APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy

Christopher B. Driscoll, Matthew R. Schuelke, Timothy Kottke, Jill M. Thompson, Phonphimon Wongthida, Jason M. Tonne, Amanda L. Huff, Amber Miller, Kevin G. Shim, Amy Molan, Cynthia Wetmore, Peter Selby, Adel Samson, Kevin Harrington, Hardev Pandha, Alan Melcher, Jose S. Pulido, Reuben Harris, Laura Evgin, Richard G. Vile

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

APOBEC3B, an anti-viral cytidine deaminase which induces DNA mutations, has been implicated as a mediator of cancer evolution and therapeutic resistance. Mutational plasticity also drives generation of neoepitopes, which prime anti-tumor T cells. Here, we show that overexpression of APOBEC3B in tumors increases resistance to chemotherapy, but simultaneously heightens sensitivity to immune checkpoint blockade in a murine model of melanoma. However, in the vaccine setting, APOBEC3B-mediated mutations reproducibly generate heteroclitic neoepitopes in vaccine cells which activate de novo T cell responses. These cross react against parental, unmodified tumors and lead to a high rate of cures in both subcutaneous and intra-cranial tumor models. Heteroclitic Epitope Activated Therapy (HEAT) dispenses with the need to identify patient specific neoepitopes and tumor reactive T cells ex vivo. Thus, actively driving a high mutational load in tumor cell vaccines increases their immunogenicity to drive anti-tumor therapy in combination with immune checkpoint blockade.

Original languageEnglish (US)
Article number790
JournalNature communications
Volume11
Issue number1
DOIs
StatePublished - Dec 1 2020

Bibliographical note

Funding Information:
The authors thank Toni L. Woltman for expert secretarial assistance. They would additionally like to thank the Genome Analysis and Bioinformatics Core Facilities for their help in obtaining and interpreting the sequencing results, and John Smestad for assistance in uploading raw sequencing data. This work was funded in part by The European Research Council, The Richard M. Schulze Family Foundation, the Mayo Foundation, Cancer Research UK, the National Institute of Health (R01CA175386 and R01CA108961), The University of Minnesota and Mayo Clinic Partnership, a grant from Terry and Judith Paul, The Shannon O’Hara Foundation, Hyundai Hope On Wheels, and a research grant from Oncolytics Biotech Inc.

Publisher Copyright:
© 2020, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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