Generation of anti-tumor immunity using mammalian heat shock protein 70 DNA vaccines for cancer immunotherapy.
In this study, we explored the protective anti-tumor potency of mouse (self) Hsp70 or Hsp110-based DNA vaccination approach targeting a tumor-associated antigen, human papilloma virus (HPV) type 16 E7 protein. Linkage of E7 to the N-terminus of the mouse Hsp70 not only elicits an E7-specific cytotoxic T cell (CTL) response, but also protects mice against challenge with E7 expressing tumors. CD8+ T-cells are crucial in both priming and effector phases for the induction of tumor immunity, whereas CD4+ T-cells and NK cells do not appear to play a major role. Furthermore, the ATP-binding domain deletion mutant Hsp70(382-641), when fused to E7, was immunologically effective, suggesting that the peptide-binding region, not the ATPase domain of Hsp70, is required for the vaccine activity of the E7-Hsp70 DNA. This study demonstrates that autologous Hsp70 is highly potent in enhancing antigen-specific immune responses. Functional domain mapping and orientation of the E7 and Hsp70 in the fusion gene may have clinical implications for the design and optimization of Hsp70-based DNA vaccines.
Li
Ying
Y
Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Subjeck
John
J
Yang
Gary
G
Repasky
Elizabeth
E
Wang
Xiang-Yang
XY
D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D009856:Oncogene Proteins, Viral / Q000276:immunology / Q000378:metabolism*; D027383:Papillomaviridae / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
D019496:Cancer Vaccines; D018840:HSP70 Heat-Shock Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D019444:Vaccines, DNA; C059731:oncogene protein E7, Human papillomavirus type 16