title: Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma.
abstract: Immunization with effective cancer vaccines can offer a much needed adjuvant therapy to fill the treatment gap after liver resection to prevent relapse of hepatocellular carcinoma (HCC). However, current HCC cancer vaccines are mostly based on native shared-self/tumor antigens that are only able to induce weak immune responses. In this study we investigated whether the HCC-associated self/tumor antigen of alpha-fetoprotein (AFP) could be engineered to create an effective vaccine to break immune tolerance and potently activate CD8 T cells to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. We found that the approach of computer-guided methodical epitope-optimization created a highly immunogenic AFP and that immunization with lentivector expressing the epitope-optimized AFP, but not wild-type AFP, potently activated CD8 T cells. Critically, the activated CD8 T cells not only cross-recognized short synthetic wild-type AFP peptides, but also recognized and killed tumor cells expressing wild-type AFP protein. Immunization with lentivector expressing optimized AFP, but not native AFP, completely protected mice from tumor challenge and reduced the incidence of carcinogen-induced autochthonous HCC. In addition, prime-boost immunization with the optimized AFP significantly increased the frequency of AFP-specific memory CD8 T cells in the liver that were highly effective against emerging HCC tumor cells, further enhancing the tumor prevention of carcinogen-induced autochthonous HCC.
  
  
  CONCLUSIONS
  Epitope-optimization is required to break immune tolerance and potently activate AFP-specific CD8 T cells, generating effective antitumor effect to prevent clinically relevant carcinogen-induced autochthonous HCC in mice. Our study provides a practical roadmap to develop effective human HCC vaccines that may result in an improved outcome compared to the current HCC vaccines based on wild-type AFP.
authors.affiliation: Cancer Immunology, Inflammation, and Tolerance Program, Georgia Regents University Cancer Center, Medical College of Georgia, Augusta, GA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Hong
authors.forename: Yibing
authors.initials: Y
authors.lastname: Peng
authors.forename: Z Sheng
authors.initials: ZS
authors.lastname: Guo
authors.forename: Jose
authors.initials: J
authors.lastname: Guevara-Patino
authors.forename: Junfeng
authors.initials: J
authors.lastname: Pang
authors.forename: Lisa H
authors.initials: LH
authors.lastname: Butterfield
authors.forename: Nahid F
authors.initials: NF
authors.lastname: Mivechi
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: David L
authors.initials: DL
authors.lastname: Bartlett
authors.forename: Yukai
authors.initials: Y
authors.lastname: He
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D004195:Disease Models, Animal; D000939:Epitopes; D007108:Immune Tolerance / Q000502:physiology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D016896:Treatment Outcome; D000509:alpha-Fetoproteins / Q000235:genetics*
chemical_list: D019496:Cancer Vaccines; D002273:Carcinogens; D000939:Epitopes; D000509:alpha-Fetoproteins