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Immunology |
Departments of Adult Oncology [N. M., S. G., G. D.] and Cancer Immunology and AIDS [S. B. W.], Dana-Farber Cancer Institute, and Department of Medicine [N. M., S. G., G. D.], Harvard Medical School, Boston, Massachusetts 02115; Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, New York 12208 [C. S.]; and Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts 02114 [M. M.]
Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and
flt3-ligand (FL) induce the development of dendritic cells (DCs). To
compare the functional properties of DCs stimulated by these cytokines
in vivo, we used retroviral-mediated gene transfer to
generate murine tumor cells secreting high levels of each molecule.
Injection of tumor cells expressing either GM-CSF or FL resulted in the
dramatic increase of CD11c+ cells in the spleen and tumor
infiltrate. However, vaccination with irradiated, GM-CSF-secreting
tumor cells stimulated more potent antitumor immunity than vaccination
with irradiated, FL-secreting tumor cells. The superior antitumor
immunity elicited by GM-CSF involved a broad T cell cytokine response,
in contrast to the limited Th1 response elicited by FL. DCs generated
by GM-CSF were CD8
- and expressed higher levels of
B7–1 and CD1d than DCs cells generated by FL. Injection sites of
metastatic melanoma patients vaccinated with irradiated, autologous
tumor cells engineered to secrete GM-CSF demonstrated similar, dense
infiltrates of DCs expressing high levels of B7–1. These findings
reveal critical differences in the abilities of GM-CSF and FL to
enhance the function of DCs in vivo and have important
implications for the crafting of tumor vaccines.
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