WNT/β-catenin regulatory roles on PD-(L)1 and immunotherapy responses

Abstract

Dysregulation of WNT/β-catenin is a hallmark of many cancer types and a key mediator of metastasis in solid tumors. Overactive β-catenin signaling hampers dendritic cell (DC) recruitment, promotes CD8⁺ T cell exclusion and increases the population of regulatory T cells (Tregs). The activity of WNT/β-catenin also induces the expression of programmed death-ligand 1 (PD-L1) on tumor cells and promotes programmed death-1 (PD-1) upregulation. Increased activity of WNT/β-catenin signaling after anti-PD-1 therapy is indicative of a possible implication of this signaling in bypassing immune checkpoint inhibitor (ICI) therapy. This review is aimed at giving a comprehensive overview of the WNT/β-catenin regulatory roles on PD-1/PD-L1 axis in tumor immune ecosystem, discussing about key mechanistic events contributed to the WNT/β-catenin-mediated bypass of ICI therapy, and representing inhibitors of this signaling as promising combinatory regimen to go with anti-PD-(L)1 in cancer immunotherapy. Ideas presented in this review imply the synergistic efficacy of such combination therapy in rendering durable anti-tumor immunity.

Keywords: Immune checkpoint inhibitor (ICI); Programmed death-1 (PD-1); Programmed death-ligand 1 (PD-L1); Resistance; Tumor microenvironment (TME); β-catenin.

Fig. 1

WNT/β-catenin signaling. Different steps are involved in the activity of WNT/β-catenin signaling. First, WNT palmitoylation occurs under the impact of porcupine (PORCN), which causes WNT secretion and activation. The active WNT interacts with Frizzled (Fzd)/lipoprotein receptor related proteins 5 and 6 (LRP5/6) complex in target cell and subsequently causes inactivation of β-catenin degrading complex and the resultant β-catenin cytosolic accumulation and its stabilization. The stabilized β-catenin translocate into the nucleus where it bonds to the T cell transcription factor (Tcf)/lymphoid enhancer-binding factor 1 (Lef1) for regulation of target genes. β-catenin signaling is inactivated when glycogen synthase kinase 3β (GSK3β) and the inhibitory complex is active, which subsequently promotes β-catenin proteasomal degradation. APC, adenomatosis polyposis coli; ZEB, Zinc finger E-box binding homeobox; IDO, indoleamine 2,3-dioxygenase; PPARγ, peroxisome proliferator-activated receptor-γ; and PD-L1, programmed death-ligand 1. Inhibitors of different paths in this signaling are marked as dashed rectangles

Fig. 2

The impact of WNT/β-catenin signaling on immune cells within tumor microenvironment (TME). β-catenin activation downregulates chemokine (C–C motif) ligand 5 (CCL5) activity, re-expression of which restores immune surveillance. Defective CD8⁺ T cell priming, impaired recruitment of dendritic cells (DCs) and CD8⁺ T cells, and increased recruitment of regulatory T cells (Tregs) and granulocytic-myeloid-derived suppressor cells (G-MDSCs) are outcomes of elevated WNT/β-catenin signaling in cancer. Shifting macrophage reprogramming into pro-tumor type 2 (M2) phenotype is another outcome, which is contributed to the intensification of immunosuppressive tumor profile. PPARγ, peroxisome proliferator-activated receptor-γ

Fig. 3

WNT/β-catenin signaling in tumor metabolism. A highly glycolytic tumor microenvironment (TME) represents high lactate release, which further acts for expression of programmed death-1 (PD-1) on regulatory T cells (Tregs). WNT5a/β-catenin induces indoleamine 2,3-dioxygenase (IDO)1 in tumor-associated dendritic cells (DCs) through activating peroxisome proliferator-activated receptor-γ (PPARγ). PPARγ reprograms DC metabolism toward oxidative phosphorylation (OXPHOS), which further increases IDO1 activity in DCs. IDO1 catalyzes tryptophan degradation, and the resultant kynurenine accumulation promotes Treg activity

Fig. 4

Signaling pathways related to the WNT/β-catenin activity and checkpoint regulation in cancer. Epidermal growth factor (EGF) inhibits glycogen synthase kinase 3β (GSK3β), induces β-catenin, and stimulates programmed death-ligand 1 (PD-L1) glycosylation. Activation of GSK3β destabilizes PD-L1 through promoting its ubiquitination and proteasomal degradation. β-catenin activity increases c-Myc, the activity of which enforces PD-L1 expression in tumor microenvironment (TME) and the subsequent apoptosis of T cells. The histone demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX1) suppresses Jumonji domain-containing 1A (JMJD1A) and its downstream β-catenin, and downregulates PD-L1 on tumor cells. Prostaglandin E2 (PGE2) stimulates the activity of β-catenin for maintaining cancer stemness. PGE2 release from M2 macrophages also induces PD-L1 expression on tumor cells. Promoter of cyclooxygenase-2 (COX-2) contains Tcf4 binding element to which β-catenin is bonded for upregulation of COX-2 expression. PTEN, phosphatase and tensin homolog deleted on chromosome 10; and LKB1, liver kinase B1

Fig. 5

Epithelial mesenchymal plasticity in β-catenin and checkpoint regulation. Zinc finger E-box binding homeobox1 (ZEB1) is an epithelial-mesenchymal transition (EMT)-related transcription factor that its expression is induced by the β-catenin/Tcf4 complex. The N-glycosyltransferase STT3 is stimulated by EMT inducible effect on β-catenin in cancer cells and cancer stem cells (CSCs) to promote programmed death-ligand 1 (PD-L1) upregulation. Conversion into mesenchymal–epithelial transition (MET) phenotype reduces nuclear β-catenin, downregulates PD-L1, and sensitizes tumor cells to immunotherapy