title: B7h triggering inhibits the migration of tumor cell lines.
abstract: Vascular endothelial cells (ECs) and several cancer cells express B7h, which is the ligand of the ICOS T cell costimulatory molecule. We have previously shown that B7h triggering via a soluble form of ICOS (ICOS-Fc) inhibits the adhesion of polymorphonuclear and tumor cell lines to HUVECs; thus, we suggested that ICOS-Fc may act as an anti-inflammatory and antitumor agent. Because cancer cell migration and angiogenesis are crucial for metastasis dissemination, the aim of this work was to evaluate the effect of ICOS-Fc on the migration of cancer cells and ECs. ICOS-Fc specifically inhibited the migration of HUVECs, human dermal lymphatic ECs, and the HT29, HCT116, PC-3, HepG2, JR8, and M14 tumor cell lines expressing high levels of B7h, whereas it was ineffective in the RPMI7932, PCF-2, LM, and BHT-101 cell lines expressing low levels of B7h. Furthermore, ICOS-Fc downmodulated hepatocyte growth factor facilitated the epithelial-to-mesenchymal transition in HepG2 cells. Moreover, ICOS-Fc downmodulated the phosphorylation of focal adhesion kinase and the expression of β-Pix in both HUVECs and tumor cell lines. Finally, treatment with ICOS-Fc inhibited the development of lung metastases upon injection of NOD-SCID-IL2Rγnull mice with CF-PAC1 cells, as well as C57BL/6 mice with B16-F10 cells. Therefore, the B7h-ICOS interaction may modulate the spread of cancer metastases, which suggests the novel use of ICOS-Fc as an immunomodulatory drug. However, in the B16-F10-metastasized lungs, ICOS-Fc also increased IL-17A/RORc and decreased IL-10/Foxp3 expression, which indicates that it also exerts positive effects on the antitumor immune response.
authors.affiliation: Department of Drug Science and Technology, University of Torino, 10125 Torino, Italy;
authors.forename: Chiara
authors.initials: C
authors.lastname: Dianzani
authors.forename: Rosalba
authors.initials: R
authors.lastname: Minelli
authors.forename: Casimiro Luca
authors.initials: CL
authors.lastname: Gigliotti
authors.forename: Sergio
authors.initials: S
authors.lastname: Occhipinti
authors.forename: Mirella
authors.initials: M
authors.lastname: Giovarelli
authors.forename: Laura
authors.initials: L
authors.lastname: Conti
authors.forename: Elena
authors.initials: E
authors.lastname: Boggio
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Shivakumar
authors.forename: Gianluca
authors.initials: G
authors.lastname: Baldanzi
authors.forename: Valeria
authors.initials: V
authors.lastname: Malacarne
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orilieri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cappellano
authors.forename: Roberto
authors.initials: R
authors.lastname: Fantozzi
authors.forename: Daniele
authors.initials: D
authors.lastname: Sblattero
authors.forename: Junji
authors.initials: J
authors.lastname: Yagi
authors.forename: Josè Maria
authors.initials: JM
authors.lastname: Rojo
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000276:immunology*; D056945:Hep G2 Cells; D064593:Heterografts; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000235:genetics / Q000276:immunology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology
chemical_list: C556692:ICOS protein, human; C498514:ICOSLG protein, human; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D007141:Immunoglobulin Fc Fragments; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D011993:Recombinant Fusion Proteins