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Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1.

ABSTRACT: Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme that catabolizes tryptophan (Trp) metabolism to promote regulatory T cells (Tregs) and suppress CD8⁺ T cells, is regulated by several intrinsic signaling pathways. Here, we found that tobacco smoke, a major public health concern that kills 8 million people each year worldwide, induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo. The carcinogen nicotine-derived nitrosaminoketone (NNK) was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun, which has a binding site for the IDO1 promoter. The NNK receptor α7 nicotinic acetylcholine receptor (α7nAChR) was required for NNK-induced c-Jun activation and IDO1 upregulation. In A/J mice, NNK reduced CD8⁺ T cells and increased Tregs. Clinically, smoker patients with non-small-cell lung cancer (NSCLC) exhibited high IDO1 levels and low Trp/kynurenine (Kyn) ratios. In NSCLC patients, smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1. These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis, and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients, whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.

SUBMITTER: Liang F

PROVIDER: S-EPMC9448807 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1.

Liang Fan F Wang Gui-Zhen GZ Wang Yan Y Yang Ya-Ning YN Wen Zhe-Sheng ZS Chen Dong-Ni DN Fang Wen-Feng WF Zhang Bin B Yang Lu L Zhang Chen C Han Si-Chong SC Yang Fu-Ying FY Wang Di D Liang Li-Jun LJ Wang Zheng Z Zhao Yong Y Wang Chang-Li CL Zhang Li L Zhou Guang-Biao GB

Signal transduction and targeted therapy 20220907 1

Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme that catabolizes tryptophan (Trp) metabolism to promote regulatory T cells (Tregs) and suppress CD8<sup>+</sup> T cells, is regulated by several intrinsic signaling pathways. Here, we found that tobacco smoke, a major public health concern that kills 8 million people each year worldwide, induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo. The carcinogen nicotine-derived nitrosaminoketone (NNK) was the tobacco compound ...[more]

PMID: 36068203

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Project description:ObjectivesExtrahepatic tryptophan (Trp)-kynurenine (Kyn) metabolism via indoleamine 2,3-dioxygenase 1 (IDO1) induction was found to be associated with intrinsic immune regulation. However, the Trp-Kyn metabolism-associated immune regulation in dermatomyositis (DM) remains unknown. Therefore, we aimed to investigate the clinical relevance of the Trp-Kyn metabolism via IDO1 induction in DM.MethodsLiquid chromatography-mass spectrometry (HPLC-MS) was used to examine the serum Kyn and Trp concentrations in DM. In addition, we used X-tile software to determine the optimal cutoff value of the Kyn/Trp ratio, a surrogate marker for Trp-Kyn metabolism. Spearman analysis was performed to evaluate the association of Trp-Kyn metabolism with muscle enzymes and inflammatory markers.ResultsDM patients had significantly higher serum Kyn/Trp ratio (× 10-3) when compared with the healthy controls. The serum Kyn/Trp ratio was positively correlated with the levels of muscle enzymes and inflammatory markers. In addition, the serum Kyn/Trp ratio significantly decreased (36.89 (26.00-54.00) vs. 25.00 (18.00-37.00), P = 0.0006) after treatment. DM patients with high serum Kyn/Trp ratio had a significantly higher percentage of muscle weakness symptoms (62.5% vs. 20.0%, P = 0.019) and higher levels of LDH (316.0 (236.0-467.0) vs. 198.0 (144.0-256.0), P = 0.004) and AST (56.5 (35.0-92.2) vs. 23.0 (20.0-36.0), P = 0.002)) than those with low serum Kyn/Trp ratio. Multiple Cox regression analyses identified ln(Kyn/Trp) (HR 4.874, 95% CI 1.105-21.499, P = 0.036) as an independent prognostic predictor of mortality in DM.ConclusionsDM patients with enhanced Trp-Kyn metabolism at disease onset are characterized by more severe disease status and poor prognosis. Intrinsic immune regulation function via enhanced Trp-Kyn metabolism by IDO1 induction may be a potential therapeutic target in DM. Key Points • HPLC-MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment. • Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM. • Monitoring intrinsic immune regulation function should be considered a potential therapeutic target in DM patients.

Project description:Kynurenine (Kyn), a metabolite of tryptophan (Trp), is a key regulator of mammal immune responses such as cancer immune tolerance. Indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are main enzymes regulating the first and rate-limiting step of the Kyn pathway. To identify new small molecule inhibitors of TDO, we selected A172 glioblastoma cell line constitutively expressed TDO. Characterization of this cell line using kinase inhibitor library resulted in identification of MEK/ERK pathway-dependent TDO expression. After knowing the properties for TDO expression, we further proceeded to screen chemical library for TDO inhibitors. We previously determined that S-benzylisothiourea derivatives are enzymatic inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1) and suggested that the isothiourea moiety could be an important pharmacophore for binding to heme. Based on this premise, we screened an in-house library composed of various isothiourea derivatives and identified a bisisothiourea derivative, PVZB3001, as an inhibitor of TDO. Interestingly, PVZB3001 also inhibited the enzymatic activity of IDO1 in both cell-based and cell-free assays but did not inhibit other heme enzymes. Molecular docking studies suggested the importance of isothiourea moieties at the ortho position of the phenyl ring for the inhibition of catalytic activity. PVZB3001 showed competitive inhibition against TDO, and this was supported by the docking simulation. PVZB3001 recovered natural killer (NK) cell viability and functions by inhibiting Kyn accumulation in conditioned medium of both IDO1- and TDO-expressing cells. Furthermore, oral administration of IDO1-overexpressing tumor-bearing mice with PVZB3001 significantly inhibited tumor growth. Thus, we identified a novel selective dual inhibitor of IDO1 and TDO using the Kyn production assay with a glioblastoma cell line. This inhibitor could be a useful pharmacological tool for modulating the Kyn pathway in a variety of experimental systems.

Dataset Information

Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1.

Publications

Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1.

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