title: 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.
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.
  
  
  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.
authors.affiliation: Section of Gastroenterology, Medizinische Klinik und Poliklinik IV, University of Munich, Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bauer
authors.forename: Alexander
authors.initials: A
authors.lastname: Sterzik
authors.forename: Franz
authors.initials: F
authors.lastname: Bauernfeind
authors.forename: Peter
authors.initials: P
authors.lastname: Duewell
authors.forename: Claudius
authors.initials: C
authors.lastname: Conrad
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Kiefl
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Andreas
authors.initials: A
authors.lastname: Eigler
authors.forename: Max
authors.initials: M
authors.lastname: Schnurr
authors.forename: Marc
authors.initials: M
authors.lastname: Dauer
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology*; D000818:Animals; D000918:Antibody Specificity; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D019496:Cancer Vaccines / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D004354:Drug Screening Assays, Antitumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007111:Immunity, Cellular / Q000187:drug effects; D056724:Immunity, Humoral / Q000187:drug effects; D007165:Immunosuppression Therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D019496:Cancer Vaccines; C110366:OVA-8; D010446:Peptide Fragments; D003841:Deoxycytidine; D010047:Ovalbumin; D000093542:Gemcitabine