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

  • Focussed Research Review
  • Published:
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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 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.

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Abbreviations

ARG:

Arginase

BM:

Bone marrow

CCL:

C-C motif ligand

CCR:

C-C motif receptor

CXCL:

C-X-C motif ligand

CXCR:

C-X-C motif receptor

DCs:

Dendritic cells

GM–CSF:

Granulocyte–macrophage colony-stimulating factor

HIF:

Hypoxia-inducible factor

IFN:

Interferon

IL:

Interleukin

M:

Monocytic

MDSCs:

Myeloid-derived suppressor cells

NF-κB:

Nuclear factor-κB

NO:

Nitric oxide

PD-1:

Programmed death receptor

PD-L1:

Programmed death-ligand 1

PMN:

Polymorphonuclear

ROS:

Reactive oxygen species

TGF:

Transforming growth factor

TNF:

Tumor necrosis factor

Tregs:

Regulatory T cells

VEGF:

Vascular endothelial growth factor

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Acknowledgements

This work was supported by Grants from the German Research Council (RTG2099 to J. Utikal, V. Umansky and GE-2152/1-2 to C. Gebhardt), the Cooperation between German Cancer Research Center (DKFZ) and Ministry of Science, Technology and Space of Israel (MOST) in Cancer Research (CA157 to V. Umansky and C. Blattner) and the German Cancer Aid (109312 to J. Utikal). This work was kindly backed by the COST Action “European Network of Investigators Triggering Exploratory Research on Myeloid Regulatory Cells” (Mye-EUNITER). COST is supported by the EU Framework Program Horizon 2020.

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Authors and Affiliations

  1. Skin Cancer Unit (G300), German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Viktor Umansky, Carolin Blattner, Christoffer Gebhardt & Jochen Utikal

  2. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht Karl University of Heidelberg, Mannheim, Germany

    Viktor Umansky, Carolin Blattner, Christoffer Gebhardt & Jochen Utikal

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  1. Viktor Umansky
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Correspondence to Viktor Umansky.

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This paper is a Focussed Research Review based on a presentation given at the conference Regulatory Myeloid Suppressor Cells: From Basic Discovery to Therapeutic Application which was hosted by the Wistar Institute in Philadelphia, PA, USA, 16th–19th June, 2016. It is part of a Cancer Immunology, Immunotherapy series of Focussed Research Reviews.

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Umansky, V., Blattner, C., Gebhardt, C. et al. CCR5 in recruitment and activation of myeloid-derived suppressor cells in melanoma. Cancer Immunol Immunother 66, 1015–1023 (2017). https://doi.org/10.1007/s00262-017-1988-9

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