APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy.
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Embargo End Date
ICR Authors
Authors
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
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
Document Type
Journal Article
Date
2020-02-07
Date Accepted
2020-01-21
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.
Citation
Nature communications, 2020, 11 (1), pp. 790 - ?
Source Title
Publisher
NATURE PORTFOLIO
ISSN
2041-1723
eISSN
2041-1723
Research Team
Targeted Therapy
Translational Immunotherapy
Translational Immunotherapy