Hepatoma cell-derived leptin downregulates the immunosuppressive function of regulatory T-cells to enhance the anti-tumor activity of CD8+ T-cells.

The adaptive immune response against hepatocellular carcinoma (HCC) could be a therapeutic target to restrain HCC initiation and growth. The interactions between hepatoma cells and immune cells modify the anti-tumor immunity to influence hepatoma cell survival. To explore the potential interplay between hepatoma cells and anti-HCC T-cells, we conducted a HCC induction mouse model to analyze the phenotypic and functional alterations of T-cell subsets. We found that both hepatoma tissues and hepatoma cell lines substantially produced higher leptin, which is an adipokine usually expressed in fat tissue, than normal liver tissue or hepatocytes. We also found that regulatory T-cells (Tregs), effector CD4(+) T-cells and CD8(+) T-cells upregulated expression of leptin receptor (LEPR) in spleens and livers after HCC induction. In vitro study showed that macrophages and dendritic cells isolated from HCC livers upregulated LEPR expression on T-cells. Leptin inhibited Treg activation and function in vitro, demonstrated by lower expression of TGF-β, IL-10, CTLA4 and GITR in Tregs, as wells weaker suppression of CD8(+) T-cell proliferation and production of cytotoxic mediators. In addition, silencing LEPR in Tregs favored tumor growth in a hepatoma cell line allograft model. Taken together, our study suggests that hepatoma cells could enhance anti-HCC immunity through secreting leptin to down-regulate Treg activity and subsequently promote CD8(+) T-cell response.