Melanoma-initiating cells exploit M2 macrophage TGFβ and arginase pathway for survival and proliferation

// Muly Tham 1 , Kar Wai Tan 1,7 , Jo Keeble 1 , Xiaojie Wang 1 , Sandra Hubert 1 , Luke Barron 2 , Nguan Soon Tan 3 , Masashi Kato 4 , Armelle Prevost-Blondel 5 , Veronique Angeli 6 and Jean-Pierre Abastado 1,8 1 Singapore Immunology Network, BMSI, A-STAR, Singapore 2 Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA 3 School of Biological Sciences, Nanyang Technological University, Singapore 4 Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Japan 5 Institut Cochin, Université Paris Descartes, CNRS UMR, Paris, France 6 Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 7 Department of Clinical Research, Singapore General Hospital, Singapore 8 Institut de Recherche Internationales Servier, 50 rue Carnot, Suresnes cedex, France Correspondence: Muly Tham, email: // Keywords : Arginase, Macrophages, TGFβ, Tumor-initiating cell Received : July 13, 2014 Accepted : September 15, 2014 Published : September 16, 2014 Abstract M2 macrophages promote tumor growth and metastasis, but their interactions with specific tumor cell populations are poorly characterized. Using a mouse model of spontaneous melanoma, we showed that CD34 - but not CD34 + tumor-initiating cells (TICs) depend on M2 macrophages for survival and proliferation. Tumor-associated macrophages (TAMs) and macrophage-conditioned media protected CD34 - TICs from chemotherapy in vitro . In vivo , while inhibition of CD115 suppressed the macrophage-dependent CD34 - TIC population, chemotherapy accelerated its development. The ability of TICs to respond to TAMs was acquired during melanoma progression and immediately preceded a surge in metastatic outgrowth. TAM-derived transforming growth factor-β (TGFβ) and polyamines produced via the Arginase pathway were critical for stimulation of TICs and synergized to promote their growth.