Molecular and functional phenotypes of melanoma cells with abnormalities in HLA class I antigen expression.
Analysis of melanoma cell lines with abnormalities in HLA Class I antigen expression has identified two serological phenotypes caused by distinct molecular defects. One is characterized by lack of HLA Class I antigen expression which is not induced by IFN-gamma or by incubation at 25 degrees C for 24 hrs. This phenotype reflects structural changes in the beta(2)m gene which interfere with its transcription and/or translation or result in the synthesis of a defective beta(2)-mu polypeptide unable to associate with HLA Class I heavy chains. The other phenotype manifests very low HLA Class I antigen expression which is enhanced by IFN-gamma or by incubation at 25 degrees C for 24 hrs. This phenotype reflects abnormalities in TAP heterodimer expression, which cause defects in stable assembly and intracellular transport of the HLA Class I antigen trimolecular complex. Loss of HLA Class I antigens renders melanoma cells resistant to lysis by HLA Class I antigen-restricted cytotoxic T cells which specifically recognize melanoma associated antigens. Therefore, abnormalities in HLA Class I antigen expression may have a negative impact on the outcome of T cell based immunotherapy. Characterization of the molecular defects underlying loss of HLA Class I antigens may suggest approaches to restore their expression. Inclusion of these approaches in the protocols of T cell based immunotherapy may improve its efficacy.
Wang
Z
Z
Department of Microbiology & Immunology, New York Medical College, Valhalla, USA.
Margulies
L
L
Hicklin
D J
DJ
Ferrone
S
S
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters / Q000276:immunology; D026905:Amino Acid Transport Systems; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018076:DNA, Complementary / Q000235:genetics; D005095:Exoribonucleases; D005656:Fungal Proteins / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005805:Genes, MHC Class I; D006680:HLA Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D029701:Saccharomyces cerevisiae Proteins; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D015534:Trans-Activators / Q000276:immunology; D001613:beta 2-Microglobulin / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000276:immunology
D000071450:ATP Binding Cassette Transporter, Subfamily B, Member 3; D018528:ATP-Binding Cassette Transporters; D026905:Amino Acid Transport Systems; D000951:Antigens, Neoplasm; D018076:DNA, Complementary; D005656:Fungal Proteins; D006680:HLA Antigens; D007376:Interleukin-2; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C429825:TAT2 protein, S cerevisiae; D015534:Trans-Activators; D001613:beta 2-Microglobulin; C071692:TAP2 protein, human; D018664:Interleukin-12; D007371:Interferon-gamma; D005095:Exoribonucleases