Modulation of CD59 expression by restrictive silencer factor-derived peptides in cancer immunotherapy for neuroblastoma.
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.
Donev
Rossen M
RM
Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff, United Kingdom. donevrm@cardiff.ac.uk
Gray
Lisa C
LC
Sivasankar
Baalasubramanian
B
Hughes
Timothy R
TR
van den Berg
Carmen W
CW
Morgan
B Paul
BP
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
D018957:CD59 Antigens; D003165:Complement System Proteins; D010455:Peptides; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor