title: TIE-2 and VEGFR kinase activities drive immunosuppressive function of TIE-2-expressing monocytes in human breast tumors.
abstract: OBJECTIVE
  Tumor-associated TIE-2-expressing monocytes (TEM) are highly proangiogenic cells critical for tumor vascularization. We previously showed that, in human breast cancer, TIE-2 and VEGFR pathways control proangiogenic activity of TEMs. Here, we examine the contribution of these pathways to immunosuppressive activity of TEMs.
  
  
  METHODS
  We investigated the changes in immunosuppressive activity of TEMs and gene expression in response to specific kinase inhibitors of TIE-2 and VEGFR. The ability of tumor TEMs to suppress tumor-specific T-cell response mediated by tumor dendritic cells (DC) was measured in vitro. Characterization of TEM and DC phenotype in addition to their interaction with T cells was done using confocal microscopic images analysis of breast carcinomas.
  
  
  RESULTS
  TEMs from breast tumors are able to suppress tumor-specific immune responses. Importantly, proangiogenic and suppressive functions of TEMs are similarly driven by TIE-2 and VEGFR kinase activity. Furthermore, we show that tumor TEMs can function as antigen-presenting cells and elicit a weak proliferation of T cells. Blocking TIE-2 and VEGFR kinase activity induced TEMs to change their phenotype into cells with features of myeloid dendritic cells. We show that immunosuppressive activity of TEMs is associated with high CD86 surface expression and extensive engagement of T regulatory cells in breast tumors. TIE-2 and VEGFR kinase activity was also necessary to maintain high CD86 surface expression levels and to convert T cells into regulatory cells.
  
  
  CONCLUSIONS
  These results suggest that TEMs are plastic cells that can be reverted from suppressive, proangiogenic cells into cells that are able to mediate an antitumoral immune response.
authors: Vital-IT, Swiss Institute of Bioinformatics, CHUV, University of Lausanne, Lausanne, Switzerland.
authors: Mark
authors: M
authors: Ibberson
authors: Sylvian
authors: S
authors: Bron
authors: Nicolas
authors: N
authors: Guex
authors: Eveline
authors: E
authors: Faes-van't Hull
authors: Assia
authors: A
authors: Ifticene-Treboux
authors: Luc
authors: L
authors: Henry
authors: Hans-Anton
authors: HA
authors: Lehr
authors: Jean-François
authors: JF
authors: Delaloye
authors: George
authors: G
authors: Coukos
authors: Ioannis
authors: I
authors: Xenarios
authors: Marie-Agnès
authors: MA
authors: Doucey
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D039521:CD11c Antigen / Q000378:metabolism; D016000:Cluster Analysis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000276:immunology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism; D010641:Phenotype; D042787:Receptor, TIE-2 / Q000378:metabolism*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D051940:B7-2 Antigen; D039521:CD11c Antigen; D042787:Receptor, TIE-2; D040262:Receptors, Vascular Endothelial Growth Factor