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 and Richard G. Vile ()
Additional contact information
Christopher B. Driscoll: Mayo Clinic
Matthew R. Schuelke: Mayo Clinic
Timothy Kottke: Mayo Clinic
Jill M. Thompson: Mayo Clinic
Phonphimon Wongthida: Mayo Clinic
Jason M. Tonne: Mayo Clinic
Amanda L. Huff: Mayo Clinic
Amber Miller: Mayo Clinic
Kevin G. Shim: Mayo Clinic
Amy Molan: University of Minnesota
Cynthia Wetmore: Phoenix Children’s
Peter Selby: St James’ University Hospital, University of Leeds
Adel Samson: St James’ University Hospital, University of Leeds
Kevin Harrington: The Institute of Cancer Research
Hardev Pandha: University of Surrey
Alan Melcher: The Institute of Cancer Research
Jose S. Pulido: Mayo Clinic
Reuben Harris: University of Minnesota
Laura Evgin: Mayo Clinic
Richard G. Vile: Mayo Clinic

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14568-7

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