title: Antitumor effects of granulocyte-macrophage colony-stimulating factor production by melanoma cells.
abstract: 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 HGH18 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 n the noncoding 3'-5' orientation [HFH18/GM-CSF(-) cells] develop large tumors that reach a mean tumor volume of 3300 mm3 by day 30. In contrast, animals inoculated with two melanoma clones 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 mm3. In comparison, animals inoculated with a melanoma clone producing low levels of GM-CSF [HFH18/GM-CSF(+)] develop large tumors averaging 2000 mm3, 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.
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, Portland, Oregon, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Armstrong
authors.forename: R
authors.initials: R
authors.lastname: Botella
authors.forename: T H
authors.initials: TH
authors.lastname: Galloway
authors.forename: N
authors.initials: N
authors.lastname: Murray
authors.forename: J M
authors.initials: JM
authors.lastname: Kramp
authors.forename: I S
authors.initials: IS
authors.lastname: Song
authors.forename: J C
authors.initials: JC
authors.lastname: Ansel
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects; D018014:Gene Transfer Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000494:pharmacology / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D051379:Mice; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured; D014611:Vaccination
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor