The mutation in the ATP-binding region of JAK1, identified in human uterine leiomyosarcomas, results in defective interferon-gamma inducibility of TAP1 and LMP2.
The presentation of human leukocyte antigens (HLA) class I requires the coordinated expression of numerous components involved in antigen presentation. Tumor cells may alter the antigen presentation by HLA class I, allowing them to evade antitumor immunity. In many cases, the lack of antigen presentation can be attributed to the downregulation of genes needed for antigen processing, such as the transporters associated with antigen processing (TAP) 1, and the proteasomal component, low molecular weight proteins (LMP) 2. The TAP1 and LMP2 genes are transcribed from a shared bidirectional promoter containing an interferon (IFN)-gamma-response factor element; thus, the IFN-gamma-signal strongly induces both TAP1 and LMP2 expression. Low molecular weight proteins2-deficient mice exhibited the development of uterine leiomyosarcomas. Here, the differential responsiveness to IFN-gamma of the SKN human uterine leiomyosarcomas cell line was investigated. We now identify the G871E mutation in the ATP-binding region of Janus kinases 1, suggesting that the loss of TAP1 and LMP2 induction is a defect in the earliest steps of the IFN-gamma-signal pathway, resulting in the inability of SKN cells to upregulate the antigen-processing pathway. Understanding the mechanisms by which these tumors circumvent cytokine signalling, thereby evading antitumor-specific immunity, would greatly aid the efficacy of immunotherapy for treating uterine leiomyosarcomas.
Department of Immunology and Infectious Diseases, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan. takuma-h@sch.md.shinshu-u.ac.jp
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Hayashi
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Kobayashi
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Kohsaka
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Sano
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology; D000255:Adenosine Triphosphate / Q000235:genetics / Q000276:immunology; D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005805:Genes, MHC Class I / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology; D053613:Janus Kinase 1; D007889:Leiomyoma / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D051379:Mice; D018345:Mice, Knockout; D017354:Point Mutation / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D017434:Protein Structure, Tertiary / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000276:immunology; D012509:Sarcoma / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects / Q000235:genetics* / Q000276:immunology; D014594:Uterine Neoplasms / Q000235:genetics* / Q000276:immunology / Q000628:therapy
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; D000951:Antigens, Neoplasm; C073119:TAP1 protein, human; C071313:LMP-2 protein; D007371:Interferon-gamma; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D003546:Cysteine Endopeptidases