Mechanisms of dendritic cell reprogramming of regulatory T-cell suppression 2181

Description Tregs are essential for preventing autoimmunity; however, their suppressive capacity can also promote cancer progression. In some settings, Tregs can be reprogrammed to lose their suppressive activity while gaining immune-stimulatory functions. In several forms of autoimmune disease, Tregs have been found to convert from suppressive to inflammatory cells, promoting disease severity. While DCs are known to induce Treg differentiation from conventional CD4+ T cells, whether DCs can instruct thymicTregs to reprogram into a proinflammatory phenotype for the treatment of cancer has not been investigated. Our preliminary data shows that tumor-bearing mice treated with a Toll-like receptor (TLR) 2 ligand, Pam3CSK4, intratumorally exhibited increased Treg reprogramming (Foxp3 loss), and improved tumor control. Using a co-culture system ofTregs and DCs stimulated with different TLR ligands, we found that varying DC stimulation can drive loss of Foxp3 in Tregs in vitro. Using a pooled genetic screen in Tregs, I will investigate the mechanism by which DCs instruct Treg reprogramming. Preliminary results suggest that a soluble factor induced by the interaction of DCs and Tregs is sufficient to enforce Treg destabilization. This work will be important in furthering our understanding of how Treg function is regulated by DCs within the tumor, and may uncover new mechanisms to promote better cancer immunotherapies. 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)