APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy
Open Access
- 7 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-14
- https://doi.org/10.1038/s41467-020-14568-7
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.Funding Information
- U.S. Department of Health & Human Services | National Institutes of Health (R01 CA175386, R01 CA108961)
- U.S. Department of Health & Human Services | National Institutes of Health
This publication has 68 references indexed in Scilit:
- An APOBEC cytidine deaminase mutagenesis pattern is widespread in human cancersNature Genetics, 2013
- Evidence for APOBEC3B mutagenesis in multiple human cancersNature Genetics, 2013
- APOBEC3B is an enzymatic source of mutation in breast cancerNature, 2013
- Mutational Processes Molding the Genomes of 21 Breast CancersCell, 2012
- Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanomaNature Biotechnology, 2012
- Activating Systemic T-Cell Immunity Against Self Tumor Antigens to Support Oncolytic Virotherapy with Vesicular Stomatitis VirusHuman Gene Therapy, 2011
- The Role of Amino-Terminal Sequences in Cellular Localization and Antiviral Activity of APOBEC3BJournal of Virology, 2011
- Monitoring of Tumor Growth and Post‐Irradiation Recurrence in a Diffuse Intrinsic Pontine Glioma Mouse ModelBrain Pathology, 2010
- Eukaryotic cold shock domain proteins: highly versatile regulators of gene expressionBioEssays, 2010
- Safety and Immunogenicity of Tyrosinase DNA Vaccines in Patients with MelanomaMolecular Therapy, 2007