Tumor-associated antigens are poorly immunogenic in the host. Dendritic cells (DCs) are the most potent antigen presenting cells (APCs). Various strategies have been used to enhance the ability of DCs to activate T-cell responses to multiple antigens. We report here the analysis of the ability of a Saccharomyces cerevisiae vector containing a transgene encoding CEA (Yeast-CEA) to activate human DC and to stimulate specific T-cell immune responses. Activation of DCs exposed to Yeast-CEA was studied by phenotypic analysis and cytokine and chemokine production profiles. The functional activity of DCs exposed to Yeast-CEA was analyzed by their ability to activate CEA-specific T cells as measured by IFN-γ production and their ability to function as APC for the generation of CEA-specific T cell lines. In addition, the gene expression profiles of 260 APC related genes of the DCs exposed to Yeast-CEA were also investigated. Our results have demonstrated that Yeast-CEA can be used to activate human DCs as a consequence the level the expression of CD80 and CD83 increases substantially. The increase in the expression of CD54, CD58, MHC class II on Yeast-CEA treated DCs is moderate. There was no increase in the expression of MHC class I since nearly 100% of the human DCs were MHC class I positive. Increases in the production of IL-12p70, TNF-α, and IFN-γ were also observed in the Yeast-CEA treated DCs. Human DCs exposed to Yeast-CEA were shown to be able to activate CEA-specific T cell lines. In addition, human DCs exposed to Yeast-CEA can be used as APC to generate CEA-specific T-cell line which in turn was shown to be capable of lysing human tumor cells expressing CEA. Analysis of the gene expression profiles of human DCs exposed to Yeast-CEA have shown the increases in the expression of chemokines, cytokines and their receptors genes and genes related to antigen uptake, antigen presentation as well as signal transduction. These studies provide the rationale for the clinical evaluation of the S. cerevisiae vector containing a transgene encoding CEA in patients with a range of carcinomas expressing CEA.
AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics-- Oct 22-26, 2007; San Francisco, CA