An unbiased approach to defining bona fide cancer neoepitopes that elicit immune-mediated cancer rejection

Cory A. Brennick; Mariam M. George; Marmar R. Moussa; Adam T. Hagymasi; Sahar Al Seesi; Tatiana V. Shcheglova; Ryan P. Englander; Grant L.J. Keller; Jeremy L. Balsbaugh; Brian M. Baker; Andrea Schietinger; Ion I. Mandoiu; Pramod K. Srivastava

doi:10.1172/JCI142823

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Brennick, C. in: JCI | PubMed | Google Scholar |

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by George, M. in: JCI | PubMed | Google Scholar

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Moussa, M. in: JCI | PubMed | Google Scholar |

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Hagymasi, A. in: JCI | PubMed | Google Scholar

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Al Seesi, S. in: JCI | PubMed | Google Scholar |

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Shcheglova, T. in: JCI | PubMed | Google Scholar

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Englander, R. in: JCI | PubMed | Google Scholar |

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Keller, G. in: JCI | PubMed | Google Scholar |

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Balsbaugh, J. in: JCI | PubMed | Google Scholar |

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Baker, B. in: JCI | PubMed | Google Scholar |

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Schietinger, A. in: JCI | PubMed | Google Scholar |

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Mandoiu, I. in: JCI | PubMed | Google Scholar |

¹Department of Immunology, University of Connecticut School of Medicine, Farmington, United States of America

²Computer Science and Engineering, Smith College, Northampton, United States of America

³Department of Chemistry and Biochemistry and Harper Cancer Research Institu, University of Notre Dame, Notre Dame, United States of America

⁴Proteomics and Metabolomics Facility, University of Connecticut, Storrs, United States of America

⁵Department of Chemistry & Biochemistry, Notre Dame, Notre Dame, United States of America

⁶Immunology Program, Memorial Sloan Kettering Cancer Center, New York, United States of America

⁷Department of Computer Science and Engineering, University of Connecticut, Storrs, United States of America

Find articles by Srivastava, P. in: JCI | PubMed | Google Scholar |

Published December 15, 2020 - Version history

Identification of neoepitopes that are effective in cancer therapy is a major challenge in creating cancer vaccines. Here, using an entirely unbiased approach, we queried all possible neoepitopes in a mouse cancer model and asked which of those are effective in mediating tumor rejection, and independently, in eliciting a measurable CD8 response. This analysis uncovered a large trove of effective anticancer neoepitopes which have strikingly different properties from conventional epitopes and suggested an algorithm to predict them. It also revealed that our current methods of prediction discard the overwhelming majority of true anticancer neoepitopes. These results from a single mouse model were validated in another, antigenically distinct mouse cancer model, and are consistent with data reported in human studies. Structural modeling showed how the MHC I-presented neoepitopes have an altered conformation, higher stability, or increased exposure to T cell receptors as compared to the un-mutated counterparts. T cells elicited by the active neoepitopes identified here demonstrated a stem-like early dysfunctional phenotype associated with effective responses against viruses and tumors of transgenic mice. These abundant anticancer neoepitopes, which have not been tested in human studies thus far, can be exploited for the generation of personalized human cancer vaccines.

Version 1 (December 15, 2020): In-Press Preview

An unbiased approach to defining bona fide cancer neoepitopes that elicit immune-mediated cancer rejection

Cory A. Brennick,¹ Mariam M. George,¹ Marmar R. Moussa,¹ Adam T. Hagymasi,¹ Sahar Al Seesi,² Tatiana V. Shcheglova,¹ Ryan P. Englander,¹ Grant L.J. Keller,³ Jeremy L. Balsbaugh,⁴ Brian M. Baker,⁵ Andrea Schietinger,⁶ Ion I. Mandoiu,⁷ and Pramod K. Srivastava¹

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An unbiased approach to defining bona fide cancer neoepitopes that elicit immune-mediated cancer rejection

Cory A. Brennick,1 Mariam M. George,1 Marmar R. Moussa,1 Adam T. Hagymasi,1 Sahar Al Seesi,2 Tatiana V. Shcheglova,1 Ryan P. Englander,1 Grant L.J. Keller,3 Jeremy L. Balsbaugh,4 Brian M. Baker,5 Andrea Schietinger,6 Ion I. Mandoiu,7 and Pramod K. Srivastava1

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Cory A. Brennick,¹ Mariam M. George,¹ Marmar R. Moussa,¹ Adam T. Hagymasi,¹ Sahar Al Seesi,² Tatiana V. Shcheglova,¹ Ryan P. Englander,¹ Grant L.J. Keller,³ Jeremy L. Balsbaugh,⁴ Brian M. Baker,⁵ Andrea Schietinger,⁶ Ion I. Mandoiu,⁷ and Pramod K. Srivastava¹