CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma

Abstract

Malignant melanoma is characterized by the development of chronic inflammation in the tumor microenvironment, leading to the accumulation of myeloid-derived suppressor cells (MDSCs). Using ret transgenic mouse melanoma model, we found a significant migration of MDSCs expressing C-C chemokine receptor (CCR)5 into primary tumors and metastatic lymph nodes, which was correlated with tumor progression. An increased CCR5 expression on MDSCs was associated with elevated concentrations of CCR5 ligands in melanoma microenvironment. In vitro experiments showed that the upregulation of CCR5 expression on CD11bGr1 immature myeloid cells was induced by CCR5 ligands, IL-6, GM-CSF, and other inflammatory factors. Furthermore, CCR5 MDSCs infiltrating melanoma lesions displayed a stronger immunosuppressive pattern than their CCR5 counterparts. Targeting CCR5/CCR5 ligand signaling via a fusion protein mCCR5-Ig, which selectively binds and neutralizes all three CCR5 ligands, increased the survival of tumor-bearing mice. This was associated with a reduced migration and immunosuppressive potential of tumor MDSCs. In melanoma patients, circulating CCR5 MDSCs were increased as compared to healthy donors. Like in melanoma-bearing mice, we observed an enrichment of these cells and CCR5 ligands in tumors as compared to the peripheral blood. Our findings define a critical role for CCR5 not only in the recruitment but also in the activation of MDSCs in tumor lesions, suggesting that novel strategies of melanoma treatment could be based on blocking CCR5/CCR5 ligand interactions.

Clinicopathological significance of chemokine receptor (CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4) expression in head and neck squamous cell carcinomas

“…The CCL3/CCR5 axis also promotes pro‐tumorigenic effects in oral cancer . Furthermore, CCR5 expression is associated with the recruitment of myeloid‐derived suppressor cells in melanoma, promoting the tumour progression, but this association was not being studied in HNSCCs. Additionally, polymorphisms in CCR5 were associated with increased risk of oral squamous cell carcinoma .…”

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

“…Recently, Blattner et al [114] found a high frequency of CCR5 + neutrophils (described in the study as CD11b + Ly6G + Ly6C low PMN-MDSCs) in melanoma lesions, spleen, and metastatic lymph nodes. CCR5 + neutrophils also showed stronger immunosuppressive phenotype than the CCR5 À fraction [115].…”

Blockade of CCR5 in melanoma: An alternative immune checkpoint modulator

“…It was shown in mice, that MDSCs‐CCR5+ were recruited to the melanoma microenvironment where CCL5 was highly expressed. Furthermore, MDSCs‐CCR5+ were higher in melanoma patients compared to healthy controls . We recently showed that melanoma expression of CCL5 is regulated by Notch1.…”

“…C-motif chemokine receptor 5 (CCR5) is found on T lymphocytes, macrophages, monocytes, basophils, myeloid derived suppressor cells (MDSCs) and neutrophils. [20,21] CCR5 is known in microbiology as a ligand of the HIV-1gp120 protein. CCR5-tropic HIV-1 utilizes…”

“…Furthermore, MDSCs-CCR5+ were higher in melanoma patients compared to healthy controls. [21] We recently showed that melanoma expression of CCL5 is regulated by Notch1. Notch1 contributes to immune suppression in the tumor microenvironment.…”