The CCL5/CCR5 Axis in Cancer Progression

Abstract

<jats:p>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.</jats:p>

Immune modulatory effects of oncogenic KRAS in cancer

“…Chemokine C-C motif ligand 5 (CCL5), also known as Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES), mediates migration and chemotaxis of cells and is expressed by several cell types such as fibroblasts, epithelial cells, tumour cells and immune cells. Although CCL5 is implicated in tumour progression and its elevated levels are detected in several cancers, it also promotes anti-tumour immunity via the recruitment of T cells and dendritic cells to the TME 40 . Research has uncovered a role for CCL5 in KRAS-induced lung cancer, where it is involved in a cytokine circuit along with IL-6 and STAT3 driving tumorigenesis 41 .…”

Targeting the Calcium Signalling Machinery in Cancer

“…Similarly, release of the inflammatory chemokine C-C motif chemokine 5 (CCL-5) from TAMs induced migration of glioma cells in a process dependent on increases in cytosolic [Ca 2+ ] and phosphorylation of CaMKII [ 263 ]. Indeed, CCL-5 has previously been implicated in invasive behaviour and metastasis in a range of tumours, including prostate, bone, and breast cancers [ 264 ].…”

Identification of Co-Expressed Genes Promoting CD8+ T Cell Infiltration in Melanoma Tumor Microenvironments

“…We found that the yellow module had the strongest correlation with CD8 + T cells in the TCGA-SKCM cohort (Cor = 0.69; P = 1e- 26 ). Based on these ndings, we supplemented the heat map of the correlation between the factors in the yellow module and CD8 + T cells and the yellow module ( Fig.…”

“…CCL5 is a chemokine expressed by T lymphocytes, macrophages, platelets, synovium broblasts, renal tubular epithelial cells and tumor cells [26] . Harlin et al found that CCL5 produced by melanoma cells helped chemokine recruitment of CD8 + effector T cells, and lack of key chemokines may limit CD8 + T cell migration, thereby limiting the effectiveness of anti-tumor immunity [27] .…”