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Wendy L. Havran, PhD: 1955–2020
 
 
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Article

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

by
Hannah Jonescheit
†,
Hans-Heinrich Oberg
†,
Daniel Gonnermann
,
Martin Hermes
,
Vjola Sulaj
,
Christian Peters
,
Dieter Kabelitz
and
Daniela Wesch
*
Institute of Immunology, University Hospital Schleswig-Holstein Campus Kiel, D-24105 Kiel, Germany
*
Author to whom correspondence should be addressed.
†
Shared first authorship.
Cells 2020, 9(5), 1140; https://doi.org/10.3390/cells9051140
Submission received: 3 April 2020 / Revised: 28 April 2020 / Accepted: 5 May 2020 / Published: 6 May 2020
(This article belongs to the Special Issue Gamma Delta T Cells (γδ T Cells) in Health and Disease: In Memory of Professor Wendy Havran)
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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 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.
Keywords: gamma delta T cells; ductal pancreatic adenocarcinoma; indoleamine-2,3-dioxygenase; kynurenine; cytotoxicity; bispecific antibody gamma delta T cells; ductal pancreatic adenocarcinoma; indoleamine-2,3-dioxygenase; kynurenine; cytotoxicity; bispecific antibody

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MDPI and ACS Style

Jonescheit, H.; Oberg, H.-H.; Gonnermann, D.; Hermes, M.; Sulaj, V.; Peters, C.; Kabelitz, D.; Wesch, D. Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells. Cells 2020, 9, 1140. https://doi.org/10.3390/cells9051140

AMA Style

Jonescheit H, Oberg H-H, Gonnermann D, Hermes M, Sulaj V, Peters C, Kabelitz D, Wesch D. Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells. Cells. 2020; 9(5):1140. https://doi.org/10.3390/cells9051140

Chicago/Turabian Style

Jonescheit, Hannah, Hans-Heinrich Oberg, Daniel Gonnermann, Martin Hermes, Vjola Sulaj, Christian Peters, Dieter Kabelitz, and Daniela Wesch. 2020. "Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells" Cells 9, no. 5: 1140. https://doi.org/10.3390/cells9051140

APA Style

Jonescheit, H., Oberg, H.-H., Gonnermann, D., Hermes, M., Sulaj, V., Peters, C., Kabelitz, D., & Wesch, D. (2020). Influence of Indoleamine-2,3-Dioxygenase and Its Metabolite Kynurenine on γδ T Cell Cytotoxicity against Ductal Pancreatic Adenocarcinoma Cells. Cells, 9(5), 1140. https://doi.org/10.3390/cells9051140

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