Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells
Armstrong, C.A.; Botella, R.; Galloway, T.H.; Murray, N.; Kramp, J.M.; Song, I.S.; Ansel, J.C.
Cancer Research 56(9): 2191-2198
1996
ISSN/ISBN: 0008-5472 PMID: 8616871 Document Number: 466385
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-stimulating factor (GM-CSF) to inhibit melanoma progression in a murine model. The HFH18 murine melanoma cell line was transfected with the murine GM-CSF gene in a SV40 expression vector that resulted in melanoma clones that produced varying amounts of GM-CSF. Syngeneic mice inoculated s.c. with HFH18 parental melanoma cells or HFH18 cells transfected with 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 clones producing high levels of GM-CSF (H18/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 GMCSF (HFH18/GM-CSF-(+)) develop large tumors averaging 2000 mm-3, thus demonstrating a dose-response effect of tumor inhibition by melanoma-derived GM-CSF. Additionally, vaccination with irradiated GM-CSF-producing melanoma cells conferred optimal immunogenicity against a subsequent challenge with HFH18 cells. Tissue sections from excised GM-CSF-producing tumor cell inoculation sites but not from HFH18 parental or HFH18/GM-CSF-(-) inoculation sites demonstrate a dense inflammatory infiltrate composed of neutrophils, tissue macrophages, and numerous CD4- and CD8-positive lymphocytes but few melanoma cells. Large numbers of dendritic cells and cells expressing the B7-2 costimulatory molecule are detected only within HFH18/GM-CSF-(+++) melanoma inoculation sites. Our results lend further support to clinical trials of GM-CSF gene therapy in the treatment of advanced malignant melanoma, possibly by the recruitment of dendritic antigen-presenting cells.