Silencing of the TGF-β1 Gene Increases the Immunogenicity of Cells From Human Ovarian Carcinoma

Cells from many tumors produce transforming growth factor (TGF)-beta 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-beta 1 gene. We now show that cells from in vitro cultured human ovarian carcinomas (OvC) make large amounts of TGF-beta 1 and that this can be prevented by silencing the TGF-beta 1 gene. We further show that in vitro sensitization of peripheral blood mononuclear cells in the presence of either mitomycin-treated OvC cells whose TGF-beta 1 gene was silenced or in vitro matured dendritic cells that had been pulsed with homogenates from OvC cells with silenced TGF-beta 1 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-g and tumor necrosis factor-alpha-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-beta 1-silenced tumor cells, and a cytolytic lymphocyte response was generated to autologous OvC cells. Our results support clinical evaluation of TGF-beta 1-silenced tumor vaccines for immunotherapy of OvC.