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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- Bauer, C., Sterzik, A., Bauernfeind, F. et al. Cancer Immunol Immunother (2014) 63: 321. doi:10.1007/s00262-013-1510-y
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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.
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.
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.
KeywordsVaccination Dendritic cells Pancreatic carcinoma Chemotherapy Gemcitabine Survival
Carboxyfluorescein succinimidyl ester
Enzyme-linked immunosorbent assay
Fluorescence-activated cell sorter
Granulocyte macrophage colony-stimulating factor
Major histocompatibility complex I
Myeloid-derived suppressor cell
OVA protein-loaded DC
Retroviral protein expressed by Panc02 cells
Immunodominant MHC-I epitope of the ovalbumine protein
Tumor necrosis factor-α
Regulatory CD4+ Foxp3+ T-cell
Tryosinase-related peptide 2
Unloaded but LPS-stimulated DC