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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is among the most common pancreatic tumors and, with an extremely aggressive malignancy, is the 4th leading cause of cancer-related death
We focused on IDO-1 and -2, which are described to be overexpressed in some pancreatic cancer cells [54,55], and their influence on Vγ9Vδ2 γδ T cell cytotoxicity against PDAC cells and their consequences for their application in immunotherapy
By using Real-Time Cell Analyzer (RTCA), we distinguished between three different sensitivities of PDAC cells against γδ T cell-mediated cytotoxicity as follows: (i) Capan-1 and BxPC3 cells were susceptible to the lysis mediated by short-term activated Vγ9Vδ2 T cells after restimulation of the cocultured γδ T cells with phosphorylated antigens (PAg) BrHPP, while Capan-1 cells were killed by
Summary
Pancreatic ductal adenocarcinoma (PDAC) is among the most common pancreatic tumors and, with an extremely aggressive malignancy, is the 4th leading cause of cancer-related death. 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. 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. 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
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