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J Invest Dermatol. 2019 Jan;139(1):186-194. doi: 10.1016/j.jid.2018.07.006. Epub 2018 Oct 4.

CXCL5 as Regulator of Neutrophil Function in Cutaneous Melanoma.

Author information

1
Skin and Endothelium Research Division (SERD), Department of Dermatology, Medical University of Vienna, Vienna, Austria.
2
Institute of Immunology Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.
3
Institute of Molecular Biology (IMB) GmbH, Mainz, Germany.
4
Bioinformatics Unit, Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
5
Skin and Endothelium Research Division (SERD), Department of Dermatology, Medical University of Vienna, Vienna, Austria; Division of General Dermatology and Dermatooncology, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
6
Skin and Endothelium Research Division (SERD), Department of Dermatology, Medical University of Vienna, Vienna, Austria; Division of General Dermatology and Dermatooncology, Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address: robert.loewe@meduniwien.ac.at.

Abstract

Chemokines mold the tumor microenvironment by recruiting distinct immune cell populations, thereby strongly influencing disease progression. Previously, we showed that CXCL5 expression is upregulated in advanced stages of primary melanomas, which correlates with the presence of neutrophils in the tumor. The analysis of neutrophil populations in various tissues revealed a distinct phenotype of tumor-associated neutrophils. Tumor-associated neutrophils expressed PD-L1, CXCR4, CCR5, Adam17, and Nos2 and were immunosuppressive in a T-cell proliferation assay. To investigate the impact of CXCL5 and neutrophils in vivo, we established a syngeneic mouse tumor transplantation model using CXCL5-overexpressing and control melanoma cell lines. Growth behavior or vascularization of primary tumors was not affected by CXCL5 expression and neutrophils alone. However, in combination with Poly(I:C), tumor-associated neutrophils were able to attenuate induced antitumoral T-cell responses. CXCL5-overexpressing tumors had reduced lung metastasis compared with control tumors. Neutrophil depletion reversed this effect. In vitro, unstimulated lung-derived neutrophils had higher levels of reactive oxygen species compared with tumor-associated neutrophils, and CXCL5 stimulation further increased reactive oxygen species levels. In summary, in melanoma, neutrophils play a context-dependent role that is influenced by local or systemic factors, and interfere with therapies activating the acquired immune system. Actively switching neutrophils into antitumorigenic mode might be a new therapeutic strategy.

PMID:
30009831
DOI:
10.1016/j.jid.2018.07.006

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