Abstract 758: Cancer vaccine immunotherapy employing Saccharomyces cerevisiae (yeast) as a vector can modulate the balance between CD4+ T cells and regulatory T cells (Tregs) and enhance the specific antitumor immune response

Abstract

Abstract Regulatory T cells (Tregs) have been broadly related to modulation of the antitumor immune response. We have previously shown that whole, heat-killed, recombinant Saccharomyces cerevisiae yeast genetically modified to express carcinoembryonic antigen (yeast-CEA) can efficiently activate human dendritic cells (DCs) and stimulate CEA-specific CD8+ T cells. In the present study, we further investigated how the balance between CD4+ T cells and Tregs induced by yeast-treated DCs might affect the generation of a CEA-specific immune response. Autologous CD4+ T cells were co-cultured with human DCs matured by yeast vs. CD40L. Activated CD4+CD25+ effector T cells (Teffs) and CD4+CD25+CD127- Tregs isolated from the two co-cultures were analyzed. A higher Teff/Treg ratio, greater levels of Th1-related cytokines, lower expression of FoxP3 in Tregs, decreased FoxP3 demethylation levels in the Treg-specific demethylated region, and decreased Treg suppressive function were found in the cells isolated from the yeast co-culture compared to those from the CD40L co-culture. DCs isolated from the yeast co-culture showed a significant decrease in surface expression of programmed death ligand 2 (PD-L2) vs. the CD40L co-culture (55.7% vs. 31.2%). No differences were observed in programmed death ligand 1 (PD-L1) levels. Teffs isolated from the yeast co-culture had higher levels of PD-L1 (22.9% vs. 13.7%), but significantly lower levels of programmed death 1 (PD-1, 2.4% vs. 11.6%), compared to the co-culture using CD40L-matured DCs. Tregs isolated from the yeast co-culture showed a significant increase in surface expression of PD-L1 (25.5% vs. 3.6%) and no difference in levels of PD-1 (0.7% vs. 1.4%) compared to the CD40L co-culture. These pro-inflammatory changes may partially explain both the increased CEA-specific CD4+ T-cell proliferation using yeast- vs. CD40L-treated DCs pulsed with CEA protein, and the higher percentage of CEA-specific CD4+ T cells generated when yeast-matured DCs vs. CD40L-treated DCs were used as antigen-presenting cells in the presence of CEA protein. This is the first study to report on the role of yeast-treated human DCs in modulating the balance between Teffs and Tregs and thus enhancing the antitumor immune response. Altogether, these preliminary findings provide a rationale for further evaluation of yeast constructs in cancer vaccine immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 758. doi:10.1158/1538-7445.AM2011-758