title: TGF-β-inducible microRNA-183 silences tumor-associated natural killer cells.
abstract: Transforming growth factor β1 (TGF-β), enriched in the tumor microenvironment and broadly immunosuppressive, inhibits natural killer (NK) cell function by yet-unknown mechanisms. Here we show that TGF-β-treated human NK cells exhibit reduced tumor cytolysis and abrogated perforin polarization to the immune synapse. This result was accompanied by loss of surface expression of activating killer Ig-like receptor 2DS4 and NKp44, despite intact cytoplasmic stores of these receptors. Instead, TGF-β depleted DNAX activating protein 12 kDa (DAP12), which is critical for surface NK receptor stabilization and downstream signal transduction. Mechanistic analysis revealed that TGF-β induced microRNA (miR)-183 to repress DAP12 transcription/translation. This pathway was confirmed with luciferase reporter constructs bearing the DAP12 3' untranslated region as well as in human NK cells by use of sense and antisense miR-183. Moreover, we documented reduced DAP12 expression in tumor-associated NK cells in lung cancer patients, illustrating this pathway to be consistently perturbed in the human tumor microenvironment.
authors.affiliation: Departments of Immunology, Molecular Oncology, Thoracic Oncology, Cancer Epidemiology, and Anatomic Pathology, Moffitt Cancer Center, Tampa, FL 33612.
authors.forename: Sarah S
authors.initials: SS
authors.lastname: Donatelli
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Zhou
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Gilvary
authors.forename: Erika A
authors.initials: EA
authors.lastname: Eksioglu
authors.forename: Xianghong
authors.initials: X
authors.lastname: Chen
authors.forename: W Douglas
authors.initials: WD
authors.lastname: Cress
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Schabath
authors.forename: Domenico
authors.initials: D
authors.lastname: Coppola
authors.forename: Sheng
authors.initials: S
authors.lastname: Wei
authors.forename: Julie Y
authors.initials: JY
authors.lastname: Djeu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008156:Luciferases; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009369:Neoplasms / Q000276:immunology*; D055607:Receptors, Natural Killer Cell / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000276:immunology* / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C533449:MIRN183 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D055607:Receptors, Natural Killer Cell; C110546:TYROBP protein, human; D016212:Transforming Growth Factor beta; D008156:Luciferases
keywords: immune suppression; non-small cell lung cancer; posttranscriptional silencing