Immunoactivative role of indoleamine 2,3-dioxygenase in human hepatocellular carcinoma

Background: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catabolic enzyme. Recent studies have focused on the immunoregulatory role of IDO in mononuclear cells. The role of IDO in hepatocellular carcinoma (HCC) cell lines and HCC patients was examined. Methods: The expression of IDO mRNA in peripheral blood mononuclear cells (PBMC) cocultured with HCC cell lines was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The cytotoxicity of PBMC against HCC cell lines cultured with and without IDO inhibitor was examined by sodium (51)chromate release assay. In the tumor portion of 21 HCC patients, the expression of mRNA of IDO, tryptophan 2,3-dioxygenase and some cytokines was detected by RT-PCR. The expression and distribution of IDO protein in HCC specimens was analyzed by immunohistochemistry. Results: The IDO mRNA was strongly induced in PBMC cocultured with HepG2 and PLC/PRF/5 and faintly induced in PBMC cocultured with Hep3B and HuH7. The cytotoxicity of PBMC against HCC cell lines was directly proportional to the level of expression of IDO mRNA and reduced by IDO inhibitor. The expression of IDO mRNA in the tumor portion was detected in 12 out of 21 HCC patients. Immunohistochemistry revealed that the IDO-positive cells were identified to be tumor-infiltrating cells, not tumor cells. The IDO mRNA correlated significantly with gene expression of interferon-gamma, tumor necrosis factor-alpha and interleukin-1beta. The recurrence-free survival rate of IDO-positive HCC patients was significantly higher than that of IDO-negative HCC patients (P<0.05). Conclusions: These results suggest that IDO is a necessary enzyme for anticancer immune reactions of tumor-infiltrating cells. (C) 2004 Blackwell Publishing Asia Pty Ltd.