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APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy

2020; Nature Portfolio; Volume: 11; Issue: 1 Linguagem: Inglês

10.1038/s41467-020-14568-7

2041-1723

Christopher B. Driscoll, Matthew Schuelke, Timothy Kottke, Jill Thompson, Phonphimon Wongthida, Jason M. Tonne, Amanda L. Huff, Amber Miller, Kevin G. Shim, Amy M. Molan, Cynthia Wetmore, Peter J. Selby, Adel Samson, Kevin J. Harrington, Hardev Pandha, Alan Melcher, José S. Pulido, Reuben S. Harris, Laura Evgin, Richard G. Vile,

CAR-T cell therapy research

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.