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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • DeVito, NC; Sturdivant, M; Thievanthiran, B; Xiao, C; Plebanek, MP; Salama, AKS; Beasley, GM; Holtzhausen, A; Novotny-Diermayr, V; Strickler, JH; Hanks, BA

Published Date

  • May 4, 2021

Published In

Volume / Issue

  • 35 / 5

Start / End Page

  • 109071 -

PubMed ID

  • 33951424

Pubmed Central ID

  • PMC8148423

Electronic International Standard Serial Number (EISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2021.109071

Language

  • eng

Conference Location

  • United States