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Epitope-optimization creates highly immunogenic alpha fetoprotein antigen to break immune tolerance and potently activates CD8 T cells to prevents autochthonous hepatocellular carcinoma
  1. Yuan Hong1,
  2. Yibing Peng1,
  3. Sheng Z Guo3,
  4. Junfeng Pang1,
  5. Jose Guevara-patino2,
  6. David H Munn1,
  7. Nahid Mivechi1,
  8. David Bartlett3 and
  9. Yukai He1
  1. Aff1 grid.410427.40000000419370183Cancer CenterGeorgia Regents University Augusta GA USA
  2. Aff2 grid.164971.c0000000109456408SurgeryLoyola University Chicago IL USA
  3. Aff3 grid.21925.3d0000000419369000SurgeryUniversity of Pittsburgh Pittsburgh PA USA

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Meeting abstracts

In this study, we investigated whether mouse alpha fetoprotein (mAFP), the shared self/tumor antigen of hepatocellular carcinoma (HCC), could be rationally engineered to create effective vaccine to break tolerance and potently activate CD8 T cells to prevent clinically-relevant carcinogen-induced autochthonous HCC. We found that the computer-guided epitope-optimization created optimized opt-mAFP and that immunization with lentivector (lv) expressing opt-mAFP, but not wt-mAFP, potently activated CD8 cells specific for three novel H-2b restricted CD8 epitopes, which cross-recognized wt-mAFP epitopes naturally processed and presented by wt-mAFP+ tumor cells. Immunization with opt-mAFP-lv, but not wt-mAFP-lv, completely protected mice from wt-mAFP+ tumor challenge and effectively prevented carcinogen-induced autochthonous HCC. Prime-boost with opt-mAFP-lv and vaccinia vector opt-mAFP-vv significantly increased the wt-mAFP-specific CD8 T cells that were highly responsive to emerging HCC tumor cells in the liver, enhancing prevention of autochthonous HCC. Our data demonstrate that epitope-optimization creates immunogenic opt-mAFP that is able to break tolerance and activate potent CD8 responses, which can cross-recognize wt-mAFP peptides, but also recognize and kill mAFP+ tumor cells. Our study provides a practical roadmap to develop effective human vaccines that should have a better chance of success than the current human HCC vaccines based on native wt-AFP.