title: Resistance of cyclooxygenase-2 expressing pancreatic ductal adenocarcinoma cells against γδ T cell cytotoxicity.
abstract: The prostaglandin (PG) synthetase cyclooxygenase 2 (Cox-2) promotes tumorigenesis, tumor progression, and metastasis in a variety of human cancer entities including pancreatic ductal adenocarcinoma (PDAC). In this study, we demonstrate that in PDAC cells such as Colo357 cells, enhanced Cox-2 expression and increased release of the Cox-2 metabolite prostaglandin E2 (PGE2) promotes resistance against γδ T cell-mediated lysis. Co-culture with activated γδ T cells induced an upregulation of Cox-2 expression in Colo357 cells, and thereby an enhanced PGE2 release, in response to tumor necrosis factor α (TNFα) secretion from γδ T cells. The PGE2-mediated inhibition of γδ T cell cytotoxicity against Cox-2-expressing PDAC cells can be partially overcome by Cox-2 inhibitors. Our results show that differences between PDAC cells in regards to sensitivity to γδ T-cell cytotoxicity can be due to distinct levels of Cox-2 expression associated with varying amounts of PGE2 release. While γδ T cell cytotoxicity against PDAC cells expressing low levels of Cox-2 can be effectively enhanced by tribody [(Her2)2×Vγ9] with specificity for Vγ9 T cell receptor and HER-2/neu on PDAC cells, a combination of tribody [(Her2)2×Vγ9] and Cox-2 inhibitor is necessary to induce complete lysis of Cox-2 high expressing Colo357. In conclusion, our results suggest that the application of tribody [(Her2)2×Vγ9] that enhances γδ T-cell cytotoxicity and Cox-2 inhibitors that overcome PGE2-mediated resistance of PDAC cells to the cytotoxic activity of γδ T cells might offer a promising combined immunotherapy for pancreatic cancer.
authors.affiliation: Institute of Immunology; Christian-Albrechts-University; Kiel, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gonnermann
authors.affiliation: Institute of Immunology; Christian-Albrechts-University; Kiel, Germany.
authors.forename: Hans-Heinrich
authors.initials: HH
authors.lastname: Oberg
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy; Christian-Albrechts-University; Kiel, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kellner
authors.affiliation: Division of Stem Cell Transplantation and Immunotherapy; Christian-Albrechts-University; Kiel, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Peipp
authors.affiliation: Institute for Experimental Medicine; Christian-Albrechts-University ; Kiel.
authors.forename: Susanne
authors.initials: S
authors.lastname: Sebens
authors.affiliation: Institute of Immunology; Christian-Albrechts-University; Kiel, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Kabelitz
authors.affiliation: Institute of Immunology; Christian-Albrechts-University; Kiel, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Wesch
keywords: BrHPP, bromohydrin-pyrophosphate; Cox, cyclooxygenase; n-BP, nitrogen-containing bisphosphonates; PAg, phosphorylated antigen; PDAC, pancreatic ductal adenocarcinoma; PG, prostaglandins; RTCA, Real Time Cell Analyzer; TCR, T cell receptor.; Cox-2; PGE2; cytotoxicity; gammadelta T lymphocytes; human; pancreatic ductal adenocarcinoma