The immunosuppressive and pro-tumor functions of CCL18 at the tumor microenvironment. (August 2021)

• Record Type: Journal Article
• Authors: Cardoso, Ana Patrícia; Pinto, Marta Laranjeiro; Castro, Flávia; Costa, Ângela Margarida; Marques-Magalhães, Ângela; Canha-Borges, Ana; Cruz, Tânia; Velho, Sérgia; Oliveira, Maria José
• Is Part Of: Cytokine & growth factor reviews. Volume 60(2021)
• Page Start: 107
• Page End: 119
• Publication Date: 2021-08
• Subjects: ACAP4 ARF6 GTPase-activating protein 4 -- ALDH1 Aldehyde Dehydrogenase 1 -- AnxA2 Annexin A2 -- APC Antigen Presenting Cells -- ARF6 ADP-Ribosylation Factor 6 -- ARNT Arylhydrocarbon Receptor Nuclear Translocator -- Bax BCL2 Associated X -- Bmi-1 B-cell-specific Moloney leukemia virus insertion site 1 -- CCL Chemokine (C-C motif) Ligand -- CCR8 Chemokine (C-C motif) Receptor 8 -- CD Cluster of Differentiation -- CLA Conjugated Linoleic Acid -- CSF-1 Colony Stimulating Factor 1 -- CXCL Chemokine (C-X-C motif) Ligand -- DC Dendritic Cells -- ECM Extracellular Matrix -- ELISA Enzyme-Linked Immunosorbent Assay -- ELMO1 Engulfment and cell motility protein -- EMT Epithelial to Mesenchymal Transition -- EVs Extracellular Vesicles -- FAK Focal Adhesion Kinase -- Foxp3 Forkhead Box P3 -- FSP-1 Fibroblast Specific Protein -- GAG Glycosaminoglycans -- GPR77 G Protein-coupled Receptor 77 -- GTP Guanosine-5'-triphosphate -- IDO Indoleamine 2, 3-dioxigenase -- IL Interleukin -- IFN Interferon -- LDHA Lactate Dehydrogenase A -- LIMK Lim motif-containing protein kinase -- LPS Lipopolysaccharide -- MAPK Mitogen Activated Protein Kinase -- MHC Major Histocompatibility Complex -- MMP Matrix Metalloprotease -- mTOR mammalian Target Of Rapamycin -- NF-kB Nuclear Factor kappa-light-chain-enhancer of activated B cells -- NK Natural Killer -- OCT-4 Octamer Binding Transcription Factor 4 -- PCAF P300/CBP-Associated Factor -- PCR Polymerase Chain Reaction -- PDGFA Platelet Derived Growth Factor subunit A -- PD-L1 Programmed Death-Ligand 1 -- PGE2 Prostaglandin E2 -- PI3K Phosphatidylinositol 3-kinase -- PITPNM3 Membrane-associated phosphatidylinositol transfer protein 3 -- PKC Protein Kinase C -- PLC Phospholipase C -- PyK2 Proline-rich tyrosine Kinase 2 -- Rac1 Ras-related C3 botulinum toxin substrate 1 -- RAS Rat Sarcoma -- RNA Ribonucleic Acid -- TAM Tumor Associated Macrophages -- TCR T-cell Receptor -- TGF Transforming Growth Factor -- Th T helper -- TME Tumor Microenvironment -- TNF Tumor Necrosis Factor -- Treg T regulatory -- VEGF Vascular Endothelial Growth Factor -- WNT Wingless and Int-1 -- Zeb1 Zinc finger E‐box binding protein 1; Tumor microenvironment -- Chemokine -- Biomarker -- Immunosuppressive -- Cancer -- Therapeutic target; Cytokines -- Periodicals; 571.84
• DOI: 10.1016/j.cytogfr.2021.03.005
• Languages: English
• ISSNs: 1359-6101

Abstract

Graphical abstract: Highlights: Chemokines orchestrate the immune architecture of tumors, influencing progression. CCL18 is highly expressed in several tumors. CCL18 promotes an immunosuppressive microenvironment and cancer cell invasion. CCL18 has been correlated with poor prognosis in several types of cancer. This chemokine is a promising biomarker/ therapeutic target in solid cancers. Abstract: Chemokines are essential mediators of immune cell trafficking. In a tumor microenvironment context, chemotactic cytokines are known to regulate the migration, positioning and interaction of different cell subsets with both anti- and pro-tumor functions. Additionally, chemokines have critical roles regarding non-immune cells, highlighting their importance in tumor growth and progression. CCL18 is a primate-specific chemokine produced by macrophages and dendritic cells. This chemokine presents both constitutive and inducible expression. It is mainly associated with a tolerogenic response and involved in maintaining homeostasis of the immune system under physiological conditions. Recently, CCL18 has been noticed as an important component of the complex chemokine system involved in the biology of tumors. This chemokine induces T regulatory cell differentiation and recruitment to the tumor milieu, with subsequent induction of a pro-tumor (M2-like) macrophage phenotype. CCL18 is also directly involved in cancer cell-invasion, migration, epithelial-to-mesenchymal transition and angiogenesis stimulation, pinpointing an important role in the promotion of cancer progression. Interestingly, this chemokine is highly expressed in tumor tissues, particularly at the invasive front of more advanced stages (e.g. colorectal cancer), and high levels are detected in the serum of patients, correlating with poor prognosis. Despite the promising role of CCL18 as a biomarker and/or therapeutic target to hamper disease progression, its pleiotropic functions in a context of cancer are still poorly explored. The scarce knowledge concerning the receptors for this chemokine, together with the insufficient insight on the downstream signaling pathways, have impaired the selection of this molecule as an immediate target for translational research. In this Review, we will discuss recent findings concerning the role of CCL18 in cancer, integrate recently disclosed molecular mechanisms and compile data from current clinical studies.