Activation and Protection of Dendritic Cells in the Prostate Cancer Environment. Addendum

Abstract

Abstract : Final Report for research performed at the UMDNJ and VCU. Experiments have demonstrated for the first time the presence of endothelin receptors on murine dendritic cells (DC), and the fact of endothelin-1 production by murine DC upon stimulation with TNF dot and lipopolysaccharide (LPS). The modification of the endothelin axis on DC changed its resistance against prostate cancer induced apoptosis - the blockade of ETA receptors resulted in the increased apoptotic rate, while the blockade of the ETB receptors lead to the increased survival of DC in the prostate cancer environment. Blockade of ETA receptors also resulted in decreased DC capability to express costimulatory molecules and promote T cell proliferation. Based on these data, in vivo experiments were carried out, in which mice with prostate cancer (RM1 cells) were treated with intratumoral injection of modified DC (stimulated DC, with ETB receptor blocked). This treatment resulted in reduction of prostate cancer growth in mice in the experimental group, in comparison to untreated control mice. Blockade of ETB receptors and pulsing of DC with tumor antigen also led to the reduction of tumor growth after subcutaneous injection of this vaccine. Studies are under way to elicit the mechanisms of endothelin axis action on DC, as well as the underlying mechanisms of interaction between DC and prostate cancer cells.