title: MHC class I-presented lung cancer-associated tumor antigens identified by immunoproteomics analysis are targets for cancer-specific T cell response.
abstract: The development of potent cancer vaccines for common malignancies such as lung cancer requires identification of suitable target antigens. We hypothesized that peptide epitopes naturally presented by MHC class I molecules on the surface of cancer cells would be the most relevant targets. We used LC/MS/MS analysis and identified 68 MHC class I-presented peptides from lung cancer cells. Using the criteria of strong consensus for HLA-A2 binding and relevance of the source proteins to malignant phenotype, we selected 8 peptides for functional characterization. These peptides, with a range of binding affinities, were confirmed to stabilize HLA-A2 molecules and were used to activate peptide-specific CTLs that efficiently recognized lung tumor cells. No correlation between the transcript levels of the source proteins and the extent of peptide-specific T cell recognition of lung cancer cells was observed. Furthermore, the peptide specific CTLs failed to recognize HLA-A2+ normal lung cells despite expression of the mRNA encoding the source proteins from which the peptides were derived. We conclude that MHC class I associated peptide epitopes are a more relevant source of authentic tumor antigens than over-expressed proteins and the identified peptides may be used as antigens for therapeutic vaccine strategies to treat lung cancer.
authors.affiliation: Immunotope Inc., 3805 Old Easton Road, Doylestown, PA 18902, USA.
authors.forename: Vivekananda
authors.initials: V
authors.lastname: Shetty
authors.forename: Gomathinayagam
authors.initials: G
authors.lastname: Sinnathamby
authors.forename: Zacharie
authors.initials: Z
authors.lastname: Nickens
authors.forename: Punit
authors.initials: P
authors.lastname: Shah
authors.forename: Julie
authors.initials: J
authors.lastname: Hafner
authors.forename: Lisa
authors.initials: L
authors.lastname: Mariello
authors.forename: Shivali
authors.initials: S
authors.lastname: Kamal
authors.forename: Gordana
authors.initials: G
authors.lastname: Vlahović
authors.forename: H Kim
authors.initials: HK
authors.lastname: Lyerly
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Ramila
authors.initials: R
authors.lastname: Philip
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D005260:Female; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism* / Q000628:therapy; D008297:Male; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D040901:Proteomics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D015789:HLA-A2 Antigen; D010455:Peptides