H 2 S suppresses indoleamine 2, 3-dioxygenase 1 and exhibits immunotherapeutic efficacy in murine hepatocellular carcinoma

• Published in: Journal of experimental & clinical cancer research Vol. 38; no. 1; p. 88
• Main Authors: Yang, Dan, Li, Tianqi, Li, Yinlong, Zhang, Shengnan, Li, Weirui, Liang, Heng, Xing, Zikang, Du, Lisha, He, Jinchao, Kuang, Chunxiang, Yang, Qing
• Format: Journal Article
• Language: English
• Published: England 18.02.2019
• Subjects: Hydrogen sulfide; NF-κB and STAT3 signal pathways; H2S/NO crosstalk; Cancer immunotherapy; Indoleamine 2, 3 -dioxygenase 1
• ISSN: 1756-9966

Over-expression and over-activation of immunosuppressive enzyme indoleamine 2, 3 -dioxygenase 1 (IDO1) is a key mechanism of cancer immune escape. However, the regulation of IDO1 has not been fully studied. The relation between hydrogen sulfide (H S) and IDO1 is unclear. The influences of endogenous and exogenous H S on the expression of IDO1, iNOS and NF-κB and STAT3 signaling proteins were investigated using qPCR or western blot, and the production of nitric oxide (NO) was analyzed by nitrate/nitrite assay in Cse mice and MCF-7 and SGC-7901 cells. The effect of H S on IDO1 activity was investigated by HPLC and in-vitro enzymatic assay. The effect of H S on tryptophan metabolism was tested by luciferase reporter assay in MCF-7 and SGC-7901 cells. The correlation between H S-generating enzyme CSE and IDO1 was investigated by immunostaining and heatmaps analysis in clinical specimens and tissue arrays of hepatocellular carcinoma (HCC) patients. The immunotherapeutic effects of H S on H22 HCC-bearing mice were investigated. Using Cse mice, we found that H S deficiency increased IDO1 expression and activity, stimulated NF-κB and STAT3 pathways and decreased the expression of NO-generating enzyme Inos. Using IDO1-expressing MCF-7 and SGC-7901 cells, we found that exogenous H S inhibited IDO1 expression by blocking STAT3 and NF-κB pathways, and decreased IDO1 activity via H S/NO crosstalk, and combinedly decreased the tryptophan metabolism. The negative correlation between H S-generating enzyme CSE and IDO1 was further validated in clinical specimens and tissue arrays of HCC patients. Additionally, H S donors effectively restricted the tumor development in H22 HCC-bearing mice via downregulating IDO1 expression, inducing T-effector cells and inhibiting MDSCs. Thus, H S, as a novel negative regulator of IDO1, shows encouraging antitumor immunotherapeutic effects and represents a novel therapeutic target in cancer therapy.