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Background and aims It is suggested that regulatory immune cells play a critical role in cancer cell growth by facilitating cancer cells to escape from the immune surveillance. The generation of the immune regulatory cells in cancer has not been fully understood yet. This study aims to investigate the role of the hepatoma-derived growth factor (HDGF) in the generation of regulatory T cells (Treg). Methods CCL-9.1 cells (A mouse hepatoma cell line), were cultured. The expression of HDGF in CCL-9.1 cells was assessed by quantitative RT-PCR and Western blotting. The generation of Foxp3 + T cells was assessed by cell culture and flow cytometry. The immune suppressor function of the Foxp3 + T cells on CD8 + T cell activities was assessed by the carboxyfluorescein succinimidyl ester (CFSE)-dilution assay and enzyme-linked immunosorbent assay. Results The results showed that exposure to PolyIC markedly increased the expression of HDGF in CCL-9.1 cells. Coculture of CCL-9.1 cells and CD4 + CD25 − T cells in the presence of PolyIC generated the Forkhead box protein (Foxp)3 + T cells. The exposure to HDGF increased the expression of Foxp3 and decreased the expression of GATA3 in CD4 + T cells. After activation, the Foxp3 + T cells suppressed the CD8 + T cell proliferation and the release of the cytotoxic cytokines. Conclusions Liver cancer cell-derived HDGF can induce Foxp3 + T cells; the latter has the immune suppressor functions on CD8 + T cell activities. [ABSTRACT FROM AUTHOR]