Wnt Signaling Cascade in Dendritic Cells and Regulation of Anti-tumor Immunity

Abstract

Dendritic cells (DCs) control the strength and quality of antigen-specific adaptive immune responses. This is critical for launching a robust immunity against invading pathogens while maintaining a state of tolerance to self-antigens. However, this also represents a fundamental barrier to anti-tumor immune responses and cancer immunotherapy. DCs in the tumor microenvironment (TME) play a key role in this process. The factors in the TME and signaling networks that program DCs to a regulatory state are not fully understood. Recent advances point to novel mechanisms by which the canonical Wnt signaling cascade in DCs regulates immune suppression, and the same pathway in tumors is associated with the evasion of anti-tumor immunity. Here, we review these recent advances in the context of the pleiotropic effects of the Wnts in shaping anti-tumor immune responses by modulating DC functions. In addition, we will discuss how Wnt/β-catenin pathway in DCs can be targeted for successful cancer immunotherapy.Keywords: Wnt, dendritic cells, beta-catenin (β-catenin), tumor microenvironment (TME), immunotherapy, anti-tumor immunity, immunotherapy immunotherapies against a whole range of human cancers.

Disharmonic Inflammatory Signatures in COVID-19: Augmented Neutrophils’ but Impaired Monocytes’ and Dendritic Cells’ Responsiveness

“…Several pathways are involved in DC activation and/or tolerogenicity in both malignant and non-malignant conditions. In tumors, the dual state of both the proinflammatory and immunosuppressive microenvironment is well described [ 43 , 44 , 45 , 46 ]. Wnt5, a member of the Wnt family signaling pathway, which is wildly expressed by tumors and immune cells, activates the NFκB pathway and induces the tolerogenic phenotype via the release of IL-10 [ 44 ].…”

Extracellular Superoxide Dismutase, the Endothelial Basement Membrane, and the WNT Pathway: New Players in Vascular Normalization and Tumor Infiltration by T-Cells

“…Another open question is the role of the WNT pathway in TIL entry. WNT/β-catenin activation in neoplastic cells is a major T-cell exclusion pathway for different cancers ( 92 , 93 , 101 ). However, SOD3-induced T-cell extravasation relies on WNT pathway activation in EC ( 14 ).…”

“…The mechanism by which the SOD3/HIF-2α pathway boosts T cell infiltration depends on autocrine WNT pathway activation. This is paradoxical since WNT signaling deregulation has been implicated in virtually all stages of oncogenesis, including transformation, metastatic dissemination, and resistance to immunotherapy ( 92 , 93 ).…”

“…Tumor-intrinsic WNT signaling elements can be recognized by the immune system as tumor-associated antigens, serving as targets for the development of tumor-specific vaccines ( 98 , 99 ). In contrast, β-catenin signaling in cancer cells drives primary immune resistance by skewing DC maturation to a tolerogenic phenotype ( 100 ), and by excluding effector T cells from the tumor microenvironment ( 92 , 93 , 101 ). In EC, however, WNT pathway activation transcriptionally upregulates LAMA4, a permissive signal for T-cell diapedesis (see above).…”

Wnt Signaling in Leukemia and Its Bone Marrow Microenvironment

“…Wnt ligands are secreted glycoproteins that bind to Frizzled (Fzd) receptors, which are G-protein-coupled receptors (GPCRs) with seven transmembrane domains [ 20 ]. Upon binding, receptors activate multiple signaling pathways categorized as the canonical and noncanonical pathways [ 21 , 22 ]. The canonical pathway relies on the cytoplasmic stabilization of β-catenin (Ctnnb1), the key effector of Wnt signaling and a transcriptional coactivator for Wnt target genes [ 23 ].…”