Pharmacological Wnt Ligand Inhibition Overcomes Key Tumor-Mediated Resistance Pathways to Anti-PD-1 Immunotherapy

Abstract

While immune checkpoint blockade is associated with prolonged responses in multiple cancers, most patients still do not benefit from this therapeutic strategy. The Wnt-β-catenin pathway is associated with diminished T cell infiltration, however activating mutations are rare, implicating a role for autocrine/paracrine Wnt ligand-driven signaling in immune evasion. Herein, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance and that pharmacologic inhibition of Wnt ligand signaling supports anti-PD-1 efficacy by reversing dendritic cell tolerization and the recruitment of granulocytic myeloid-derived suppressor cells in autochthonous tumor models. We further demonstrate that the inhibition of Wnt signaling promotes the development of a tumor microenvironment that is more conducive to favorable responses to checkpoint blockade in cancer patients. These findings support a rationale for Wnt ligand-focused treatment approaches in future immunotherapy clinical trials and suggest a strategy for selecting those tumors more responsive to Wnt inhibition.