Pharmacological Wnt ligand inhibition overcomes key tumor-mediated resistance pathways to anti-PD-1 immunotherapy.

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. In this study, we show that proximal mediators of the Wnt signaling pathway are associated with anti-PD-1 resistance, and 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. [Display omitted] • Proximal Wnt ligand signaling activity is associated with anti-PD-1 resistance • Wnt signaling drives kynurenine production and PMN-MDSC accumulation in tumors • Wnt ligand inhibition enhances the efficacy of PD-1 blockade in transgenic models • Wnt inhibition creates a more favorable immune microenvironment in cancer patients Anti-PD-1-refractory melanoma exhibits elevated Wnt ligand signaling activity. DeVito et al. demonstrate that pharmacologic inhibition of proximal Wnt ligand signaling sensitizes transgenic models of melanoma and lung cancer to anti-PD-1 checkpoint inhibitor immunotherapy by reversing dendritic cell tolerization and suppressing recruitment of granulocytic myeloid-derived suppressor cells to the tumor bed. [ABSTRACT FROM AUTHOR]