Paracrine Wnt5a-β-Catenin Signaling Triggers a Metabolic Program that Drives Dendritic Cell Tolerization

Immunity. 2018 Jan 16;48(1):147-160.e7. doi: 10.1016/j.immuni.2017.12.004.


Despite recent advances, many cancers remain refractory to available immunotherapeutic strategies. Emerging evidence indicates that the tolerization of local dendritic cells (DCs) within the tumor microenvironment promotes immune evasion. Here, we have described a mechanism by which melanomas establish a site of immune privilege via a paracrine Wnt5a-β-catenin-peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway that drives fatty acid oxidation (FAO) in DCs by upregulating the expression of the carnitine palmitoyltransferase-1A (CPT1A) fatty acid transporter. This FAO shift increased the protoporphyrin IX prosthetic group of indoleamine 2,3-dioxgenase-1 (IDO) while suppressing interleukin(IL)-6 and IL-12 cytokine expression, culminating in enhanced IDO activity and the generation of regulatory T cells. We demonstrated that blockade of this pathway augmented anti-melanoma immunity, enhanced the activity of anti-PD-1 antibody immunotherapy, and suppressed disease progression in a transgenic melanoma model. This work implicates a role for tumor-mediated metabolic reprogramming of local DCs in immune evasion and immunotherapy resistance.

Keywords: Wnt5a; dendritic cell tolerization; fatty acid oxidation; immune evasion; immunotherapy resistance; indoleamine 2,3-dioxygenase; melanoma microenvironment; protoporphyrin IX; regulatory T cells; β-catenin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism*
  • Enzyme-Linked Immunosorbent Assay
  • Fatty Acids / metabolism
  • Female
  • Flow Cytometry
  • Immunoblotting
  • Male
  • Melanoma / immunology*
  • Melanoma / metabolism
  • Mice
  • Mice, Transgenic
  • PPAR gamma / metabolism
  • Paracrine Communication / physiology
  • Polymerase Chain Reaction
  • Signal Transduction / physiology
  • Wnt-5a Protein / metabolism*
  • beta Catenin / metabolism*


  • Fatty Acids
  • PPAR gamma
  • Wnt-5a Protein
  • Wnt5a protein, mouse
  • beta Catenin