title: CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation.
abstract: Recruitment of monocytic myeloid-derived suppressor cells (MDSCs) and differentiation of tumor-associated macrophages (TAMs) are the major factors contributing to tumor progression and metastasis. We demonstrated that differentiation of TAMs in tumor site from monocytic precursors was controlled by downregulation of the activity of the transcription factor STAT3. Decreased STAT3 activity was caused by hypoxia and affected all myeloid cells but was not observed in tumor cells. Upregulation of CD45 tyrosine phosphatase activity in MDSCs exposed to hypoxia in tumor site was responsible for downregulation of STAT3. This effect was mediated by the disruption of CD45 protein dimerization regulated by sialic acid. Thus, STAT3 has a unique function in the tumor environment in controlling the differentiation of MDSC into TAM, and its regulatory pathway could be a potential target for therapy.
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Vinit
authors.initials: V
authors.lastname: Kumar
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Pingyan
authors.initials: P
authors.lastname: Cheng
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Condamine
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Sridevi
authors.initials: S
authors.lastname: Mony
authors.affiliation: Thomas Jefferson University, Philadelphia, PA 19110, USA.
authors.forename: Lucia R
authors.initials: LR
authors.lastname: Languino
authors.affiliation: H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
authors.forename: Judith C
authors.initials: JC
authors.lastname: McCaffrey
authors.affiliation: Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE 19713, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Hockstein
authors.affiliation: Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE 19713, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Guarino
authors.affiliation: Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE 19713, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Masters
authors.affiliation: Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE 19713, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Penman
authors.affiliation: Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, DE 19713, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Denstman
authors.affiliation: University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Dario C
authors.initials: DC
authors.lastname: Altieri
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.affiliation: Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
authors.affiliation: The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: dgabrilovich@wistar.org.
authors.forename: Dmitry I
authors.initials: DI
authors.lastname: Gabrilovich
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D019281:Dimerization; D005260:Female; D000860:Hypoxia / Q000276:immunology*; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D012794:Sialic Acids / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D050796:STAT3 Transcription Factor; D012794:Sialic Acids; D010744:Phosphoric Monoester Hydrolases; D017493:Leukocyte Common Antigens