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.
CITATION STYLE
Yang, M., Zhang, Z., Chen, J., Xu, M., Huang, J., Wang, M., … Ning, Q. (2019). Soluble fibrinogen-like protein 2 promotes the growth of hepatocellular carcinoma via attenuating dendritic cell-mediated cytotoxic T cell activity. Journal of Experimental and Clinical Cancer Research, 38(1). https://doi.org/10.1186/s13046-019-1326-5
Mendeley helps you to discover research relevant for your work.