title: Levels of specific peptide-HLA class I complex predicts tumor cell susceptibility to CTL killing.
abstract: Recognition of tumor-associated Ags (TAAs) on tumor cells by CTLs and the subsequent tumor cell death are assumed to be dependent on TAA protein expression and to correlate directly with the level of peptide displayed in the binding site of the HLA class I molecule. In this study we evaluated whether the levels of Her-2/neu protein expression on human tumor cell lines directly correlate with HLA-A*0201/Her2/neu peptide presentation and CTL recognition. We developed a TCR mimic (TCRm) mAb designated 1B8 that specifically recognizes the HLA-A2.1/Her2/neu peptide (369-377) (Her2(369)-A2) complex. TCRm mAb staining intensity varied for the five human tumor cell lines analyzed, suggesting quantitative differences in levels of the Her2(369)-A2 complex on these cells. Analysis of tumor cell lines pretreated with IFN-gamma and TNF-alpha for Her2/neu protein and HLA-A2 molecule expression did not reveal a direct correlation between the levels of Her2/neu Ag, HLA-A2 molecule, and Her2(369)-A2 complex expression. However, compared with untreated cells, cytokine-treated cell lines showed an increase in Her2(369)-A2 epitope density that directly correlated with enhanced tumor cell death (p = 0.05). Although a trend was observed between tumor cell lysis and the level of the Her2(369)-A2 complex for untreated cells, the association was not significant. These findings suggest that tumor cell susceptibility to CTL-mediated lysis may be predicted based on the level of specific peptide-MHC class I expression rather than on the total level of TAA expression. Further, these studies demonstrate the potential of the TCRm mAb for validation of endogenous HLA-peptide epitopes on tumor cells.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA. jon.weidanz@ttuhsc.edu
authors.forename: Jon A
authors.initials: JA
authors.lastname: Weidanz
authors.forename: Tiffany
authors.initials: T
authors.lastname: Nguyen
authors.forename: Tito
authors.initials: T
authors.lastname: Woodburn
authors.forename: Francisca A
authors.initials: FA
authors.lastname: Neethling
authors.forename: Maurizio
authors.initials: M
authors.lastname: Chiriva-Internati
authors.forename: William H
authors.initials: WH
authors.lastname: Hildebrand
authors.forename: Joseph
authors.initials: J
authors.lastname: Lustgarten
mesh_terms: D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology*; D045744:Cell Line, Tumor; D015395:Histocompatibility Antigens Class I / Q000032:analysis*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009369:Neoplasms / Q000276:immunology* / Q000473:pathology; D010455:Peptides / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I; D007371:Interferon-gamma; D010455:Peptides; D018719:Erb-b2 Receptor Tyrosine Kinases; D014409:Tumor Necrosis Factor-alpha