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

doi:10.1038/s41467-020-14568-7

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

Molecular Biology (BMBB)

Research output: Contribution to journal › Article › peer-review

7 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 language	English (US)
Article number	790
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-14568-7
State	Published - Feb 7 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).

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Driscoll, C. B., Schuelke, M. R., Kottke, T., Thompson, J. M., Wongthida, P., Tonne, J. M., Huff, A. L., Miller, A., Shim, K. G., Molan, A., Wetmore, C., Selby, P., Samson, A., Harrington, K., Pandha, H., Melcher, A., Pulido, J. S., Harris, R., Evgin, L., & Vile, R. G. (2020). APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy. Nature communications, 11(1), [790]. https://doi.org/10.1038/s41467-020-14568-7

APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy. / Driscoll, Christopher B.; Schuelke, Matthew R.; Kottke, Timothy; Thompson, Jill M.; Wongthida, Phonphimon; Tonne, Jason M.; Huff, Amanda L.; Miller, Amber; Shim, Kevin G.; Molan, Amy; Wetmore, Cynthia; Selby, Peter; Samson, Adel; Harrington, Kevin; Pandha, Hardev; Melcher, Alan; Pulido, Jose S.; Harris, Reuben; Evgin, Laura; Vile, Richard G.

In: Nature communications, Vol. 11, No. 1, 790, 07.02.2020.

Research output: Contribution to journal › Article › peer-review

Driscoll, CB, Schuelke, MR, Kottke, T, Thompson, JM, Wongthida, P, Tonne, JM, Huff, AL, Miller, A, Shim, KG, Molan, A, Wetmore, C, Selby, P, Samson, A, Harrington, K, Pandha, H, Melcher, A, Pulido, JS, Harris, R, Evgin, L & Vile, RG 2020, 'APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy', Nature communications, vol. 11, no. 1, 790. https://doi.org/10.1038/s41467-020-14568-7

Driscoll, Christopher B. ; Schuelke, Matthew R. ; Kottke, Timothy ; Thompson, Jill M. ; Wongthida, Phonphimon ; Tonne, Jason M. ; Huff, Amanda L. ; Miller, Amber ; Shim, Kevin G. ; Molan, Amy ; Wetmore, Cynthia ; Selby, Peter ; Samson, Adel ; Harrington, Kevin ; Pandha, Hardev ; Melcher, Alan ; Pulido, Jose S. ; Harris, Reuben ; Evgin, Laura ; Vile, Richard G. / APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy. In: Nature communications. 2020 ; Vol. 11, No. 1.

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title = "APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy",

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.",

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

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{\textquoteright}Hara Foundation, Hyundai Hope On Wheels, and a research grant from Oncolytics Biotech Inc. Publisher Copyright: {\textcopyright} 2020, The Author(s).",

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AU - Wongthida, Phonphimon

AU - Tonne, Jason M.

AU - Huff, Amanda L.

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AU - Shim, Kevin G.

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AU - Selby, Peter

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N2 - 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.

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

Abstract

Bibliographical note

PubMed: MeSH publication types

UN SDGs

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