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

Cells. 2020 May 6;9(5):1140. doi: 10.3390/cells9051140.


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: bispecific antibody; cytotoxicity; ductal pancreatic adenocarcinoma; gamma delta T cells; indoleamine-2,3-dioxygenase; kynurenine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adult
  • Carcinoma, Pancreatic Ductal / metabolism*
  • Cell Communication / drug effects
  • Cell Cycle Checkpoints / drug effects
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic* / drug effects
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Interferon-gamma / metabolism
  • Kynurenine / metabolism*
  • Lysosomal-Associated Membrane Protein 1 / metabolism
  • Metabolome
  • Pancreatic Neoplasms / metabolism*
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism*
  • Tumor Necrosis Factor-alpha / pharmacology


  • IDO1 protein, human
  • IDO2 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Lysosomal-Associated Membrane Protein 1
  • Receptors, Antigen, T-Cell, gamma-delta
  • Tumor Necrosis Factor-alpha
  • Kynurenine
  • Interferon-gamma