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Review
. 2020 Jul 2;12(7):1765.
doi: 10.3390/cancers12071765.

The CCL5/CCR5 Axis in Cancer Progression

Donatella Aldinucci  1 , Cinzia Borghese  1 , Naike Casagrande  1
Affiliations
Review

The CCL5/CCR5 Axis in Cancer Progression

Donatella Aldinucci et al. Cancers (Basel). .

Abstract

Tumor cells can "hijack" chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is gaining increasing attention, since abnormal expression and activity of CCL5 and its receptor CCR5 have been found in hematological malignancies and solid tumors. Numerous preclinical in vitro and in vivo studies have shown a key role of the CCL5/CCR5 axis in cancer, and thus provided the rationale for clinical trials using the repurposed drug maraviroc, a CCR5 antagonist used to treat HIV/AIDS. This review summarizes current knowledge on the role of the CCL5/CCR5 axis in cancer. First, it describes the involvement of the CCL5/CCR5 axis in cancer progression, including autocrine and paracrine tumor growth, ECM (extracellular matrix) remodeling and migration, cancer stem cell expansion, DNA damage repair, metabolic reprogramming, and angiogenesis. Then, it focuses on individual hematological and solid tumors in which CCL5 and CCR5 have been studied preclinically. Finally, it discusses clinical trials of strategies to counteract the CCL5/CCR5 axis in different cancers using maraviroc or therapeutic monoclonal antibodies.

Keywords: CCL5; CCR5; CCR5 antagonist; cancer; drug resistance; immunosuppression; metastasis; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Involvement of the CCL5/CCR5 axis in cancer progression. (1) CCL5, secreted by tumor cells (autocrine) and by the TME (paracrine), increases tumor growth. (2) CCL5 induces collagen degradation by activating matrix metalloproteinases in macrophages and fibroblasts. (3) CCL5 increases tumor cell migration and invasion by integrin activation (adhesion) and actin polarization. (4) CCR5+ cancer cells show characteristics of cancer stem cells. (5) CCR5 expression associates with stronger repair responses to DNA damage induced by doxorubicin and γ-irradiation. (6) CCL5 secreted by tumor cells and by the TME decreases drug cytotoxic activity. (7) CCR5 engagement stimulates glucose uptake, glycolysis, pentose phosphate pathway, fatty acid synthesis, and glutamine metabolism. (8) CCL5 promotes endothelial cell migration and neovessel formation, and induces the secretion of VEGF by endothelial cells. (9) CCL5 secreted by tumor cells recruits normal cells to build the TME. (10) CCL5 induces the immunosuppressive polarization of monocytes and myeloid cells leading to M2-TAMs and MDSCs that induce exhaustion of effector T-cells. Protein kinase B, Akt; cancer-associated fibroblast, CAF; C-C chemokine ligand 5, CCL5; C-C chemokine receptor type 5, CCR5; cancer stem cell, CSC; extracellular matrix, ECM; extracellular signal-regulated kinase, ERK; janus kinase, JAK; mitogen-activated protein kinase, MAPK; matrix metalloproteinase, MMP; myeloid-derived suppressor cell, MDSC; mesenchymal stem cell, MSC; nuclear factor kappa-light-chain-enhancer of activated B cells, NF-kB; phosphoinositide-3-kinase, PI3K; signal transducer and activator of transcription protein, STAT3; tumor-associated macrophage, TAM; tumor microenvironment, TME; regulatory T cell, Treg; vascular endothelial growth factor, VEGF.
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