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

Cancer Immunol Immunother. 2014 Apr;63(4):321-33. doi: 10.1007/s00262-013-1510-y. Epub 2014 Jan 3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / immunology*
  • Animals
  • Antibody Specificity
  • Antimetabolites, Antineoplastic / pharmacology
  • Antimetabolites, Antineoplastic / therapeutic use
  • Antimetabolites, Antineoplastic / toxicity*
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / pharmacology
  • Cancer Vaccines / therapeutic use*
  • Cell Line, Tumor
  • Combined Modality Therapy
  • Dendritic Cells / immunology*
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / pharmacology
  • Deoxycytidine / therapeutic use
  • Deoxycytidine / toxicity
  • Drug Screening Assays, Antitumor
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Immunity, Cellular / drug effects
  • Immunity, Humoral / drug effects
  • Immunosuppression*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Ovalbumin / immunology
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / immunology*
  • Peptide Fragments / immunology
  • Tumor Escape / drug effects

Substances

  • Antimetabolites, Antineoplastic
  • Cancer Vaccines
  • OVA-8
  • Peptide Fragments
  • Deoxycytidine
  • Ovalbumin
  • gemcitabine