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

• Main Authors: Hannah Jonescheit, Hans-Heinrich Oberg, Daniel Gonnermann, Martin Hermes, Vjola Sulaj, Christian Peters, Dieter Kabelitz, Daniela Wesch
• Format: Article
• Language: English
• Published: MDPI AG 2020-05-01
• Series: Cells
• Subjects: gamma delta T cells; ductal pancreatic adenocarcinoma; indoleamine-2,3-dioxygenase; kynurenine; cytotoxicity; bispecific antibody
• Online Access: https://www.mdpi.com/2073-4409/9/5/1140

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 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. Methods: IDO expression was determined in PDAC cells by flow cytometry and Western blot analysis. PDAC cells were cocultured with γδ T cells in medium or were stimulated with phosphorylated antigens or bispecific antibody in the presence or absence of IDO inhibitors. Additionally, γδ 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 γδ T cell cytotoxicity only against some but not all PDAC cells. γδ T cell degranulation and cytotoxicity were significantly decreased after their treatment with recombinant kynurenine. Conclusions: Bispecific antibody drastically enhanced γδ 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 γδ T cell-mediated anti-tumor response.