Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma

Yuan Hong, Yibing Peng, Z. Sheng Guo, Jose Guevara-Patino, Junfeng Pang, Lisa H. Butterfield, Nahid F Mivechi, David H Munn, David L. Bartlett, Yukai He

Research output: Contribution to journalArticle

22 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1448-1458
Number of pages11
JournalHepatology
Volume59
Issue number4
DOIs
StatePublished - Jan 1 2014

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alpha-Fetoproteins
Carcinogens
Epitopes
Hepatocellular Carcinoma
Vaccines
Immunization
T-Lymphocytes
Immune Tolerance
Cancer Vaccines
Autoantigens
Neoplasm Antigens
Neoplasms
Liver
Liver Neoplasms

ASJC Scopus subject areas

  • Hepatology

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Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. / Hong, Yuan; Peng, Yibing; Guo, Z. Sheng; Guevara-Patino, Jose; Pang, Junfeng; Butterfield, Lisa H.; Mivechi, Nahid F; Munn, David H; Bartlett, David L.; He, Yukai.

In: Hepatology, Vol. 59, No. 4, 01.01.2014, p. 1448-1458.

Research output: Contribution to journalArticle

Hong, Yuan ; Peng, Yibing ; Guo, Z. Sheng ; Guevara-Patino, Jose ; Pang, Junfeng ; Butterfield, Lisa H. ; Mivechi, Nahid F ; Munn, David H ; Bartlett, David L. ; He, Yukai. / Epitope-optimized alpha-fetoprotein genetic vaccines prevent carcinogen-induced murine autochthonous hepatocellular carcinoma. In: Hepatology. 2014 ; Vol. 59, No. 4. pp. 1448-1458.
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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.",
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