title: CD8 T-cell recognition of human 5T4 oncofetal antigen.
abstract: The 5T4 oncofetal antigen is expressed by a wide variety of human carcinomas, including colorectal, ovarian and gastric carcinomas. The restricted expression of 5T4 on tumor tissues as well as its implication in tumor progression and bad prognosis makes 5T4 a promising new candidate for immunotherapy. An MVA vaccine encoding 5T4 antigen has been successfully evaluated in preclinical studies in a murine tumor model. Here, we report the generation of human CD8 T cells specific for the 5T4 antigen by stimulation with autologous monocyte derived DC infected with a replication defective adenovirus encoding the 5T4 cDNA (Ad5T4). Analysis of several donors confirms a repertoire of such CD8 responses. In a parallel approach, incorporating the results of proteasome-mediated digestion of 5T4 derived 35-mer peptides and the potential high affinity epitopes predicted by a computer-based algorithm, we identified 8 putative HLA-A*0201-presented CD8 MHC class I epitopes of 5T4 antigen. Two of these generated specific CD8 T cells after restimulation with peptide loaded autologous DC and assay by cytotoxicity and IFN gamma ELISPOT. Moreover these particular peptide generated T cells recognized naturally 5T4 positive tumor cells only if they expressed HLA-A*0201 as judged by IFN gamma ELISPOT or ELISA. Also, HLA-A*0201 CD8 T cells recognized these peptides in a DC-Ad5T4 polyclonal response. In conclusion, there is a repertoire of CD8 T cell recognition of 5T4 in normal human donors and some candidate HLA-A*0201 epitopes have been identified.
authors.affiliation: Immunology Group, Paterson Institute for Cancer Research, Christie Hospital NHS Trust, Manchester, United Kingdom.
authors.forename: Lucy J C
authors.initials: LJ
authors.lastname: Smyth
authors.forename: Eyad
authors.initials: E
authors.lastname: Elkord
authors.forename: Taher E I
authors.initials: TE
authors.lastname: Taher
authors.forename: Hui-Rong
authors.initials: HR
authors.lastname: Jiang
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Burt
authors.forename: Alison
authors.initials: A
authors.lastname: Clayton
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.forename: Arnoud
authors.initials: A
authors.lastname: de Ru
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Said
authors.initials: S
authors.lastname: Dermime
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hawkins
authors.forename: Peter L
authors.initials: PL
authors.lastname: Stern
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D000939:Epitopes / Q000276:immunology; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D010446:Peptide Fragments; C031192:oncofetal antigens; D007371:Interferon-gamma; D046988:Proteasome Endopeptidase Complex