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)-βwhich facilitates their escape from control by the immune system. We previously reported that non-immunogenic cells from either of two 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 (PBMC) in the presence of either mitomycin-treated OvC cells whose TGF-β1 gene was silenced or in vitro matured dendritic cells (DC) which had been pulsed with homogenates from OvC cells with silenced TGF-β1 generated a stronger Th1/Tc1 immune response to the respective WT OvC and also to the OvC antigens mesothelin and HE4 as measured by ELIspot assays. The percentage of interferon (IFN)-γ and tumor necrosis factor (TNF)-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 PBMC from a patient with OvC were sensitized to DC 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.

Atractylenolide I modulates ovarian cancer cell-mediated immunosuppression by blocking MD-2/TLR4 complex-mediated MyD88/NF-κB signaling in vitro

“…Similar to TGF-β1, the supernatant derived from SKOV3 cells could convert part of freshly isolated CD4 + /CD25 − T cells into CD25 + population with characters as CD4 + /CD25 + /FoxP3 + Treg cells. Knockdown TGF-β1 gene increases the immunogenicity of human EOC cells and impairs the tumorigenic ability of human EOC cells [ 36 , 37 ]. The role of VEGF in tumor angiogenesis has been well characterized, nevertheless, it is also known to have an immunosuppressive activity besides its angiogenic role and to promote tumor immune escape by impairing DC maturation and antitumour T cell activation in the tumor microenvironment.…”

Anti-HE4 antibodies in infertile women and women with ovarian cancer

“…HE4, human epididymis factor 4 [25], which is expressed by OvC, particularly its serous type [26, 27], and in lung adenocarcinoma [28] is attracting attention as a diagnostic marker which can complement CA125 since it is less often elevated in benign conditions and can be applied in combination with CA125 to aid diagnosis of women with a pelvic mass [20, 29-31]. It may also be a therapeutic target since it can be recognized by Th1 type lymphocytes, including cytolytic T cells [32]. …”

Increased expression of UBE2T predicting poor survival of ovarian cancer: based on comprehensive analysis of UBE2s, clinical samples and the GEO database

“…CSF1R is overexpressed in OC and the determination of its circulating levels proved useful for disease detection and the evaluation of therapeutic e cacy [67]. It has been reported that the cells of ovarian carcinoma produce large amounts of TGF-β1, which facilitates their escape from the immune system, and the clinical e cacy of immunotherapy based on TGF-β1-silenced tumor vaccines for OC has been investigated [68]. We speculate that UBE2T overexpression may cause the reduction or depletion of immune cells, leading to tumor progression by immune escape.…”