Immunosuppressive Ovarian Cancer-Infiltrating Dendritic Cells can be transformed into Immunostimulatory Cells through In situ CD40 and Toll-like Receptor 3 Stimulation (100.32)

Abstract The individualized targeting of tumor-induced immunosuppression may contribute to the advancement of therapy against lethal epithelial tumors. We find that in a newly developed transgenic model of ovarian cancer, CD11c+MHCII+ dendritic cells are the most abundant leukocyte subset at tumor sites from early tumorigenesis. We also demonstrate (using a transplantable tumor model) that in the ovarian carcinoma microenvironment, these cells spontaneously engulf tumor materials and instead of promoting anti-tumor immunity, suppress T cell function. In situ co-stimulation of CD40 and Toll-like receptor (TLR) 3 on tumor-infiltrating dendritic cells reduced their L-arginase activity as well as enhanced their production of pro-inflammatory cytokines, augmented their capacity to process antigens, and up-regulated costimulatory molecules in vivo in mice and in vitro in human dissociated tumors. Correspondingly combined CD40/TLR agonists boosted measurable T-cell-mediated antitumor immunity and induced the rejection of otherwise lethal ovarian carcinomas. These results underscore the potential of transforming tumor-infiltrating dendritic cells from an immunosuppressive to an immunostimulatory cell type. Lastly, combined administration of synergistic CD40 and TLR3 agonists could enhance their individual therapeutic effects against ovarian and other lethal epithelial cancers.