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

Publication date: May 04, 2021

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.

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Concepts Keywords
Cancers Autocrine signaling
Clinical Immune checkpoint
Myeloid Paracrine signaling
Pharmacologic Wnt signaling pathway
Pharmacological Clusters of differentiation
Therapeutic Genes
Tumor Evolutionary developmental biology
Immune system
Signal transduction
Branches of biology
Suppressor autochthonous tumor
Dioxygenase melanoma
Regulatory Tcells tumor


Type Source Name
disease MESH Lewis lung carcinoma
pathway REACTOME Immune System
drug DRUGBANK Proline
disease MESH development
pathway KEGG Wnt signaling pathway
disease MESH tumor
disease MESH tic
drug DRUGBANK L-Tryptophan
drug DRUGBANK Cycloserine
pathway KEGG Melanoma
disease MESH melanoma
drug DRUGBANK Epacadostat
drug DRUGBANK Pembrolizumab
drug DRUGBANK Protoporphyrin
drug DRUGBANK Aminolevulinic acid
drug DRUGBANK Alpha-Linolenic Acid
drug DRUGBANK Icosapent
disease MESH delayed treatment
disease MESH cholangiocarcinoma
drug DRUGBANK Trestolone
disease MESH tryptophan
disease MESH dysgeusia
disease MESH neutropenia
disease MESH tumor immune escape
drug DRUGBANK Honey
drug DRUGBANK Paclitaxel
drug DRUGBANK Gemcitabine
disease MESH pancreatic cancer
pathway KEGG Pancreatic cancer
disease MESH death
drug DRUGBANK Fenamole
disease MESH small cell lung cancer
pathway KEGG Small cell lung cancer
drug DRUGBANK Ipilimumab
drug DRUGBANK Indole
drug DRUGBANK Medium-chain triglycerides
drug DRUGBANK L-Arginine
drug DRUGBANK Guanosine
drug DRUGBANK Sulfasalazine
disease MESH microsatellite instability
drug DRUGBANK Carboplatin
disease MESH ovarian cancer
disease MESH Inflammation
drug DRUGBANK Ibuprofen
disease MESH adenocarcinoma
disease MESH carcinoma
disease MESH lung adenocarcinoma
drug DRUGBANK Nivolumab
drug DRUGBANK Diflunisal
drug DRUGBANK Thiocolchicoside
drug DRUGBANK Isoflurane
drug DRUGBANK Polyethylene glycol
drug DRUGBANK Etoperidone
drug DRUGBANK Medical air
drug DRUGBANK Carbon dioxide
drug DRUGBANK Collagenase clostridium histolyticum
drug DRUGBANK Hyaluronidase
disease MESH dissociation
drug DRUGBANK Hyaluronic acid
disease MESH separated
drug DRUGBANK Sodium lauryl sulfate
drug DRUGBANK Nitrogen
drug DRUGBANK Ammonium chloride
drug DRUGBANK Dimethyl sulfoxide
drug DRUGBANK 2′-Deoxycytidine
disease MESH infection
drug DRUGBANK Trimebutine
disease MESH non-small cell lung cancer
pathway KEGG Non-small cell lung cancer

Original Article

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