title: Regulation of the IL-23 and IL-12 balance by Stat3 signaling in the tumor microenvironment.
abstract: Interactions between tumor and immune cells either enhance or inhibit cancer progression. We show here that Stat3 signaling within the tumor microenvironment induces a procarcinogenic cytokine, IL-23, while inhibiting a central anticarcinogenic cytokine, IL-12, thereby shifting the balance of tumor immunity toward carcinogenesis. Stat3 induces expression of IL-23, which is mainly produced by tumor-associated macrophages, via direct transcriptional activation of the IL-23/p19 gene. Furthermore, Stat3 inhibits NF-kappaB/c-Rel-dependent IL-12/p35 gene expression in tumor-associated dendritic cells. Tumor-associated regulatory T cells (Tregs) express IL-23 receptor, which activates Stat3 in this cell type, leading to upregulation of the Treg-specific transcription factor Foxp3 and the immunosuppressive cytokine IL-10. These results demonstrate that Stat3 promotes IL-23-mediated procarcinogenic immune responses while inhibiting IL-12-dependent antitumor immunity.
authors.affiliation: Department of Cancer Immunotherapeutics and Tumor Immunology, Beckman Research Institute at City of Hope, Duarte, CA 91010, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kortylewski
authors.forename: Hong
authors.initials: H
authors.lastname: Xin
authors.forename: Maciej
authors.initials: M
authors.lastname: Kujawski
authors.forename: Heehyoung
authors.initials: H
authors.lastname: Lee
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Timothy
authors.initials: T
authors.lastname: Harris
authors.forename: Charles
authors.initials: C
authors.lastname: Drake
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.forename: Hua
authors.initials: H
authors.lastname: Yu
mesh_terms: D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D007107:Immune System / Q000502:physiology*; D018664:Interleukin-12 / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000473:pathology; D011401:Promoter Regions, Genetic; D018123:Receptors, Interleukin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D053759:Interleukin-23; D016328:NF-kappa B; D018123:Receptors, Interleukin; D050796:STAT3 Transcription Factor; C528688:interleukin-23 receptor, mouse; D018664:Interleukin-12