Regulation of accumulation and function of myeloid derived suppressor cells in different murine models of hepatocellular carcinoma

J Hepatol. 2013 Nov;59(5):1007-13. doi: 10.1016/j.jhep.2013.06.010. Epub 2013 Jun 22.


Background & aims: Myeloid derived suppressor cells (MDSC) are immature myeloid cells with immunosuppressive activity. They accumulate in tumor-bearing mice and humans with different types of cancer, including hepatocellular carcinoma (HCC). The aim of this study was to examine the biology of MDSC in murine HCC models and to identify a model, which mimics the human disease.

Methods: The comparative analysis of MDSC was performed in mice, bearing transplantable, diethylnitrosoamine (DEN)-induced and MYC-expressing HCC at different ages.

Results: An accumulation of MDSC was found in mice with HCC irrespective of the model tested. Transplantable tumors rapidly induced systemic recruitment of MDSC, in contrast to slow-growing DEN-induced or MYC-expressing HCC, where MDSC numbers only increased intra-hepatically in mice with advanced tumors. MDSC derived from mice with subcutaneous tumors were more suppressive than those from mice with DEN-induced HCC. Enhanced expression of genes associated with MDSC generation (GM-CSF, VEGF, IL6, IL1β) and migration (MCP-1, KC, S100A8, S100A9) was observed in mice with subcutaneous tumors. In contrast, only KC levels increased in mice with DEN-induced HCC. Both KC and GM-CSF overexpression or anti-KC and anti-GM-CSF treatment controlled MDSC frequency in mice with HCC. Finally, the frequency of MDSC decreased upon successful anti-tumor treatment with sorafenib.

Conclusions: Our data indicate that MDSC accumulation is a late event during hepatocarcinogenesis and differs significantly depending on the tumor model studied.

Keywords: BLR; Cancer vaccine; DEN; G-CSF; GM-CSF; HCC; IL; Immunotherapy; KC; L-NMMA; LAP; MCP; MDSC; N(G)-methyl-L-arginine; N(ω)-hydroxil-nor-L-arginine; N-NOHA; NK; OVA; Tumor immunology; VEGF; WT; body weight/liver weight ratio; diethylnitrosoamine; granulocyte colony stimulating factor; granulocyte-macrophage colony stimulating factor; hepatocellular carcinoma; iNOS; inducible nitric oxide synthase; interleukin; keratinocyte-derived chemokine; liver activator protein; macrophage chemotactic protein; myeloid derived suppressor cell; natural killer; ovalbumin; vascular endothelial growth factor; wild type.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Hepatocellular / chemically induced
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology*
  • Cell Movement* / drug effects
  • Cell Proliferation* / drug effects
  • Diethylnitrosamine / adverse effects
  • Disease Models, Animal*
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism
  • Heterografts
  • Humans
  • Liver Neoplasms / chemically induced
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Myeloid Cells / drug effects
  • Myeloid Cells / pathology*
  • Niacinamide / analogs & derivatives
  • Niacinamide / pharmacology
  • Phenylurea Compounds / pharmacology
  • Proto-Oncogene Proteins c-myc / metabolism
  • Sorafenib


  • Antineoplastic Agents
  • Phenylurea Compounds
  • Proto-Oncogene Proteins c-myc
  • Niacinamide
  • Diethylnitrosamine
  • Granulocyte-Macrophage Colony-Stimulating Factor
  • Sorafenib