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

TY - JOUR

T1 - CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma

AU - Umansky, Viktor

AU - Blattner, Carolin

AU - Gebhardt, Christoffer

AU - Utikal, Jochen

PY - 2017/8

Y1 - 2017/8

N2 - 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 CD11b+Gr1+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.

AB - 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 CD11b+Gr1+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.

KW - Animals

KW - Cell Differentiation

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Immunity, Cellular

KW - Immunotherapy

KW - Melanoma

KW - Melanoma, Experimental

KW - Mice

KW - Myeloid-Derived Suppressor Cells

KW - Receptors, CCR5

KW - Skin Neoplasms

KW - Tumor Microenvironment

KW - Journal Article

KW - Review

U2 - 10.1007/s00262-017-1988-9

DO - 10.1007/s00262-017-1988-9

M3 - SCORING: Review article

C2 - 28382399

VL - 66

SP - 1015

EP - 1023

JO - CANCER IMMUNOL IMMUN

JF - CANCER IMMUNOL IMMUN

SN - 0340-7004

IS - 8

ER -