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Blocking the CCL2‐CCR2 Axis Using CCL2 Neutralizing Antibody Is an Effective Therapy for Hepatocellular Cancer in a Mouse Model
Author(s) -
Teng KunYu,
Han Jianfeng,
Yu Jianhua,
Ghoshal Kalpana
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.328.10
Subject(s) - ccr2 , chemokine , cancer research , ccl2 , immunotherapy , immunology , medicine , inflammation , tumor necrosis factor alpha , downregulation and upregulation , immune system , biology , chemokine receptor , biochemistry , gene
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 high Gr1 + inflammatory myeloid cells, and inhibiting expression of IL‐6 and TNF‐a 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‐kB, the downstream target of TNF‐a, were downregulated upon CCL2 inhibition, which correlated with suppression of tumor growth. Additionally, CCL2 nab enhanced hepatic NK cell cytotoxicity and IFN‐g 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. Support or Funding Information This work was supported, in part, by NIH grants R01CA193244 (K. Ghoshal) and R01CA086978 (S. T. Jacob and K. Ghoshal) as well as by Pelotonia IDEA grants (J. Yu and K. Ghoshal) and Pelotonia Graduate Fellowship (K‐Y. Teng).CCL2 nab therapy inhibits HCC development in KO mice by modulating tumor microenvironment.