Targeting the Wnt5a-β-catenin pathway in the melanoma microenvironment to augment checkpoint inhibitor immunotherapy.

3054 Background: While checkpoint inhibitor immunotherapy has demonstrated recent success in patients with advanced melanoma, a significant fraction of these patients continue to fail therapy. The β-catenin signaling pathway plays a role in dendritic cell (DC) tolerization and regulatory T cell (Treg) differentiation however the factors responsible for inducing this pathway are unknown. Methods: We utilized a BRAFV600EPTEN-/- autochthonous model of melanoma to identify melanoma-derived factors capable of driving local Treg development and the generation of an immunotolerant microenvironment. Primary human melanoma specimens were examined for expression of these candidate factors by immunohistochemistry while sentinel lymph node-derived DCs were analyzed for expression of downstream mediators of the identified signaling pathway. Based on this data, a small molecule inhibitor of the candidate signaling pathway was tested to augment the anti-tumor immune response of checkpoint inhibitors in a murine melanoma...