Immunomodulatory Factors Control the Fate of Melanoma Tumor Initiating Cells.
Melanoma is a highly heterogeneous tumor for which recent evidence supports a model of dynamic stemness. Melanoma cells might temporally acquire tumor-initiating properties or switch from a status of tumor-initiating cells (TICs) to a more differentiated one depending on the tumor context. However, factors driving these functional changes are still unknown. We focused on the role of cyto/chemokines in shaping TICs isolated directly from tumor specimens of two melanoma patients, namely Me14346S and Me15888S. We analyzed the secretion profile of TICs and of their corresponding melanoma differentiated cells and we tested the ability of cyto/chemokines to influence TIC self-renewal and differentiation. We found that TICs, grown in vitro as melanospheres, had a complex secretory profile as compared to their differentiated counterparts. Some factors, such as CCL-2 and IL-8, also produced by adherent melanoma cells and melanocytes did not influence TIC properties. Conversely, IL-6, released by differentiated cells, reduced TIC self-renewal and induced TIC differentiation while IL-10, produced by Me15888S, strongly promoted TIC self-renewal through paracrine/autocrine actions. Complete neutralization of IL-10 activity by gene silencing and antibody-mediated blocking of the IL-10Rα was required to sensitize Me15888S to IL-6-induced differentiation. For the first time these results show that functional heterogeneity of melanoma could be directly influenced by inflammatory and suppressive soluble factors, with IL-6 favoring TIC differentiation, and IL-10 supporting TIC self-renewal. Thus, understanding the tumor microenvironment (TME) role in modulating melanoma TIC phenotype is fundamental to identifying novel therapeutic targets to achieve long-lasting regression of metastatic melanoma. Stem Cells 2016;34:2449-2460.
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.|Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Alessandra
A
Tuccitto
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.|Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Marcella
M
Tazzari
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.|Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Valeria
V
Beretta
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.|Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Francesca
F
Rini
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.|Molecular Mechanism Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Claudia
C
Miranda
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.|Molecular Mechanism Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Angela
A
Greco
Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Mario
M
Santinami
Melanoma and Sarcoma Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Roberto
R
Patuzzo
Consorzio MIA (Microscopy and Image Analysis), University of Milano-Bicocca, Milano, Italy.
Barbara
B
Vergani
Consorzio MIA (Microscopy and Image Analysis), University of Milano-Bicocca, Milano, Italy.
Antonello
A
Villa
Department of Predictive and Preventive Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Giacomo
G
Manenti
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Loredana
L
Cleris
Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Daniele
D
Giardiello
Centre for Tumour Biology, Barts Cancer Institute, Charterhouse Square, London, EC1M 6BQ, United Kingdom.
Malcolm
M
Alison
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.|Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Licia
L
Rivoltini
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. chiara.castelli@istitutotumori.mi.it.|Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy. chiara.castelli@istitutotumori.mi.it.
Chiara
C
Castelli
Unit of Immunotherapy of Human Tumors, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.|Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.
Michela
M
Perego
D019898:Autocrine Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000187:drug effects*; D000066673:Cell Self Renewal / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009500:Neutralization Tests; D019899:Paracrine Communication / Q000187:drug effects; D010641:Phenotype; D019707:Receptors, Chemokine / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D007155:Immunologic Factors; D015850:Interleukin-6; D019707:Receptors, Chemokine; D016753:Interleukin-10
Cytokines; Immune surveillance; Melanoma; Microenvironment; Tumor-initiating cells