title: Identification and characterization of enhancer agonist human cytotoxic T-cell epitopes of the human papillomavirus type 16 (HPV16) E6/E7.
abstract: Human papillomavirus (HPV) is associated with the etiology of cervical carcinoma, head and neck squamous cell carcinoma, and several other cancer types. Vaccines directed against HPV virus-like particles and coat proteins have been extremely successful in the prevention of cervical cancer through the activation of host HPV-specific antibody responses; however, HPV-associated cancers remain a major public health problem. The development of a therapeutic vaccine will require the generation of T-cell responses directed against early HPV proteins (E6/E7) expressed in HPV-infected tumor cells. Clinical studies using various vaccine platforms have demonstrated that both HPV-specific human T cells can be generated and patient benefit can be achieved. However, no HPV therapeutic vaccine has been approved by the Food and Drug Administration to date. One method of enhancing the potential efficacy of a therapeutic vaccine is the generation of agonist epitopes. We report the first description of enhancer cytotoxic T lymphocyte agonist epitopes for HPV E6 and E7. While the in silico algorithm revealed six epitopes with potentially improved binding to human leukocyte antigen-A2 allele (HLA-A2)-Class I, 5/6 demonstrated enhanced binding to HLA-Class I in cell-based assays and only 3/6 had a greater ability to activate HPV-specific T cells which could lyse tumor cells expressing native HPV, compared to their native epitope counterparts. These agonist epitopes have potential for use in a range of HPV therapeutic vaccine platforms and for use in HPV-specific adoptive T- or natural killer-cell platforms.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA.
authors.forename: Kwong Y
authors.initials: KY
authors.lastname: Tsang
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Fantini
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA.
authors.forename: Romaine I
authors.initials: RI
authors.lastname: Fernando
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Palena
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: David
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Hodge
authors.affiliation: Etubics Corporation, 41 West Harrison Street, Suite 100, Seattle, WA 98119, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Gabitzsch
authors.affiliation: Etubics Corporation, 41 West Harrison Street, Suite 100, Seattle, WA 98119, USA.
authors.forename: Frank R
authors.initials: FR
authors.lastname: Jones
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 8B09, Bethesda, MD 20892, USA. Electronic address: js141c@nih.gov.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
mesh_terms: D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D009856:Oncogene Proteins, Viral / Q000276:immunology* / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000276:immunology* / Q000378:metabolism
chemical_list: C068651:E6 protein, Human papillomavirus type 16; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16
keywords: Agonist epitope; CTLs; E6; E7; HPV16