Concomitant gemcitabine therapy negatively affects DC vaccine-induced CD8+ T-cell and B-cell responses but improves clinical efficacy in a murine pancreatic carcinoma model |
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Authors: | Christian Bauer Alexander Sterzik Franz Bauernfeind Peter Duewell Claudius Conrad Rosemarie Kiefl Stefan Endres Andreas Eigler Max Schnurr Marc Dauer |
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Affiliation: | 1. Section of Gastroenterology, Medizinische Klinik und Poliklinik IV, University of Munich, Munich, Germany 5. Massachusetts General Hospital, Harvard University, Boston, MA, USA 2. Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, University of Munich, Munich, Germany 4. Department of Internal Medicine I, Klinikum Dritter Orden, Munich, Germany 3. Department of Medicine II, Kliniken St. Elisabeth, Müller-Gnadenegg-Weg 4, 86633, Neuburg an der Donau, Germany
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Abstract: | Background Multiple studies have shown that dendritic cell (DC)-based vaccines can induce antitumor immunity. Previously, we reported that gemcitabine enhances the efficacy of DC vaccination in a mouse model of pancreatic carcinoma. The present study aimed at investigating the influence of gemcitabine on vaccine-induced anti-tumoral immune responses in a syngeneic pancreatic cancer model. Materials and methods Subcutaneous or orthotopic pancreatic tumors were induced in C57BL/6 mice using Panc02 cells expressing the model antigen OVA. Bone marrow-derived DC were loaded with soluble OVA protein (OVA-DC). Animals received gemcitabine twice weekly. OVA-specific CD8+ T-cells and antibody titers were monitored by FACS analysis and ELISA, respectively. Results Gemcitabine enhanced clinical efficacy of the OVA-DC vaccine. Interestingly, gemcitabine significantly suppressed the vaccine-induced frequency of antigen-specific CD8+ T-cells and antibody titers. DC migration to draining lymph nodes and antigen cross-presentation were unaffected. Despite reduced numbers of tumor-reactive T-cells in peripheral blood, in vivo cytotoxicity assays revealed that cytotoxic T-cell (CTL)-mediated killing was preserved. In vitro assays revealed sensitization of tumor cells to CTL-mediated lysis by gemcitabine. In addition, gemcitabine facilitated recruitment of CD8+ T-cells into tumors in DC-vaccinated mice. T- and B-cell suppression by gemcitabine could be avoided by starting chemotherapy after two cycles of DC vaccination. Conclusions Gemcitabine enhances therapeutic efficacy of DC vaccination despite its negative influence on vaccine-induced T-cell proliferation. Quantitative analysis of tumor-reactive T-cells in peripheral blood may thus not predict vaccination success in the setting of concomitant chemotherapy. |
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