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*
Department of Medicine and Vanderbilt Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232;
Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213; and
Department of Pathology and Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL 60153
The cytokine FLT3 ligand (FL) enhances dendritic cell (DC)
generation and has therefore been proposed as a means to boost
antitumor immunity. Vascular endothelial growth factor (VEGF) is
produced by a large percentage of tumors and is required for
development of tumor neovasculature. We previously showed that VEGF
decreases DC production and function in vivo. In this study, we tested
the hypothesis that VEGF regulates FL effects on DC generation. In
seven experiments, four groups of mice were treated with PBS, VEGF
alone (100 ng/h), FL alone (10 µg/day), or with the combination of FL
and VEGF. VEGF and PBS were administered continuously for 14 days via
s.c. pumps. FL was given s.c. daily for 9 days, beginning on day 4.
Tissues were collected and the number, phenotype, and function of lymph
node, splenic, and thymic DCs were analyzed on day 14. As expected,
treatment with FL resulted in a marked increase in the number of lymph
node and spleen DCs and a smaller increase in thymic DC. Pretreatment
of mice with VEGF inhibited these FL effects in lymph nodes and thymus
by about 50%, whereas spleen DC numbers were undiminished by VEGF.
VEGF treatment in vivo also inhibited the ability of FL to increase the
number of hemopoietic precursor cells and the level of maturity
exhibited by DC derived from these hemopoietic precursor cells in
vitro. VEGF inhibited FL-inducible activation of transcription factor
NF-
B. These data suggest that VEGF interferes with the ability of FL
to promote dendritic cell differentiation from bone marrow progenitor
cells in mice and therefore may decrease the therapeutic efficacy of FL
in settings where increased numbers of DCs might provide clinical
benefits.
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