Both CD4+ and CD8+ T cell epitopes fused to heat shock cognate protein 70 (hsc70) can function to eradicate tumors.
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.
Mizukami
Shusaku
S
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.
Kajiwara
Chiaki
C
Ishikawa
Hiroshi
H
Katayama
Ichiro
I
Yui
Katsuyuki
K
Udono
Heiichiro
H
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
D000951:Antigens, Neoplasm; D015704:CD4 Antigens; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D050883:HSC70 Heat-Shock Proteins; D011993:Recombinant Fusion Proteins