title: Multiple antigenic peptides based on H-2K(b)-restricted CTL epitopes from murine heparanase induce a potent antitumor immune response in vivo.
abstract: Accumulating research suggests that heparanase may be a universal tumor-associated antigen (TAA). Several heparanase T-cell epitopes from humans and mice have already been identified. However, because of low immunogenicity, polypeptide vaccines usually have difficulty inducing effective antitumor immune responses in vivo. In this study, to increase the immunogenicity of polypeptide vaccines, we designed and synthesized two four-branch multiple antigenic peptides (MAP) on the basis of mouse heparanase (mHpa) T-cell epitopes (mHpa398 and mHpa519). The dendritic cells (DC) from mice bone marrow loaded with above MAP vaccines from heparanase were used to evaluate immune response against various tumor cell lines, compared with immune response to their corresponding linear peptides, ex vivo and in vivo. We further assessed IFN-γ release both in CD4(+) T-cell-depleted and nondepleted mice. The results showed that effectors generated from DCs, loaded with MAP-vaccinated mice splenocytes, induced a stronger immune response against target cells expressing both heparanase and H-2K(b) than did effectors generated from mice vaccinated with their corresponding linear peptides. Heparanase-specific CD8(+) T-cell responses induced by MAP and linear peptide vaccination required synergy of CD4(+) T cells. In addition, heparanse-derived MAP vaccines significantly inhibited the growth of B16 murine melanoma in C57BL/6 mice, while also increasing the survival rate of tumor-bearing mice. Our data suggest that MAP vaccines based on T-cell epitopes from heparanase are efficient immunogens for tumor immunotherapy.
authors.affiliation: Institute of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing, PR China.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Tang
authors.forename: Guo-Zhen
authors.initials: GZ
authors.lastname: Wang
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.forename: Mu-Han
authors.initials: MH
authors.lastname: Lü
authors.forename: Chuan
authors.initials: C
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Chao
authors.forename: Chang-Zhu
authors.initials: CZ
authors.lastname: Li
authors.forename: Yu-Yun
authors.initials: YY
authors.lastname: Wu
authors.forename: Chang-Jiang
authors.initials: CJ
authors.lastname: Hu
authors.forename: Dian-Chun
authors.initials: DC
authors.lastname: Fang
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D005966:Glucuronidase / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D006183:H-2 Antigens / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D007167:Immunotherapy; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy; D010455:Peptides / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000099175:Heparanase
chemical_list: D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D005966:Glucuronidase; D006183:H-2 Antigens; D007371:Interferon-gamma; D010455:Peptides; D000099175:Heparanase; C032876:H-2Kb protein, mouse