microenvironment, the interaction between CCL2 and C-C motif chemokine receptor 2 (CCR2) could regulates chemotaxis of TAMs and contributes to the cancer progression.…”