title: Enhanced tumor immunogenicity through coupling cytokine expression with antigen presentation.
abstract: The density of tumor antigen in conjunction with major histocompatibility complex (MHC) class I molecules on the cell surface affects cytotoxic T cell (CTL) function in an active antitumor immune response. Thus, methods to enhance antigen expression/presentation could augment the effect of cancer immune therapy. In the present study, we investigated the feasibility of modifying a cytokine signal peptide with a tumor antigenic epitope. We inserted the genes encoding the MHC class I-restricted antigenic epitope of chicken ovalbumin and tyrosinase-related protein 2 into the signal sequence of the interleukin-2 gene, replacing part of the signal sequence at different positions. Our results showed that these modified signal peptides still functioned, as indicated by cytokine secretion. The antigenic epitope within the modified signal peptide could be processed properly and presented on tumor cell surface. Tumor cells demonstrated enhanced immunogenicity as indicated by increased susceptibility to CTL lysis in vitro and decreased tumor grow in vivo after gene modification. These data provide potential perspectives in designing therapeutic or vaccine strategies in immuno-gene therapy of cancer.
authors.affiliation: Gene Therapy Group, Department of Microbiology and Immunology, University of Arizona, Tucson, Arizona 85721, USA. davidh@u.arizona.edu
authors.forename: Xianghui
authors.initials: X
authors.lastname: He
authors.forename: Tom C
authors.initials: TC
authors.lastname: Tsang
authors.forename: Phoebe
authors.initials: P
authors.lastname: Luo
authors.forename: Tong
authors.initials: T
authors.lastname: Zhang
authors.forename: David T
authors.initials: DT
authors.lastname: Harris
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D002455:Cell Division; D045744:Cell Line, Tumor; D016207:Cytokines / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000627:therapeutic use; D000939:Epitopes / Q000235:genetics / Q000276:immunology; D015316:Genetic Therapy; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007167:Immunotherapy; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology; D016415:Sequence Alignment; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007376:Interleukin-2; D021382:Protein Sorting Signals; D007371:Interferon-gamma