The shedded ectodomain of Lyve-1 expressed on M2-like tumor-associated macrophages inhibits melanoma cell proliferation
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Claudia Dollt1, Kathrin Becker1, Julia Michel2, Susanne Melchers1, Cleo-Aron Weis3, Kai Schledzewski1, Andreas Krewer1, Loreen Kloss1, Christoffer Gebhardt1,4, Jochen Utikal1,4 and Astrid Schmieder1
1Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany
2Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
3Institute of Pathology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
4Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
Claudia Dollt, email: [email protected]
Keywords: M2-like macrophages; tumor-associated macrophages; Lyve-1; melanoma; decoy receptor
Received: July 22, 2017 Accepted: September 20, 2017 Published: October 10, 2017
Targeting immune cells that support tumor growth is an effective therapeutic strategy in tumor entities such as melanoma. M2-like tumor-associated macrophages (TAM) sustain tumor growth by secreting anti-inflammatory cytokines, proteases and growth factors. In this study, we show that a protein derived from M2-like macrophages namely the shedded ectodomain of Lyve-1 (sLyve-1) decreases human HT144 and murine B16F1 melanoma cell proliferation significantly by acting as a decoy receptor for low-molecular weight hyaluronic acid (LMW-HA) although the LMW-HA/Lyve-1 interaction on lymphatic endothelial cells has been described to induce lymphangiogenesis. This is in line with our finding that the number of LYVE-1+ TAM decreases in higher human melanoma stages and that the early growth of B16 transplant tumors is enhanced in Lyve-1 knockout mice when compared to wild-type mice due to an increased melanoma cell proliferation. LYVE-1 expressing TAM are however true M2 macrophages as they co-express typical M2-markers such as CD163 and CD206. The results of the present study highlight the necessity to carefully determine the net effect particular TAM subpopulations have on tumors before establishing a treatment to target these immune cells.
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