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

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SummaryDespite 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.Graphical AbstractHighlightsMelanomas metabolically reprogram local DCs to induce immune toleranceMelanoma-derived Wnt5a triggers DC FAO via a β-catenin-PPAR-γ pathwayDC FAO drives IDO enzymatic activity by promoting protoporphyrin IX synthesisInhibiting the Wnt5a-β-catenin-CPT1A pathway enhances anti-PD-1 antibody activityPrevious studies suggest that DC tolerization plays a role in tumor-mediated immune evasion. The mechanism by which cancers promote this process remains poorly understood. Zhao et al. demonstrate that melanomas generate a site of immune privilege by driving DC fatty acid oxidation via a Wnt5a-β-catenin-PPAR-γ signaling pathway that culminates in the induction of IDO enzyme activity. Inhibiting this pathway reverses DC tolerization and enhances anti-PD-1 antibody efficacy in a transgenic model of melanoma.

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