Journal Article

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

Sterzik, Alexander, Bauer, Christian, Bauernfeind, Franz, Conrad, Claudius, Duewell, Peter, Kiefl, Rosemarie, Schnurr, Max, Dauer, Marc, Eigler, Andreas, Endres, Stefan

2014

Overview

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.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V
• Subject: Adenocarcinoma - drug therapy / Adenocarcinoma - immunology / Animals / Antibody Specificity / Antigens / Antimetabolites, Antineoplastic - pharmacology / Antimetabolites, Antineoplastic - therapeutic use / Antimetabolites, Antineoplastic - toxicity / B-Lymphocytes - drug effects / B-Lymphocytes - immunology / Cancer Research / Cancer therapies / Cancer Vaccines - pharmacology / Cancer Vaccines - therapeutic use / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Cell Line, Tumor / Chemotherapy / Combined Modality Therapy / Cytotoxicity / Dendritic cells / Dendritic Cells - immunology / Deoxycytidine - analogs & derivatives / Deoxycytidine - pharmacology / Deoxycytidine - therapeutic use / Deoxycytidine - toxicity / Drug Screening Assays, Antitumor / Enzyme-Linked Immunosorbent Assay / Female / Gemcitabine / Immunity, Cellular - drug effects / Immunity, Humoral - drug effects / Immunology / Immunosuppression Therapy / Immunotherapy / Medical prognosis / Medicine / Medicine & Public Health / Mice / Mice, Inbred C57BL / Mice, Transgenic / Oncology / Original / Original Article / Ovalbumin - immunology / Pancreatic cancer / Pancreatic Neoplasms - drug therapy / Pancreatic Neoplasms - immunology / Peptide Fragments - immunology / Proteins / Tumor Escape - drug effects / Tumors / Vaccines