The shedded ectodomain of Lyve-1 expressed on M2-like tumor-associated macrophages inhibits melanoma cell proliferation

// Claudia Dollt 1 , Kathrin Becker 1 , Julia Michel 2 , Susanne Melchers 1 , Cleo-Aron Weis 3 , Kai Schledzewski 1 , Andreas Krewer 1 , Loreen Kloss 1 , Christoffer Gebhardt 1, 4 , Jochen Utikal 1, 4 and Astrid Schmieder 1 1 Department of Dermatology, Venereology and Allergology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, and Center of Excellence in Dermatology, Mannheim, Germany 2 Department of Innate Immunity and Tolerance, Institute of Transfusion Medicine and Immunology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany 3 Institute of Pathology, University Medical Center and Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany 4 Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany Correspondence to: Claudia Dollt, email: claudia.dollt@gmx.de Keywords: M2-like macrophages; tumor-associated macrophages; Lyve-1; melanoma; decoy receptor Received: July 22, 2017     Accepted: September 20, 2017     Published: October 10, 2017 ABSTRACT 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.