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

Publication date: Feb 07, 2020

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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Driscoll, C.B., Schuelke, Kottke, T., Thompson, J.M., Wongthida, P., Tonne, J.M., Huff, A.L., Miller, A., Shim, K.G., Molan, A., Wetmore, C., Selby, P., Samson, A., Harrington, K., Pandha, H., Melcher, A., Pulido, J.S., Harris, R., Evgin, L., and Vile, R.G. APOBEC3B-mediated corruption of the tumor cell immunopeptidome induces heteroclitic neoepitopes for cancer immunotherapy. 25743. 2020 Nat Commun (11):1.

Concepts Keywords
Chemotherapy Corruption tumor
Cross Tumors
Epitope Prime anti tumor
Evolution Overexpression APOBEC3B tumors
HEAT Parental unmodified tumors
Immune Checkpoint Blockade Immunotherapy
Immunogenicity Chemotherapy
Immunotherapy Medical specialties
Melanoma Branches of biology
Murine Medicine
Plasticity Immunology
Prime Genomics
Subcutaneous Applied genetics
Tumor Biotechnology
Vaccine Medical genetics
Viral APOBEC3B
Vivo Neoepitope
Immunogenicity
Chemotherapy

Semantics

Type Source Name
disease MESH tumor
drug DRUGBANK Cytidine
disease MESH melanoma
pathway KEGG Melanoma
drug DRUGBANK Amber
disease MESH noma
drug DRUGBANK Coenzyme M
disease MESH Herpes Simplex
drug DRUGBANK Deoxythymidine
disease MESH stop codon
disease MESH tumor escape
disease MESH growth
disease MESH autoimmunity
drug DRUGBANK Caffeine
disease MESH infection
drug DRUGBANK Amino acids
disease MESH **p
drug DRUGBANK Proline
drug DRUGBANK Pentaerythritol tetranitrate
disease MESH frameshift mutations
drug DRUGBANK Puromycin
drug DRUGBANK Methylergometrine
drug DRUGBANK Heparin
drug DRUGBANK Phosphate ion
drug DRUGBANK Nitrogen
disease MESH carcinoma
disease MESH weight loss
drug DRUGBANK Dinoprostone
drug DRUGBANK Fluorescein
drug DRUGBANK Urea
disease MESH glioblastoma
disease MESH immuno
disease MESH breast cancer
pathway KEGG Breast cancer
disease MESH lung cancer
drug DRUGBANK Gold
disease MESH neuroblastoma
disease MESH small cell lung cancer
pathway KEGG Small cell lung cancer
disease MESH tick borne encephalitis
disease MESH metastasis
disease MESH diffuse intrinsic pontine glioma

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