Abstract
BackgroundSoluble 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.MethodsT 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.ResultsThe 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.ConclusionsOur 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.
Highlights
Soluble fibrinogen-like protein 2, 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); sFGL2 function in HCC remains largely unknown
Fibrinogen-like protein 2 (FGL2)-antibody treatment or Fgl2 knockout inhibits tumor growth in subcutaneously transplanted HCC models To investigate the role of sFGL2 in HCC progression, the growth of BNL or Hepa1–6 cells was evaluated in subcutaneous murine HCC models in Fgl2−/− mice or treated with the anti-FGL2 antibody in WT mice with a BALB/c or C57BL/6 background
We found significantly lower IL-35 levels in tumor homogenate from Fgl2−/− mice relative to that from WT mice (2637 ± 383.7 pg/mL vs. 4938 ± 1348 pg/mL; P < 0.05) (Fig. 2a)
Summary
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); sFGL2 function in HCC remains largely unknown. We elucidated the potential role of sFGL2 in HCC progression. Resistance to HCC treatment is widely attributed to immune-regulatory cells, such as regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages (TAMs) in the tumor microenvironment [3]. Interleukin (IL)-10 and transforming growth factor (TGF)-β, immunosuppressive cytokines secreted mainly by Tregs, are commonly detected in the serum of HCC patients in many cases, with both cytokines capable of inhibiting immune surveillance and protecting tumor growth by attenuating T cell activation [4, 5]. It is important to elucidate an expanded spectrum of immune regulators in the tumor microenvironment in order to identify potential therapeutic targets
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