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- Title
APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy.
- Authors
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.
- 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. DNA mutations induced by dysregulated APOBEC3 expression are associated with tumour-progression and therapeutic resistance, but also with the generation of neoepitopes. Here, the authors show that APOBEC3 function can be exploited in a vaccine setting to generate heteroclitic neoepitopes, enhancing sensitivity to immunotherapy.
- Subjects
CANCER vaccines; CYTIDINE deaminase; T cells; IMMUNOTHERAPY; GENETIC load; PROGRAMMED cell death 1 receptors
- Publication
Nature Communications, 2020, Vol 11, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-020-14568-7