title: Immunologic consequences of signal transducers and activators of transcription 3 activation in human squamous cell carcinoma.
abstract: Paracrine cross-talk between tumor cells and immune cells within the tumor microenvironment underlies local mechanisms of immune evasion. Signal transducer and activator of transcription 3 (STAT3), which is constitutively activated in diverse cancer types, is a key regulator of cytokine and chemokine expression in murine tumors, resulting in suppression of both innate and adaptive antitumor immunity. However, the immunologic effects of STAT3 activation in human cancers have not been studied in detail. To investigate how STAT3 activity in human head and neck squamous cell carcinoma (HNSCC) might alter the tumor microenvironment to enable immune escape, we used small interfering RNA and small-molecule inhibitors to suppress STAT3 activity. STAT3 inhibition in multiple primary and established human squamous carcinoma lines resulted in enhanced expression and secretion of both proinflammatory cytokines and chemokines. Although conditioned medium containing supernatants from human HNSCC inhibited lipopolysaccharide-induced dendritic cell activation in vitro, supernatants from STAT3-silenced tumor cells reversed this immune evasion mechanism. Moreover, supernatants from STAT3-silenced tumor cells were able to stimulate the migratory behavior of lymphocytes from human peripheral blood in vitro. These results show the importance of STAT3 activation in regulating the immunomodulatory mediators by human tumors and further validate STAT3 as a promising target for therapeutic intervention.
authors.affiliation: Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Emilia
authors.initials: E
authors.lastname: Albesiano
authors.forename: Meghan
authors.initials: M
authors.lastname: Davis
authors.forename: Alfred P
authors.initials: AP
authors.lastname: See
authors.forename: James E
authors.initials: JE
authors.lastname: Han
authors.forename: Michael
authors.initials: M
authors.lastname: Lim
authors.forename: Drew M
authors.initials: DM
authors.lastname: Pardoll
authors.forename: Young
authors.initials: Y
authors.lastname: Kim
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003713:Dendritic Cells / Q000276:immunology; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007962:Leukocytes / Q000276:immunology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction; D014162:Transfection; D019139:Tumor Escape / Q000276:immunology
chemical_list: D016207:Cytokines; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human