Soluble fibrinogen-like protein 2 promotes the growth of hepatocellular carcinoma via attenuating dendritic cell-mediated cytotoxic T cell activity

J Exp Clin Cancer Res. 2019 Aug 13;38(1):351. doi: 10.1186/s13046-019-1326-5.


Background: Soluble fibrinogen-like protein 2 (sFGL2), a secretory protein expressed by regulatory T cells (Tregs) with immunosuppressive activity, is highly expressed in both the peripheral blood and tumor tissue of patients with hepatocellular carcinoma (HCC); however, sFGL2 function in HCC remains largely unknown. Here, we elucidated the potential role of sFGL2 in HCC progression.

Methods: T cells, dendritic cells (DCs), and related cytokines in the tumor microenvironment were comparatively analyzed in BALB/c and C57BL/6 mice bearing transplanted hepatomas harboring Fgl2-knockout or receiving sFGL2-antibody treatment. Additionally, the effects of sFGL2 on DCs and T cells were evaluated in vivo and ex vivo.

Results: The growth of both subcutaneously and orthotopically transplanted hepatomas was inhibited in Fgl2-knockout mice and those treated with the sFGL2 antibody, respectively, as compared with controls. Moreover, sFGL2 depletion enhanced the proportion and cytotoxicity of cytotoxic T cells, promoted DC maturation, and improved DC activity to proliferate T cells in the tumor microenvironment. Furthermore, we detected lower levels of interleukin (IL)-35 in both types of transplanted hepatomas and higher level of IL-6 in orthotopically transplanted hepatomas following sFGL2 depletion. Mechanistically, we found that sFGL2 impaired bone-marrow-derived DC (BMDCs) function by inhibiting phosphorylation of Akt, nuclear factor-kappaB, cAMP response element binding protein, and p38 and downregulating the expression of major histocompatibility complex II, CD40, CD80, CD86, and CD83 on BMDCs in vitro.

Conclusions: Our data suggest that sFGL2 promotes hepatoma growth by attenuating DC activity and subsequent CD8+ T cell cytotoxicity, suggesting sFGL2 as a novel potential therapeutic target for HCC treatment.

Keywords: Dendritic cells; Hepatocellular carcinoma; Immunosuppression; Soluble fibrinogen-like protein 2; Tumor microenvironment.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology
  • Biomarkers
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / immunology
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic* / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Disease Models, Animal
  • Female
  • Fibrinogen / antagonists & inhibitors
  • Fibrinogen / genetics
  • Fibrinogen / metabolism*
  • Fibrinogen / pharmacology
  • Heterografts
  • Humans
  • Immunophenotyping
  • Liver Neoplasms / genetics
  • Liver Neoplasms / immunology
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Knockout
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction / drug effects
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism*


  • Antibodies, Monoclonal
  • Biomarkers
  • Cytokines
  • FGL2 protein, human
  • Fibrinogen
  • Proto-Oncogene Proteins c-akt