C-C motif glycoprotein ligand 5 (CCL5) and its GPCR CCR5: Macromolecular game-changers in cancer biology
1Department of Pharmacology and Toxicology, School of Pharmacy; Cellular and Molecular Research Center, Jundishapur University of Medical Sciences, Ahvaz, Iran.
Abstract:
The C-C motif chemokine ligand 5 (CCL5; also known as RANTES) and its primary G-protein-coupled receptor (GPCR), CCR5, establish complicated signaling pathways, affecting tumor progression through context-dependent immunomodulation and direct contacts with neoplastic cells. This review summarizes current structural and functional evidence linking CCL5's O-linked glycosylation, oligomerization, and glycosaminoglycan interactions to its affinity for CCR5, tissue retention, and gradient formation-molecular attributes that govern leukocyte recruitment, stromal remodeling, angiogenesis, and metastasis. It also discusses mechanistic data showing how CCL5/CCR5 signaling promotes protumorigenic processes, including the recruitment of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), polarization of tumor-associated macrophages (TAMs), epithelial-mesenchymal transition (EMT), stabilization of programmed cell death-ligand 1 (PD-L1), and therapeutic resistance. In particular, in immune-activating conditions, the recruitment of conventional type 1 dendritic cells (cDC1s), natural killer (NK) cells, and CD8+ T cells is augmented, hence fortifying anticancer immunity. Data from several tumors reveal both detrimental and beneficial effects, dependent on the tumor microenvironment (TME) and therapeutic context. Translational techniques employing CCR5 antagonists such as Maraviroc, GAG-binding modulators, glycoengineered CCL5 variants, delivery systems, and their integration with immune checkpoint inhibitors (ICIs) and targeted therapies are highlighted for their considerable therapeutic promise. Critical research priorities, encompassing single-cell phenotyping, CRISPR-mediated screening of chemokine pathways, and structural-functional mapping, are outlined to facilitate precise modulation of the CCL5/CCR5 axis in targeted cancer therapy. This review addresses structural biology and tumor immunology to identify the CCL5/CCR5 axis as a multifaceted yet promising biological target for innovative cancer therapeutics.
Insights
The C-C motif chemokine ligand 5 (CCL5) and its receptor (CCR5) play complex roles in cancer, influencing tumor growth and immune response. Targeting this axis shows promise for novel cancer therapies.
Area of Science:
- Structural biology
- Tumor immunology
- Molecular signaling
Background:
- The C-C motif chemokine ligand 5 (CCL5) and its receptor CCR5 are implicated in tumor progression via immunomodulation and direct cell interactions.
- CCL5's structural features, including glycosylation and oligomerization, influence its binding to CCR5, affecting leukocyte recruitment, angiogenesis, and metastasis.
Purpose of the Study:
- To review structural and functional evidence linking CCL5/CCR5 signaling to cancer progression and therapeutic strategies.
- To explore the dual role of CCL5/CCR5 in promoting or inhibiting anti-tumor immunity based on the tumor microenvironment (TME).
Main Methods:
- Literature review of structural and functional data on CCL5 and CCR5 in cancer.
- Analysis of mechanistic studies on CCL5/CCR5 signaling pathways in protumorigenic processes.
- Evaluation of translational approaches and therapeutic interventions targeting the CCL5/CCR5 axis.
Main Results:
- CCL5/CCR5 signaling promotes protumorigenic processes like Treg/MDSC recruitment, TAM polarization, EMT, PD-L1 stabilization, and therapeutic resistance.
- Conversely, CCL5/CCR5 can augment anti-cancer immunity by recruiting cDC1s, NK cells, and CD8+ T cells under immune-activating conditions.
- The effects of CCL5/CCR5 are context-dependent, varying with the TME and therapeutic setting.
Conclusions:
- The CCL5/CCR5 axis is a multifaceted target in cancer, with both detrimental and beneficial roles.
- Targeting CCL5/CCR5 with antagonists, modulators, or in combination with other therapies holds significant therapeutic potential.
- Further research priorities include single-cell phenotyping and pathway screening for precise modulation of the CCL5/CCR5 axis.
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