title: Modulation of CD59 expression by restrictive silencer factor-derived peptides in cancer immunotherapy for neuroblastoma.
abstract: Tumor cells escape clearance by complement by abundantly expressing CD59 and other membrane complement regulators. Existing strategies for blocking/knocking down these regulators can contribute to tumor immunoclearance in vitro; however, there are numerous difficulties restricting their use in vivo. Here, we report a new strategy for suppression of CD59 expression in neuroblastoma using peptides that target regulators of CD59 expression. We identified the neural-restrictive silencer factor (REST) as a target for modulation of CD59 expression in neuroblastoma. We next designed plasmids that encoded peptides comprising different DNA-binding domains of REST and transfected them into neuroblastoma cell lines. These peptides suppressed CD59 expression, sensitizing neuroblastoma to complement-mediated killing triggered by anti-GD2 therapeutic monoclonal antibody. These CD59-modulating peptides might be effective therapeutic adjuvants to therapeutic monoclonal antibodies used for treatment of neuroblastoma and other cancer types sharing the same mechanism for regulation of CD59 expression.
authors.affiliation: Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom. donevrm@cardiff.ac.uk
authors.forename: Rossen M
authors.initials: RM
authors.lastname: Donev
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Gray
authors.forename: Baalasubramanian
authors.initials: B
authors.lastname: Sivasankar
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hughes
authors.forename: Carmen W
authors.initials: CW
authors.lastname: van den Berg
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
mesh_terms: D001932:Brain Neoplasms / Q000276:immunology* / Q000628:therapy*; D018957:CD59 Antigens / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D003165:Complement System Proteins; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D009447:Neuroblastoma / Q000276:immunology* / Q000628:therapy*; D010455:Peptides / Q000737:chemistry; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D018957:CD59 Antigens; D003165:Complement System Proteins; D010455:Peptides; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor