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[Cancer Research 60, 3239-3246, June 15, 2000]
© 2000 American Association for Cancer Research

Immunology

Differences in Dendritic Cells Stimulated in Vivo by Tumors Engineered to Secrete Granulocyte-Macrophage Colony-stimulating Factor or Flt3-Ligand1

Nicolas Mach2, Silke Gillessen2, S. Brian Wilson, Christine Sheehan, Martin Mihm and Glenn Dranoff3

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{alpha}- 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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