title: The antigen processing machinery of class I human leukocyte antigens: linked patterns of gene expression in neoplastic cells.
abstract: The ultimate outcome of an immune response (escape or surveillance) depends on a delicate balance of opposing signals delivered by activating and inhibitory immune receptors expressed by cytotoxic T lymphocytes and natural killer cells. In this light, loss and down-regulation of human leukocyte antigens (HLA) class I molecules, while important for keeping tumors below the T-cell detection levels, may incite recognition of missing self. Conversely, the maintenance of normal levels of expression (or even up-regulation) may be favorable to tumors, at least in certain cases. In this study, we took advantage of a previously characterized panel of 15 early passage tumor cell lines (mainly from melanoma and lung carcinoma lesions) enriched with class I-low phenotypes. These cells were systematically characterized by Northern and/or Western blotting (e.g., mini-transcriptome/mini-proteome analysis) for the expression of HLA-A, -B, -C, beta(2)-microglobulin, and the members of the "antigen processing machinery" of class I molecules (LMP2, LMP7, TAP1, TAP2, tapasin, calreticulin, calnexin, and ERp57). In addition, we established four pairs of cultures, each comprising melanoma cells and normal melanocytes from the same patient. We found that approximately 97% of the 185 tested gene products are expressed (although often weakly), and in many cases coordinately regulated in 18 of 19 tumor cell lines. Linked expression patterns could be hierarchically arranged by statistical methods and graphically described as a class I HLA "coordinome." Deviations (both down- and up-regulation) from the coordinome expression pattern inherited from the normal, paired melanocyte counterpart, were allowed but limited in magnitude, as if melanoma cells were trying to keep a "low profile" HLA phenotype. We conclude that irreversible HLA loss is a rare event, and class I expression in tumor cells almost invariably results from reversible gene regulatory (rather than gene disruption) events.
authors.affiliation: Laboratory of Immunology, Regina Elena Cancer Institute CRS, 00158 Rome, Italy.
authors.forename: Ezio
authors.initials: E
authors.lastname: Giorda
authors.forename: Leonardo
authors.initials: L
authors.lastname: Sibilio
authors.forename: Aline
authors.initials: A
authors.lastname: Martayan
authors.forename: Sara
authors.initials: S
authors.lastname: Moretti
authors.forename: Irene
authors.initials: I
authors.lastname: Venturo
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.forename: Giovan Battista
authors.initials: GB
authors.lastname: Ferrara
authors.forename: Sandra
authors.initials: S
authors.lastname: Cappellacci
authors.forename: Laura
authors.initials: L
authors.lastname: Eibenschutz
authors.forename: Caterina
authors.initials: C
authors.lastname: Catricalà
authors.forename: Paola
authors.initials: P
authors.lastname: Grammatico
authors.forename: Patrizio
authors.initials: P
authors.lastname: Giacomini
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D016130:Immunophenotyping; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I