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.

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Item Type:	Article
Authors/Creators:	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 https://orcid.org/0000-0002-3081-7850 Harrington, K Pandha, H Melcher, A Pulido, JS Harris, R Evgin, L Vile, RG
Copyright, Publisher and Additional Information:	© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Dates:	Accepted: 21 January 2020 Published (online): 7 February 2020 Published: 7 February 2020
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Biomarkers and Therapy (Leeds)
Funding Information:	Funder Grant number Cancer Research UK A29039
Depositing User:	Symplectic Publications
Date Deposited:	30 Jan 2020 15:19
Last Modified:	25 Jun 2023 22:08
Status:	Published
Publisher:	Nature Research
Identification Number:	10.1038/s41467-020-14568-7
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:156242

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APOBEC3B-mediated Corruption of the Tumor Cell Immunopeptidome Induces Heteroclitic Neoepitopes for Cancer Immunotherapy

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