Abstract
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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 3
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ATP-Binding Cassette Transporters / immunology
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Amino Acid Transport Systems*
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Antigens, Neoplasm / biosynthesis
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / immunology*
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DNA, Complementary / genetics
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Exoribonucleases*
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Fungal Proteins / immunology
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Gene Expression Regulation, Neoplastic* / drug effects
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Genes, MHC Class I*
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HLA Antigens / biosynthesis
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HLA Antigens / genetics
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HLA Antigens / immunology*
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Humans
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Immunophenotyping
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Immunotherapy, Adoptive
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Interferon-gamma / pharmacology
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Interleukin-12 / pharmacology
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Interleukin-2 / pharmacology
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Killer Cells, Natural / immunology
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Lymphocytes, Tumor-Infiltrating / immunology
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Melanoma / genetics
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Melanoma / immunology*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / deficiency
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology
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Recombinant Proteins / pharmacology
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Saccharomyces cerevisiae Proteins
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T-Lymphocytes, Cytotoxic / immunology
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Trans-Activators / immunology
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beta 2-Microglobulin / biosynthesis
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beta 2-Microglobulin / deficiency
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beta 2-Microglobulin / genetics
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beta 2-Microglobulin / immunology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 3
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ATP-Binding Cassette Transporters
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Amino Acid Transport Systems
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Antigens, Neoplasm
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DNA, Complementary
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Fungal Proteins
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HLA Antigens
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Interleukin-2
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Neoplasm Proteins
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Recombinant Proteins
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Saccharomyces cerevisiae Proteins
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TAT2 protein, S cerevisiae
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Trans-Activators
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beta 2-Microglobulin
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TAP2 protein, human
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Interleukin-12
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Interferon-gamma
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Exoribonucleases