A Review of the Role of Wnt in Cancer Immunomodulation

Abstract

Alterations in the Wnt signaling pathway are associated with the advancement of cancers; however, the exact mechanisms responsible remain largely unknown. It has recently been established that heightened intratumoral Wnt signaling correlates with tumor immunomodulation and immune suppression, which likely contribute to the decreased efficacy of multiple cancer therapeutics. Here, we review available literature pertaining to connections between Wnt pathway activation in the tumor microenvironment and local immunomodulation. We focus specifically on preclinical and clinical data supporting the hypothesis that strategies targeting Wnt signaling could act as adjuncts for cancer therapy, either in combination with chemotherapy or immunotherapy, in a variety of tumor types.

Keywords: Wnt; cancer; immunomodulation; immunotherapy; tumor microenvironment; β-catenin.

Figure 1

Overview of the canonical Wnt signaling pathway illustrating therapeutic intervention points targeted by Wnt modulators. The lower half of the figure represents a zoomed in portion of the cell. Porcupine (PORCN) inhibitors (e.g., LGK974) block secretion of WNTs by inhibiting their palmitoylation. AXIN1 activators (e.g., niclosamide) promote β-catenin degradation. Dickkopf 1 (DKK1) antibodies may increase Wnt/β-catenin signaling by blocking DKK1 binding to LRP5/6; beneficial effects in cancer may be through inhibition of DKK1 binding to CKAP4 or indirect effects on immune cells. Wnt receptor decoys (e.g., OMP54F28) prevent Wnt binding to Fzd receptors. WNT5A mimic (Foxy-5) is a peptide that activates noncanonical Wnt signals. CBP/beta-catenin inhibitors (e.g., PRI-724) disrupt the interaction between CREB-binding protein (CBP) and β-catenin. Created with BioRender.com. Proteins and cell compartments are not drawn to scale.

Figure 2

Wnt/β-catenin signaling and tumor immunomodulation. A magnified tumor cell (top left), illustrates Wnt signaling leading to elevated cytosolic and nuclear β-catenin. Increased Wnt signaling is associated with heightened survival of Tregs, skewed differentiation of CD4⁺ T cells to a pro-tumorigenic Th17 subtype, conversion of dendritic cells to a regulatory state with enhanced IL-10 and IL-12 secretion, and decreased effector differentiation and function in CD8⁺ T cells. DKK1 inhibits Wnt ligand/receptor interactions. Elevated DKK1 leads to an accumulation of MDSC in the TME and subsequent inhibition of effector CD8⁺ T cell function. Created with BioRender.com. Not drawn to scale.