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Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on ?? T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells.

ABSTRACT: BACKGROUND:Pancreatic ductal adenocarcinoma (PDAC) is a malignant gastrointestinal disease. The enzyme indoleamine-2,3-dioxgenase (IDO) is often overexpressed in PDAC and its downstream metabolite kynurenine has been reported to inhibit T cell activation and proliferation. Since ?? T cells are of high interest for T cell-based immunotherapy against PDAC, we studied the impact of IDO and kynurenine on ?? T cell cytotoxicity against PDAC cells. METHODS:IDO expression was determined in PDAC cells by flow cytometry and Western blot analysis. PDAC cells were cocultured with ?? T cells in medium or were stimulated with phosphorylated antigens or bispecific antibody in the presence or absence of IDO inhibitors. Additionally, ?? T cells were treated with recombinant kynurenine. Read-out assays included degranulation, cytotoxicity and cytokine measurement as well as cell cycle analysis. RESULTS:Since IDO overexpression was variable in PDAC, IDO inhibitors improved ?? T cell cytotoxicity only against some but not all PDAC cells. ?? T cell degranulation and cytotoxicity were significantly decreased after their treatment with recombinant kynurenine. CONCLUSIONS:Bispecific antibody drastically enhanced ?? T cell cytotoxicity against all PDAC cells, which can be further enhanced by IDO inhibitors against several PDAC cells, suggesting a striking heterogeneity in PDAC escape mechanisms towards ?? T cell-mediated anti-tumor response.

SUBMITTER: Jonescheit H

PROVIDER: S-EPMC7290398 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells.

Jonescheit Hannah H Oberg Hans-Heinrich HH Gonnermann Daniel D Hermes Martin M Sulaj Vjola V Peters Christian C Kabelitz Dieter D Wesch Daniela D

Cells 20200506 5

<h4>Background</h4>Pancreatic ductal adenocarcinoma (PDAC) is a malignant gastrointestinal disease. The enzyme indoleamine-2,3-dioxgenase (IDO) is often overexpressed in PDAC and its downstream metabolite kynurenine has been reported to inhibit T cell activation and proliferation. Since γδ T cells are of high interest for T cell-based immunotherapy against PDAC, we studied the impact of IDO and kynurenine on γδ T cell cytotoxicity against PDAC cells.<h4>Methods</h4>IDO expression was determined ...[more]

PMID: 32384638

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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.

Dataset Information

Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on ?? T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells.

Publications

Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells.

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