title: Analysis of the major histocompatibility complex class I antigen presentation machinery in normal and malignant renal cells: evidence for deficiencies associated with transformation and progression.
abstract: In some human tumors, reduced or defective MHC class I surface expression has been attributed to functional deficiencies of the genes of the antigen-processing machinery, the proteasome subunits low molecular weight (LMP)-2 and LMP-7, as well as the peptide transporters associated with antigen processing (TAP)-1 and TAP-2. Using normal epithelial kidney cells (MZ1851NN) and renal cell carcinoma cell lines established from the primary tumor (MZ1851RC) and a lymph node metastasis (MZ1851LN) of the same patient, we investigated whether the modulation of MHC class I antigens, TAP and LMP molecules, occurs during transformation and subsequent progression. The mRNA and protein expression of MHC class I heavy and light chain TAP and LMP was strongly reduced in MZ1851RC when compared to the corresponding normal kidney cells MZ1851NN, and this suppression was even more pronounced in the metastatic cell line MZ1851LN. In addition, the activity of the TAP molecules, as measured by peptide translocation assays, was also markedly diminished in MZ1851RC compared to MZ1851NN cells and was further down-regulated in cells of the metastatic lesion. MHC class I surface expression was enhanced by either culturing MZ1851RC and MZ1851LN cells at 26 degrees C instead of 37 degrees C or by incubation of both cell lines with class I-specific binding peptides, whereas MHC class I surface expression of MZ1851NN cells was not affected under these culture conditions. IFN-alpha and in particular IFN-gamma treatment enhances the steady-state mRNA and/or protein levels of TAP, LMP, and MHC class I genes of MZ1851 cell lines but had no additional effect on the stability of MCH class I surface expression. These data indicate that malignant transformation and subsequent in vivo selection of renal tubular cells can lead to the recovery of carcinoma cells that show stable expression of an immune escape phenotype. Deficiencies associated with this phenotype involve all levels of the MHC class I-restricted antigen presentation machinery, are at least partially reversible by IFN treatment, and are even more pronounced in cells that had acquired metastatic potential.
authors.affiliation: Johannes Gutenberg-Universitat, III. Medizinische Klinik, Abteilung fur Hamatologie/Onkologie, Mainz, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Seliger
authors.forename: A
authors.initials: A
authors.lastname: Hohne
authors.forename: A
authors.initials: A
authors.lastname: Knuth
authors.forename: H
authors.initials: H
authors.lastname: Bernhard
authors.forename: T
authors.initials: T
authors.lastname: Meyer
authors.forename: R
authors.initials: R
authors.lastname: Tampe
authors.forename: F
authors.initials: F
authors.lastname: Momburg
authors.forename: C
authors.initials: C
authors.lastname: Huber
mesh_terms: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000595:Amino Acid Sequence; D000906:Antibodies; D002292:Carcinoma, Renal Cell / Q000276:immunology*; D002460:Cell Line; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis*; D005434:Flow Cytometry; D015870:Gene Expression; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis*; D006801:Humans; D007370:Interferon Type I / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000276:immunology*; D007680:Kidney Neoplasms / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008207:Lymphatic Metastasis; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009842:Oligopeptides / Q000138:chemical synthesis / Q000276:immunology; D011509:Proteoglycans / Q000096:biosynthesis; D011994:Recombinant Proteins; D012016:Reference Values; D014407:Tumor Cells, Cultured
chemical_list: D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000906:Antibodies; D016326:Extracellular Matrix Proteins; D015395:Histocompatibility Antigens Class I; D007370:Interferon Type I; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; D011509:Proteoglycans; D011994:Recombinant Proteins; C073119:TAP1 protein, human