title: Both CD4+ and CD8+ T cell epitopes fused to heat shock cognate protein 70 (hsc70) can function to eradicate tumors.
abstract: Vaccination with heat shock proteins (HSP) protects mice from challenge with the tumor from which the HSP were isolated. The antigenicity of HSP vaccination is thought to result from HSP-associated endogenous major histocompatibility complex class I peptides or their precursors. The vaccination effect can be achieved in an adjuvant-free manner and is mediated by CD8(+) T cells, indicating that HSP can act as a natural adjuvant and cross-prime T cells in vivo. We previously devised a recombinant vaccine composed of a CD8(+) T cell epitope fused to the carboxyl-terminus of hsc70 and demonstrated efficient generation of antigen-specific cytotoxic T lymphocyte (CTL) after vaccination with a few micrograms of the hsc70-CTL epitope fusion protein. The present study aimed to determine if the fusion protein vaccine could control tumor growth in vivo and whether simultaneous fusion of a CD4(+) T cell epitope to the amino terminus of the hsc70-CTL epitope would be a more potent vaccine compared to the CTL epitope alone. Ovalbumin (OVA)-derived 8 mer peptide, OVA(257-264), and 16mer peptide, OVA(265-280), were used as CD8(+) and CD4(+) T cell epitopes, respectively. Vaccination with hsc70-OVA(257-264) generated peptide specific CTL more effectively than a peptide plus incomplete Freund's adjuvant combination, and suppressed growth of OVA expressing EL4 (E.G7) and B16 melanoma tumor cells. Addition of OVA(265-280) to the amino-terminus of hsc70-OVA(257-264) (OVA(265-280)-hsc70-OVA(257-264)) enhanced the generation of the OVA(257-264)-specific CTL population, leading to better eradication of MO5 lung metastasis compared to hsc70-OVA(257-264). Our results suggest that fusion of both CD4(+) and CD8(+) T cell epitopes to hsc70 enhances tumor immunity beyond the effect of the CD8(+) T cell epitope alone.
authors.affiliation: Laboratory for Immunochaperones, Research Center for Allergy and Immunology (RCAI), RIKEN Yokohama Institute, 1-7-22 Suehiro-Cho, Tsurumi-Ku, Yokohama-Shi 230-0045, Japan.
authors.forename: Shusaku
authors.initials: S
authors.lastname: Mizukami
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kajiwara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishikawa
authors.forename: Ichiro
authors.initials: I
authors.lastname: Katayama
authors.forename: Katsuyuki
authors.initials: K
authors.lastname: Yui
authors.forename: Heiichiro
authors.initials: H
authors.lastname: Udono
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D015704:CD4 Antigens; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use*; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000627:therapeutic use*; D005434:Flow Cytometry; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D015704:CD4 Antigens; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D050883:HSC70 Heat-Shock Proteins; D011993:Recombinant Fusion Proteins