Abstract 2340: Differentiation of pro- and anti-inflammatory features of monocyte-derived dendritic cells

Abstract

Abstract Background: Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system and are consequently exploited in cancer immunotherapy in order to present tumor-associated antigens to lymphocytes. The ability of tumor cells to induce tolerogenic DCs and avoid the immune system challenges DC-based immunotherapies. Utilizing buffycoats of healthy blood donors we have investigated the activation of gene expression programs conventionally associated with either pro- or anti-inflammatory features of monocyte-derived DCs. Methodology: Following isolation of monocytes from buffycoats, various culture conditions were tested to generate immature DCs and to mature and activate them in vitro. Genome-wide gene expression, secretion of cytokines and tryptophan metabolites, surface expression of maturation and activation markers, and functional abilities were analyzed. Specifically, beta-catenin and indoleamine 2,3-dioxigenase 1 (IDO-1) activation were examined using both agonists and inhibitors of those pathways. Results: A considerable variability among buffycoats of different healthy blood donors was observed regarding DC yield and cytokine secretion. Induction time to generate immature DCs with interleukin-4 and granulocyte-macrophage colony-stimulating factor affected DC differentiation. Several maturation conditions induced strong IDO-1 expression. Activation of beta-catenin during DC maturation induced anti-inflammatory features that could be competed by adding beta-catenin inhibitors during cultivation of the cells. Pro- and anti-inflammatory features often co-existed in mature DCs. Conclusions: Beta-catenin and IDO-1 activation are prevalent according to different conditions of monocyte-derived DC maturation and associated with anti-inflammatory features. Both pathways can be inhibited by specific antagonists. More robust pro-inflammatory DC generation is desirable for more effective cancer immunotherapy. Citation Format: Ragnhild Maukon Bakke, Waqas Azeem, Silke Appel, Karl-Henning Kalland, Anne Margrete Oyan. Differentiation of pro- and anti-inflammatory features of monocyte-derived dendritic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2340.