The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment
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NON-TTHEMATIC REVIEW
The emerging role of Wnt5a in the promotion of a pro-inflammatory and immunosuppressive tumor microenvironment Pablo Lopez-Bergami 1,2 & Gastón Barbero 1,2
# Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Wnt5a is the prototypical activator of the non-canonical Wnt pathways, and its overexpression has been implicated in the progression of several tumor types by promoting cell motility, invasion, EMT, and metastasis. Recent evidences have revealed a novel role of Wnt5a in the phosphorylation of the NF-κB subunit p65 and the activation of the NF-κB pathway in cancer cells. In this article, we review the molecular mechanisms and mediators defining a Wnt5a/NF-κB signaling pathway and propose that the aberrant expression of Wnt5a in some tumors drives a Wnt5a/NF-κB/IL-6/STAT3 positive feedback loop that amplifies the effects of Wnt5a. The evidences discussed here suggest that Wnt5a has a double effect on the tumor microenvironment. First, it activates an autocrine ROR1/Akt/p65 pathway that promotes inflammation and chemotaxis of immune cells. Then, Wnt5a activates a TLR/MyD88/p50 pathway exclusively in myelomonocytic cells promoting the synthesis of the anti-inflammatory cytokine IL-10 and a tolerogenic phenotype. As a result of these mechanisms, Wnt5a plays a negative role on immune cell function that contributes to an immunosuppressive tumor microenvironment and would contribute to resistance to immunotherapy. Finally, we summarized the development of different strategies targeting either Wnt5a or the Wnt5a receptor ROR1 that can be helpful for cancer therapy by contributing to generate a more immunostimulatory tumor microenvironment. Keywords Wnt5a . NF-κB . Akt . ROR1 . Cytokine . Immunotherapy
Abbreviations ADC Antibody-drug conjugates Akt RAC-alpha serine/threonine-protein kinase BiTE Bi-specific T cell engager BRAF vRaf murine sarcoma viral oncogen CaMKII Calmoduline kinase II CAR-T Chimeric antigen receptor T cell CCL Chemokine (C-C motif) ligand CE Convergent extension cGMP Cyclic guanosine monophosphate CK2 Casein kinase 2 CLL Chronic lymphocytic leukemia CREB cAMP response element binding
* Pablo Lopez-Bergami [email protected] 1
Centro de Estudios Biomédicos, Básicos, Aplicados y Desarrollo (CEBBAD), Universidad Maimonides, Hidalgo 775, Buenos Aires, Argentina
2
Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
CTL CTLA-4 CXCL DC Dkk Dvl EMT ERK FOXC1 FOXM1 IDO IKK IL ICT IκB JAK JNK LPD LPR LPS LTA mAbs
Cytotoxic T lymphocyte Cytotoxic T-lymphocyte antigen 4 Chemokine (C-X-C motif) ligand Dendritic cells Dickkopf Dishevelled Epithelial-mesenchymal transition Extracellular regulated kinase Forkhead box C1 Forkhead box transcription factor M1 Indoleamine 2,3-dioxygenase-1 IκB kinase Interleukin Immune checkpoint therapy Inhibitor of NF-κB Janus kinase c-Jun N-terminal kinase Lipid-protamine-DNA Lipoprotein receptor–related protein Lipopolysaccharide Lipoteichoic acid Monoclonal antibodies
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