title: Loss of STAT3 in murine NK cells enhances NK cell-dependent tumor surveillance.
abstract: The members of the signal transducer and activator of transcription (STAT) family of transcription factors modulate the development and function of natural killer (NK) cells. NK cell-mediated tumor surveillance is particularly important in the body's defense against hematological malignancies such as leukemia. STAT3 inhibitors are currently being developed, although their potential effects on NK cells are not clear. We have investigated the function of STAT3 in NK cells with Stat3(Δ/Δ)Ncr1-iCreTg mice, whose NK cells lack STAT3. In the absence of STAT3, NK cells develop normally and in normal numbers, but display alterations in the kinetics of interferon-γ (IFN-γ) production. We report that STAT3 directly binds the IFN-γ promoter. In various in vivo models of hematological diseases, loss of STAT3 in NK cells enhances tumor surveillance. The reduced tumor burden is paralleled by increased expression of the activating receptor DNAM-1 and the lytic enzymes perforin and granzyme B. Our findings imply that STAT3 inhibitors will stimulate the cytolytic activity of NK cells against leukemia, thereby providing an additional therapeutic benefit.
authors.affiliation: Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, and.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Gotthardt
authors.affiliation: Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, and.
authors.forename: Eva M
authors.initials: EM
authors.lastname: Putz
authors.affiliation: Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, and.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Straka
authors.affiliation: Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, and.
authors.forename: Petra
authors.initials: P
authors.lastname: Kudweis
authors.affiliation: Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria; and.
authors.forename: Mario
authors.initials: M
authors.lastname: Biaggio
authors.affiliation: Molecular Biotechnology Center, University of Turin, Torino, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Poli
authors.affiliation: Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria; and.
authors.forename: Birgit
authors.initials: B
authors.lastname: Strobl
authors.affiliation: Institute of Animal Breeding and Genetics, Department for Biomedical Sciences, University of Veterinary Medicine Vienna, Vienna, Austria; and.
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Pharmacology and Toxicology, Department for Biomedical Sciences, and.
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D053804:Granzymes / Q000378:metabolism; D007157:Immunologic Surveillance / Q000187:drug effects; D019426:Integrases / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007422:Intestines / Q000473:pathology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008546:Melanoma, Experimental / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055627:Natural Cytotoxicity Triggering Receptor 1 / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism*; D054353:Perforin / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013154:Spleen / Q000473:pathology
chemical_list: D000950:Antigens, Ly; D016207:Cytokines; D055627:Natural Cytotoxicity Triggering Receptor 1; C118384:Ncr1 protein, mouse; D050796:STAT3 Transcription Factor; D054353:Perforin; D007371:Interferon-gamma; C045073:Cre recombinase; D019426:Integrases; D053804:Granzymes