Paracrine wnt-β-catenin signaling inhibition as a strategy to enhance the efficacy of anti-PD-1 antibody (Ab) therapy in a transgenic model of melanoma.

Abstract

3053 Background: Activation of the Wnt-β-catenin signaling pathway is associated with poor T cell infiltration of tumors. We have previously demonstrated that paracrine Wnt5a-β-catenin signaling is a critical trigger of dendritic cell (DC) tolerization and regulatory T cell (Treg) differentiation in the melanoma microenvironment. In a transgenic BRAFV600EPTEN-/- model, the genetic silencing of melanoma-derived Wnt5a potently enhances infiltrating CD8+T cell effector function and promotes responses to anti-PD-1 Ab therapy. Ipafricept (IPA) is a recombinant Wnt decoy receptor and Vantictumab (VAN) is a Fzd receptor monoclonal Ab. Both molecules inhibit Wnt-β-catenin signaling and have been well-tolerated in ongoing phase I/Ib clinical trials. We explored the ability of IPA/VAN to reverse tumor-mediated immune tolerance and enhance the efficacy of anti-PD-1 Ab immunotherapy in a pre-clinical model that closely recapitulates human melanoma. Methods: Both IPA and VAN were utilized to investigate Wnt-β-catenin inhibition as a strategy for suppressing melanoma-induced DC indoleamine 2,3-dioxygenase (IDO) expression and Treg differentiation in vitro. These agents were further tested for their ability to enhance anti-tumor T cell responses and to augment the efficacy of anti-PD-1 Ab therapy in syngeneic and autochthonous models of BRAFV600EPTEN-/- melanoma. Results: IPA and VAN effectively inhibit Wnt5a and melanoma-induced DC IDO expression and Treg differentiation in vitro. Further studies demonstrate that IPA and VAN significantly augment anti-PD-1 Ab-mediated suppression of primary and metastatic tumor progression in both syngeneic and autochthonous BRAFV600EPTEN-/- melanoma models. These anti-tumor effects correlated with suppressed IDO enzymatic activity, enhanced tumor-infiltrating CD8+T cell/Treg ratios, and increased activation of TRP2 antigen-specific effector T cells. Conclusions: The pharmacological inhibition of paracrine Wnt-β-catenin signaling with IPA and VAN augment the anti-tumor efficacy of anti-PD-1 Ab therapy and represent a promising strategy for further phase I testing in melanoma and other solid tumors.