Wnt/beta-catenin pathway: modulating anticancer immune response

Abstract

Wnt/β-catenin signaling, a highly conserved pathway through evolution, regulates key cellular functions including proliferation, differentiation, migration, genetic stability, apoptosis, and stem cell renewal. The Wnt pathway mediates biological processes by a canonical or noncanonical pathway, depending on the involvement of β-catenin in signal transduction. β-catenin is a core component of the cadherin protein complex, whose stabilization is essential for the activation of Wnt/β-catenin signaling. As multiple aberrations in this pathway occur in numerous cancers, WNT-directed therapy represents an area of significant developmental therapeutics focus. The recently described role of Wnt/β-catenin pathway in regulating immune cell infiltration of the tumor microenvironment renewed the interest, given its potential impact on responses to immunotherapy treatments. This article summarizes the role of Wnt/β-catenin pathway in cancer and ongoing therapeutic strategies involving this pathway.

Keywords: Cancer immune regulation; Immune exclusion; Immunotherapy; Wnt; β-catenin.

Fig. 1

Canonical Wnt/β-catenin pathway: “WNT ON state”: WNT proteins, by binding to frizzled receptors and the LRP co-receptor, act to suppress the activity of glycogen synthase kinase-3β (GSK-3β). ZNRF3 promotes degradation of WNT receptor functioning as tumor suppressors. This prevents phosphorylation of downstream molecules allowing β-catenin association with Tcf/Lef in the nucleus and subsequent increased cell proliferation. “WNT OFF state”: In the absence of WNT ligand, the destruction complex of β-catenin (marked by dotted line box), a tertiary complex formed by axin, APC, CK1α and GSK 3β, will phosphorylate β-catenin, which subsequently undergoes proteasomal degradation

Fig. 2

Therapeutic targets in Wnt/β-catenin pathway and developmental therapeutics. Multiple strategies have been under investigation to counteract the canonical pathway of Wnt signaling. a, b Wnt soluble receptors and antibodies directed to Frizzled receptors impair the interaction ligand/receptor and its conveyed signal. c COX inhibitors reduces β-catenin cytoplasmic levels through different ways. PGE2, the main product of COX2 enzyme, is thought to mediate β-catenin transcription. Also, COX inhibitors such as aspirin were related to increase β-catenin ubiquitination and proteasomal destruction. d Tankyrase activates axin through induction of PARsylation and proteasomal degradation; tankyrase inhibitors increase the levels of axin, facilitating the formation of the β-catenin destruction complex and reducing β-catenin availability. e CBP inhibitors reduce the interaction between CBP and Tcf/Lef, reducing Tcf/Lef activity. f. PORCN inhibitors reduce the essential palmitoylation of Wnt, precluding its release to the extracellular space. g SAM68 is a regulator of alternative splicing of Tcf and impairs β-catenin/Tcf/Lef interaction

Fig. 3

Mechanisms of immune exclusion through Wnt/beta-catenin pathway: Activation of Wnt/beta-catenin pathway in tumor leads to noninflammatory milieu through multiple mechanisms. a By acting on Batf3-lineage CD103⁺ dendritic cells, decreasing CCL4 production by inducing the gene expression of the transcription repressor ATF3. This in turn reduces CD8⁺ T cell priming and infiltration. b By interacting with tumor-associated macrophages (TAM) through Snail (a soluble factor product of a Wnt-regulated gene) which can in turn increase beta-catenin activity by IL-1β. c β-catenin can enhance Treg survival through unknown mechanisms