ANTITUMOR EFFECTS OF GRANULOCYTE-MACROPHAGE COLONY-STIMULATING FACTORPRODUCTION BY MELANOMA-CELLS

The use of immunomodulating gene therapy in the treatment of malignant disease is under intensive investigation, In this study, we examined the potential of melanoma-derived granulocyte-macrophage colony-stimul ating factor (GM-CSF) to inhibit melanoma progression in a murine mode l, The HFH18 murine melanoma cell line was transfected with the murine GM-CSF gene in a SV40 expression vector that resulted in melanoma clo nes that produced varying amounts of GM-CSF. Syngeneic mice inoculated s.c. with HFH18 parental melanoma cells or HFH18 cells transfected wi th the GM-CSF gene in the noncoding 3'-5' orientation [HFH18/GM-CSF(-) cells] develop large tumors that reach a mean tumor volume of 3300 mm (3) by day 30, In contrast, animals inoculated with two melanoma clone s producing high levels of GM-CSF [HFH18/GM-CSF(++) and HFH18/GM-CSF(++)] either completely reject the tumor cells or develop tumors with a mean volume of only 40 mm(3), In comparison, animals inoculated with a melanoma clone producing low levels of GM-CSF [HFH18/GM-CSF(+)] deve lop large tumors averaging 2000 mm(3), thus demonstrating a dose-respo nse effect of tumor inhibition by melanoma-derived GM-CSF. Additionall y, vaccination with irradiated GM-CSF-producing melanoma cells conferr ed optimal immunogenicity against a subsequent challenge with HFH18 ce lls, Tissue sections from excised GM-CSF-producing tumor cell inoculat ion sites but not from HFH18 parental or HFH18/GM-CSF(-) inoculation s ites demonstrate a dense inflammatory infiltrate composed of neutrophi ls, tissue macrophages, and numerous CD4- and CD8-positive lymphocytes but few melanoma cells, Large numbers of dendritic cells and cells ex pressing the B7-2 costimulatory molecule are detected only within HFH1 8/GM-CSF(+++) melanoma inoculation sites, Our results lend further sup port to clinical trials of GM-CSF gene therapy in the treatment of adv anced malignant melanoma, possibly by the recruitment of dendritic ant igen-presenting cells.