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

Abstract

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. Electronic supplementary material The online version of this article (10.1186/s13046-019-1326-5) contains supplementary material, which is available to authorized users.

Fibrinogen‐like protein 2 in gastrointestinal stromal tumour

“…It is unknown whether frequent FGL2 expression in GIST hinders the clinical efficiency of checkpoint inhibitors. FGL2 mediates a wide variety of immunological effects and sFGL2 is immunosuppressive, and could, therefore, promote cancer growth 9,22 . In this study, FGL2 expression was associated with low numbers of tumour‐infiltrating CD3+, CD8+, CD20+ and Foxp3+ lymphocytes, which is in agreement with the immunosuppressive role of sFGL2 9 .…”

Stat4 rs7574865 polymorphism promotes the occurrence and progression of hepatocellular carcinoma via the Stat4/CYP2E1/FGL2 pathway

“…FGL2, also known as FGL2 prothrombinase, is a member of the fibrinogen-related protein superfamily [ 40 ]. FGL2 was reported to be not only significantly increased in hepatitis [ 41 , 42 ] and nonalcoholic fatty liver [ 43 ] but also highly expressed in liver cancer [ 44 , 45 ]. The results of Liu indicated that knocking out FGL2 expression can significantly inhibit the growth of liver implant tumors and slow down the progression of liver cancer [ 45 ].…”

The role of Fibrinogen-like proteins in Cancer

“…sFGL2 inhibited macrophages by binding to FcγRIIB receptor to block the release of monocyte chemoattractant protein-1 (MCP-1), and by suppressing the activation of c-Jun N-terminal kinase 53 . sFGL2 can restrain the expression of MHCII, CD40, CD80, CD86, and CD83 in bone marrow derived mesenchymal stem cells in vitro by inhibiting the phosphorylation of Akt, NFκB, cAMP response element binding protein (CREB), and p38 in DC, and can decrease the cytotoxicity in HCC tissues and reinforce the burden of tumor 54 . sFGL2 levels were detected for the first time in the Egyptian HCV-infected and HCC patients, which provided a potential immune target for the treatment of HCV and HCC in the future ( Figure 2 ) 55 .…”