title: Enhancement of HLA class II-restricted CD4+ T cell recognition of human melanoma cells following treatment with bryostatin-1.
abstract: The majority of melanoma cells express detectable levels of HLA class II proteins, and an increased threshold of cell surface class II is crucial for the stimulation of CD4+ T cells. Bryostatin-1, a protein kinase C (PKC) activator, has been considered as a potent chemotherapeutic agent in a variety of in vitro tumor models. Little is known about the role of bryostatin-1 in HLA class II Ag presentation and immune activation in malignant tumors, especially in melanoma. In this study, we show that bryostatin-1 treatment enhances CD4+ T cell recognition of melanoma cells in the context of HLA class II molecules. We also show that bryostatin-1 treatment of melanoma cells increases class II protein levels by upregulating the class II transactivator (CIITA) gene. Flow cytometry and confocal microscopic analyses revealed that bryostatin-1 treatment upregulated the expression of costimulatory molecules (CD80 and CD86) in melanoma cells, which could prolong the interaction of immune cells and tumors. Bryostatin-1 also induced cellular differentiation in melanoma cells, and reduced tumorigenic factors such as pro-cathepsins and matrix-metalloproteinase-9. These data suggest that bryostatin-1 could be used as a chemo-immunotherapeutic agent for reducing tumorigenic potential of melanoma cells while enhancing CD4+ T cell recognition to prevent tumor recurrence.
authors: Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Dan
authors: D
authors: Zhao
authors: Shereen
authors: S
authors: Amria
authors: Azim
authors: A
authors: Hossain
authors: Kumaran
authors: K
authors: Sundaram
authors: Peter
authors: P
authors: Komlosi
authors: Mitzi
authors: M
authors: Nagarkatti
authors: Azizul
authors: A
authors: Haque
mesh_terms: D017951:Antigen Presentation / Q000187:drug effects; D018122:B7-1 Antigen / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D001483:Base Sequence; D054713:Bryostatins / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors; D006681:HLA-D Antigens / Q000378:metabolism*; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D009687:Nuclear Proteins / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics
chemical_list: D018122:B7-1 Antigen; D051940:B7-2 Antigen; D054713:Bryostatins; C497964:CD86 protein, human; D004791:Enzyme Inhibitors; D004792:Enzyme Precursors; D006681:HLA-D Antigens; C083728:MHC class II transactivator protein; D061965:Matrix Metalloproteinase Inhibitors; D009687:Nuclear Proteins; D012334:RNA, Neoplasm; D015534:Trans-Activators; C046785:bryostatin 1; C057832:procathepsin B; D002401:Cathepsin B; C058345:procathepsin D; D002402:Cathepsin D