title: A novel autocrine pathway of tumor escape from immune recognition: melanoma cell lines produce a soluble protein that diminishes expression of the gene encoding the melanocyte lineage melan-A/MART-1 antigen through down-modulation of its promoter.
abstract: We have observed that malignant melanoma cells produce a soluble protein factor(s), which down-regulates melanocyte lineage Melan-A/MART-1 Ag expression by melanoma cells with concomitant loss of recognition by Melan-A/MART-1-specific T cells. This down-modulation of Melan-A/MART-1 expression, which we refer to as "Ag silencing," is mediated via its minimal promoter, whereas the promoter for the restricting Ag-presenting HLA-A2 molecule is not affected. Significantly, this Ag silencing is reversible, as removal of factor-containing supernatants from Melan-A/MART-1-expressing cells results in up-regulation of the promoter for the gene encoding this Ag, and renewed expression of the protein. We have evaluated over 20 known factors, none of which accounts for the Ag-silencing activity of the melanoma cell culture supernatants. The existence of this autocrine pathway provides an additional novel explanation for melanoma tumor progression in vivo in the presence of CTL specific for this melanocyte lineage Ag. These observations may have important implications for Melan-A/MART-1-specific CTL-mediated immunotherapy of melanoma tumors.
authors.affiliation: Department of Pathology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA. kurnick@helix.mgh.harvard.edu
authors.forename: J T
authors.initials: JT
authors.lastname: Kurnick
authors.forename: T
authors.initials: T
authors.lastname: Ramirez-Montagut
authors.forename: L A
authors.initials: LA
authors.lastname: Boyle
authors.forename: D M
authors.initials: DM
authors.lastname: Andrews
authors.forename: F
authors.initials: F
authors.lastname: Pandolfi
authors.forename: P J
authors.initials: PJ
authors.lastname: Durda
authors.forename: D
authors.initials: D
authors.lastname: Butera
authors.forename: I S
authors.initials: IS
authors.lastname: Dunn
authors.forename: E M
authors.initials: EM
authors.lastname: Benson
authors.forename: S J
authors.initials: SJ
authors.lastname: Gobin
authors.forename: P J
authors.initials: PJ
authors.lastname: van den Elsen
mesh_terms: D000951:Antigens, Neoplasm; D019898:Autocrine Communication / Q000276:immunology*; D018920:Coculture Techniques; D003601:Cytotoxicity Tests, Immunologic; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D020868:Gene Silencing / Q000276:immunology; D006801:Humans; D019169:Jurkat Cells; D058965:MART-1 Antigen; D008544:Melanocytes / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000276:immunology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D012995:Solubility; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D014158:Transcription, Genetic / Q000276:immunology; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D058965:MART-1 Antigen; C437370:MASA protein, human; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D012333:RNA, Messenger