title: Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte-mediated lysis and induces apoptosis.
abstract: Here, we report the functional expression of CD40 on human malignant melanomas (MMs). Comparison of tumor specimen from MM precursor lesions, primary tumors, and metastases revealed that CD40 surface expression is down-regulated during tumor progression. CD40 expression was confirmed in 7 human MM cell lines established from immunogenic primary tumors or metastases, whereas 11 cell lines established from advanced stages were CD40 negative. CD40 expression could be enhanced in CD40-positive MM by stimulation with IFN-gamma and tumor necrosis factor-alpha but not by interleukin (IL)-1beta or CD40 triggering. CD40 ligation on MM by CD40L-transfected murine L-cells or by a soluble CD40L fusion protein up-regulated their expression of intercellular adhesion molecule-1 and MHC class I and class II molecules and their secretion of IL-6, IL-8, tumor necrosis factor-a, and granulocyte macrophage colony-stimulating factor and also induced a rapid activation of the transcription factor nuclear factor kappaB. Furthermore, CD40 ligation of a HLA-A2+, MelanA/MART1+ MM cell line enhanced its susceptibility to specific lysis by a HLA-A2-restricted, MelanA/MART-1-specific CTL clone. Finally, CD40 ligation induced growth inhibition and apoptosis in MM. These results indicate that CD40-CD40L interactions may play an important role in augmenting antitumor immunity and inducing apoptosis in some CD40-positive immunogenic human MMs.
authors: Institute for Biology II, University of Freiburg, Germany.
authors: A
authors: A
authors: von Leoprechting
authors: P
authors: P
authors: van der Bruggen
authors: H L
authors: HL
authors: Pahl
authors: A
authors: A
authors: Aruffo
authors: J C
authors: JC
authors: Simon
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology*; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology*; D002455:Cell Division; D016207:Cytokines / Q000276:immunology / Q000502:physiology; D006801:Humans; D017403:In Situ Hybridization; D016131:Lymphocyte Subsets / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D016207:Cytokines; D016328:NF-kappa B; D014157:Transcription Factors