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Abstract
BackgroundOver-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 (H2S) and IDO1 is unclear.MethodsThe influences of endogenous and exogenous H2S 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 H2S on IDO1 activity was investigated by HPLC and in-vitro enzymatic assay. The effect of H2S on tryptophan metabolism was tested by luciferase reporter assay in MCF-7 and SGC-7901 cells. The correlation between H2S-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 H2S on H22 HCC-bearing mice were investigated.ResultsUsing Cse−/− mice, we found that H2S 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 H2S inhibited IDO1 expression by blocking STAT3 and NF-κB pathways, and decreased IDO1 activity via H2S/NO crosstalk, and combinedly decreased the tryptophan metabolism. The negative correlation between H2S-generating enzyme CSE and IDO1 was further validated in clinical specimens and tissue arrays of HCC patients. Additionally, H2S donors effectively restricted the tumor development in H22 HCC-bearing mice via downregulating IDO1 expression, inducing T-effector cells and inhibiting MDSCs.ConclusionsThus, H2S, as a novel negative regulator of IDO1, shows encouraging antitumor immunotherapeutic effects and represents a novel therapeutic target in cancer therapy.
Highlights
Over-expression and over-activation of immunosuppressive enzyme indoleamine 2, 3 -dioxygenase 1 (IDO1) is a key mechanism of cancer immune escape
We find that Hydrogen sulfide (H2S) downregulates IDO1 expression by blocking nuclear factor-κB (NF-κB) and STAT3 pathways, and inhibits IDO1 activity via H2S/nitric oxide (NO) crosstalk
To test if H2S regulates IDO1, we measured the serum IDO1 activity and expression profile in different tissues of Cse−/− mice, a genetic mouse model that has a lower level of endogenous H2S than that of wild-type mice [30]
Summary
Over-expression and over-activation of immunosuppressive enzyme indoleamine 2, 3 -dioxygenase 1 (IDO1) is a key mechanism of cancer immune escape. Indoleamine 2,3-dioxygenase 1 (IDO1), a ubiquitous monomeric heme-containing enzyme, is the first rate-limiting enzyme in the kynurenine pathway (KP) that catabolizes tryptophan (Trp) into kynurenine [1]. Over-expression and over-activation of IDO1 in tumors and antigen-presenting cells play important roles in tumor-induced tolerance and suppression of the immune system by depleting the essential amino acid tryptophan and producing toxic tryptophan metabolites [2,3,4]. Pharmacological inhibition of IDO1 reverses the immune suppression in tumor microenvironments and improves the efficacy of therapeutic vaccination, chemotherapy or radiation therapy [8,9,10]. Inhibition of IDO1 has emerged as an attractive strategy for cancer immunotherapy
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