APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy.
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Date
2020-02-07Author
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
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Killer Cells, Natural
T-Lymphocytes
Cell Line, Tumor
Animals
Mice, Inbred C57BL
Humans
Melanoma
Melanoma, Experimental
Cytidine Deaminase
Cancer Vaccines
Minor Histocompatibility Antigens
Epitopes
Immunotherapy
Tumor Escape
Drug Resistance, Neoplasm
Mutation
Female
Research team
Targeted Therapy
Translational Immunotherapy
Language
eng
Date accepted
2020-01-21
License start date
2020-02-07
Citation
Nature communications, 2020, 11 (1), pp. 790 - ?
Publisher
NATURE PUBLISHING GROUP