A novel therapeutic fusion protein vaccine by two different families of heat shock proteins linked with HPV16 E7 generates potent antitumor immunity and antiangiogenesis.
Human papillomaviruses (HPV), particularly HPV16, is considered a necessary cause of cervical and oral cancer. Thus, the development of a therapeutic vaccine against HPV is important for the control of cervical cancer. However, therapeutic vaccination has been limited by inadequate antigen-specific immune responses. Heat shock proteins (HSP), including calreticulin (CRT), HSP70 and gp96, have been shown to act as potent immunoadjuvant to enhance antigen-specific tumor immunity. Previous studies have shown that N domain CRT (NCRT) or C-terminal half of HSP70 (hsp) linked with HPV16 E7 are capable of inducing potent antigen-specific CTL activity in experimental animal models. Here we developed a recombinant NCRT/E7/hsp fusion protein to investigate the synergistic effects of NCRT and hsp for enhancing the potency of HPV16 E7 therapeutic vaccine and evaluated the immune responses induced by this fusion protein. Our results demonstrated that NCRT and hsp synergistically exhibited significant increases in E7-specific CD8(+) T cell responses and impressive antitumor effects against E7-expressing tumors. Furthermore, the NCRT/E7/hsp fusion protein also generates potent antiangiogenic effects. These results indicate that NCRT/E7/hsp fusion protein is a promising therapeutic vaccine for treatment of cervical cancer through a combination of antigen-specific immunotherapy and antiangiogenesis, with possible therapeutic potential in clinical settings.
Liu
Bo
B
Department of Cellular and Molecular Biology, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, P.O. Box 2258, Beijing 100021, PR China.
Ye
Dongxia
D
Song
Xinxin
X
Zhao
Xinhua
X
Yi
Linan
L
Song
Jietao
J
Zhang
Zhiyuan
Z
Zhao
Qingzheng
Q
D000481:Allantoin / Q000276:immunology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D002645:Chickens / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D005260:Female; D005434:Flow Cytometry; D006360:Heat-Shock Proteins / Q000276:immunology*; D052162:Human papillomavirus 16 / Q000276:immunology*; D007150:Immunohistochemistry; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology* / Q000517:prevention & control*; D009389:Neovascularization, Pathologic / Q000276:immunology* / Q000517:prevention & control*; D010957:Plasmids / Q000276:immunology; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use
D019496:Cancer Vaccines; D006360:Heat-Shock Proteins; D014614:Vaccines, Synthetic; D000481:Allantoin; D007371:Interferon-gamma