Abstract LB-320: Inhibition of TGFß1 improves the therapeutic efficacy of non-immunologic tumor cell based vaccine

Abstract

Abstract Background and objectives of the study: Many cancers, including ovarian cancer, over-express transforming growth factor-beta (TGF-ß), which helps them evade immune control through a variety of mechanisms. We investigated whether the efficacy of tumor cells to induce an immune response, when used intact or as part of a dendritic cell (DC)-based vaccine can be enhanced by inhibiting their production of TGFß1 via anti-sense. Methodology: The TGFß1 expression by two ovarian cancer cell lines was silenced by transfection with a non-replicating lentivirus shRNA. Autologous PBMC were co-cultivated, in the presense of IL-2, with Mitomycin-C (MMC) treated cancer cells or mature dendritic DC that had been pulsed with tumor lysates. The in vitro sensitized lymphoid cells were evaluated by ELISPOT for production of IFN-γ and by flow cytometry. Preliminary data: Quanitative ELISA showed that TGFß1 production in the two ovarian cancer lines was signficantly inhibited by transfection with shRNA. In vitro sensitization of autologous PBMC with either tumor cells where the TGFß1 gene had been silenced or with DC that had been pulsed with homogenates of tumor cells with a silencd TGFß1 gene induced a stronger IFNγ release and increased the frequency of NK cells and DC while it decreased the population of Treg cells. We are presently investigating the anti-tumor response in a mouse melanoma model after vaccination with murine bone-marrow derived DC which have benn pulsed with TGFß silenced tumor lysates. Conclusions: The production, by many tumors, of TGFß1 interferes with their ability to induce an anti-tumor response. This is true both when intact tumor cells and DC pulsed with tumor homogenate are used as immunogen. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-320.