title: Establishment of animal models to analyze the kinetics and distribution of human tumor antigen-specific CD8⁺ T cells.
abstract: Many patients develop tumor antigen-specific T cell responses detectable in peripheral blood mononuclear cells (PBMCs) following cancer vaccine. However, measurable tumor regression is observed in a limited number of patients receiving cancer vaccines. There is a need to re-evaluate systemically the immune responses induced by cancer vaccines. Here, we established animal models targeting two human cancer/testis antigens, NY-ESO-1 and MAGE-A4. Cytotoxic T lymphocyte (CTL) epitopes of these antigens were investigated by immunizing BALB/c mice with plasmids encoding the entire sequences of NY-ESO-1 or MAGE-A4. CD8(+) T cells specific for NY-ESO-1 or MAGE-A4 were able to be detected by ELISPOT assays using antigen presenting cells pulsed with overlapping peptides covering the whole protein, indicating the high immunogenicity of these antigens in mice. Truncation of these peptides revealed that NY-ESO-1-specific CD8(+) T cells recognized D(d)-restricted 8mer peptides, NY-ESO-181-88. MAGE-A4-specific CD8(+) T cells recognized D(d)-restricted 9mer peptides, MAGE-A4265-273. MHC/peptide tetramers allowed us to analyze the kinetics and distribution of the antigen-specific immune responses, and we found that stronger antigen-specific CD8(+) T cell responses were required for more effective anti-tumor activity. Taken together, these animal models are valuable for evaluation of immune responses and optimization of the efficacy of cancer vaccines.
authors.affiliation: Departments of Cancer Vaccine, Mie University Graduate School of Medicine, Mie 514-8507, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Muraoka
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Nishikawa
authors.forename: Takuro
authors.initials: T
authors.lastname: Noguchi
authors.forename: Linan
authors.initials: L
authors.lastname: Wang
authors.forename: Naozumi
authors.initials: N
authors.lastname: Harada
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sato
authors.forename: Immanuel
authors.initials: I
authors.lastname: Luescher
authors.forename: Eiichi
authors.initials: E
authors.lastname: Nakayama
authors.forename: Takuma
authors.initials: T
authors.lastname: Kato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shiku
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology; D045142:Cross-Priming; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000276:immunology; D010455:Peptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013737:Testis / Q000276:immunology; D013997:Time Factors
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D010455:Peptides