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or Cytidine-Phosphate-Guanosine DNA Drives T Cell Activation In Vitro and Therapeutic Anti-Tumor Immune Responses In Vivo1
Divisions of
*
Clinical Pharmacology and
Neuroendocrinology,
Departments of Medicine and Radiation Therapy, Ludwig-Maximilians-University of Munich, Munich, Germany;
Institute of Pathology, University of Mainz, Mainz, Germany;
¶ Department of Internal Medicine, University of Iowa, Iowa City, IA 52242;
||
Coley Pharmaceutical Group, Wellesley, MA 02481; and
#
Veteran Affairs Medical Center, Iowa City, IA 52246
Dendritic cells (DC) manipulated ex vivo can induce tumor immunity
in experimental murine tumor models. To improve DC-based tumor
vaccination, we studied whether DC maturation affects the T
cell-activating potential in vitro and the induction of tumor immunity
in vivo. Maturation of murine bone marrow-derived DC was induced by
GM-CSF plus IL-4 alone or by further addition of TNF-
or a
cytidine-phosphate-guanosine (CpG)-containing oligonucleotide
(ODN-1826), which mimics the immunostimulatory effect of bacterial DNA.
Flow cytometric analysis of costimulatory molecules and MHC class II
showed that DC maturation was stimulated most by ODN-1826, whereas
TNF- had an intermediate effect. The extent of maturation correlated
with the secretion of IL-12 and the induction of alloreactive T cell
proliferation. In BALB/c mice, s.c. injection of colon carcinoma cells
resulted in rapidly growing tumors. In this model, CpG-ODN-stimulated
DC cocultured with irradiated tumor cells also induced prophylactic
protection most effectively and were therapeutically effective when
administered 3 days after tumor challenge. Thus, CpG-ODN-enhanced DC
maturation may represent an efficient means to improve clinical tumor
vaccination.
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