Intratumoral Tregs impede antigen uptake by dendritic cells 3779

Abstract Description Immune-based cancer therapies have revolutionized the treatment of cancer; however, T regulatory cell (Treg) immunosuppression within tumors remains a major obstacle. One way in which Tregs dampen the adaptive immune response to cancer is by modulating antigen presenting cells (APCs), most importantly, dendritic cells (DCs). Our lab has identified a novel mechanism in which tumor-infiltrating Tregs suppress adaptive immune responses through limiting antigen uptake by DCs. We found that depleting Tregs in mCherry+ tumors by intratumoral (IT) diphtheria toxin (DT) treatment in Foxp3-DTR mice led to a significant increase in mCherry+ DCs. Next, we developed a system in which single cell suspensions of immune cells from tumors with or without IT Treg ablation are cultured with antigens ex vivo and monitored for antigen uptake. We found that DCs from tumors with Tregs ablated showed increased endocytosis of 1μm beads and soluble OVA protein. The endocytosis of the 1μm fluospheres suggests Tregs may specifically be inhibiting phagocytosis. Furthermore, in the ex vivo assay, we demonstrated that macrophages, monocytes, and monocyte progenitors found in tumors with IT Tregs ablated also showed increased antigen uptake. Additional investigation into when, where, and what factors Tregs use to limit endocytosis could have broad implications for improving cancer therapeutics and may provide new insights into mechanisms of Treg suppression in autoimmune and infectious diseases. Funding Sources This research was supported by 1DP2CA247830-01 from the National Institutes of Health (NCI) and C23CR5612 from the UC CRCC Cancer Research Coordinating Committee. M.D. is a Pew-Stewart Scholar and a St. Baldrick’s Scholar with generous support from Hope with Hazel. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)