title: Identification and characterization of a cytotoxic T-lymphocyte agonist epitope of brachyury, a transcription factor involved in epithelial to mesenchymal transition and metastasis.
abstract: The transcription factor brachyury is a major driver of epithelial to mesenchymal transition in human carcinoma cells. It is overexpressed in several human tumor types versus normal adult tissues, except for testes and thyroid. Overexpression is associated with drug resistance and poor prognosis. Previous studies identified a brachyury HLA-A2 cytotoxic T-lymphocyte epitope. The studies reported here describe an enhancer epitope of brachyury. Compared to the native epitope, the agonist epitope: (a) has enhanced binding to MHC class I, (b) increased the IFN-γ production from brachyury-specific T cells, (c) generated brachyury-specific T cells with greater levels of perforin and increased proliferation, (d) generated T cells more proficient at lysing human carcinoma cells endogenously expressing the native epitope, and (e) achieved greater brachyury-specific T-cell responses in vivo in HLA-A2 transgenic mice. These studies also report the generation of a heat-killed recombinant Saccharomyces cerevisiae (yeast) vector expressing the full-length brachyury gene encoding the agonist epitope. Compared to yeast-brachyury (native) devoid of the agonist epitope, the yeast-brachyury (agonist) enhanced the activation of brachyury-specific T cells, which efficiently lysed human carcinoma cells. In addition to providing the rationale for the recombinant yeast-brachyury (agonist) as a potential vaccine in cancer therapy, these studies also provide the rationale for the use of the agonist in (a) dendritic cell (DC) vaccines, (b) adjuvant or liposomal vaccines, (c) recombinant viral and/or bacterial vaccines, (d) protein/polypeptide vaccines, (e) activation of T cells ex vivo in adoptive therapy protocols, and (f) generation of genetically engineered targeted T cells.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, MSC 1750, Bethesda, MD, 20892, USA.
authors.forename: Jo A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Caroline
authors.initials: C
authors.lastname: Jochems
authors.forename: Benjamin
authors.initials: B
authors.lastname: Boyerinas
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fallon
authors.forename: John W
authors.initials: JW
authors.lastname: Greiner
authors.forename: Claudia
authors.initials: C
authors.lastname: Palena
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Rodell
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: Kwong-Yok
authors.initials: KY
authors.lastname: Tsang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D005326:Fetal Proteins / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D020825:T-Box Domain Proteins / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000098908:Brachyury Protein
chemical_list: D018984:Epitopes, T-Lymphocyte; D005326:Fetal Proteins; D020825:T-Box Domain Proteins; D000098908:Brachyury Protein