title: Silencing of the TGF-β1 gene increases the immunogenicity of cells from human ovarian carcinoma.
abstract: Cells from many tumors produce transforming growth factor (TGF)-β which facilitates their escape from control by the immune system. We previously reported that nonimmunogenic cells from either of 2 transplantable mouse tumors became effective as therapeutic tumor vaccines after lentivirus-mediated shRNA interference to "silence" the TGF-β1 gene. We now show that cells from in vitro cultured human ovarian carcinomas (OvC) make large amounts of TGF-β1 and that this can be prevented by "silencing" the TGF-β1 gene. We further show that in vitro sensitization of peripheral blood mononuclear cells in the presence of either mitomycin-treated OvC cells whose TGF-β1 gene was silenced or in vitro matured dendritic cells that had been pulsed with homogenates from OvC cells with silenced TGF-β1 generated a stronger Th1/Tc1 immune response to the respective wild-type OvC and also to the OvC antigens mesothelin and HE4 as measured by ELIspot assays. The percentage of interferon-γ and tumor necrosis factor-α-producing CD4+ and CD8+ T cells increased while there were fewer cells expressing markers characteristic for regulatory T cells or myeloid-derived suppressor cells. Similar results were obtained when peripheral blood mononuclear cells from a patient with OvC were sensitized to dendritic cells pulsed with homogenate from autologous TGF-β1-silenced tumor cells, and a cytolytic lymphocyte response was generated to autologous OvC cells. Our results support clinical evaluation of TGF-β1-silenced tumor vaccines for immunotherapy of OvC.
authors.affiliation: Department of Pathology, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA.
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.forename: Pu
authors.initials: P
authors.lastname: Liu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Swisher
authors.forename: Yuen Yee
authors.initials: YY
authors.lastname: Yip
authors.forename: Jee Hang
authors.initials: JH
authors.lastname: Tse
authors.forename: Kathy
authors.initials: K
authors.lastname: Agnew
authors.forename: Karl Erik
authors.initials: KE
authors.lastname: Hellström
authors.forename: Ingegerd
authors.initials: I
authors.lastname: Hellström
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D002277:Carcinoma / Q000235:genetics* / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins / Q000276:immunology; D020868:Gene Silencing; D006801:Humans; D000090204:Mesothelin; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000276:immunology*; D011506:Proteins / Q000276:immunology; D034622:RNA Interference; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D000081102:WAP Four-Disulfide Core Domain Protein 2
chemical_list: D000951:Antigens, Neoplasm; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D011506:Proteins; D053773:Transforming Growth Factor beta1; D000081102:WAP Four-Disulfide Core Domain Protein 2; C569698:WFDC2 protein, human; D000090204:Mesothelin