Downregulation of sphingosine kinase-1 induces protective tumor immunity by promoting M1 macrophage response in melanoma
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Marguerite Mrad1,2,3, Caroline Imbert1,2, Virginie Garcia1,2, Florian Rambow4, Nicole Therville1,2, Stéphane Carpentier1,2, Bruno Ségui1,2, Thierry Levade1,2,5, Rania Azar3, Jean-Christophe Marine4, Mona Diab-Assaf3, Céline Colacios1,2, Nathalie Andrieu-Abadie1,2
1Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France
2Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France
3Molecular Tumorigenesis and Anticancer Pharmacology, EDST, Lebanese University, Hadath, Lebanon
4VIB, Center for the Biology of Disease, Leuven, Belgium
5Laboratoire de Biochimie Métabolique, Centre Hospitalier Universitaire Toulouse, Toulouse, France
Nathalie Andrieu-Abadie, email: [email protected]
Keywords: inflammation, melanoma, macrophage, polarization, sphingosine 1-phosphate
Received: December 09, 2015 Accepted: September 24, 2016 Published: September 30, 2016
The infiltration of melanoma tumors by macrophages is often correlated with poor prognosis. However, the molecular signals that regulate the dialogue between malignant cells and the inflammatory microenvironment remain poorly understood. We previously reported an increased expression of sphingosine kinase-1 (SK1), which produces the bioactive lipid sphingosine 1-phosphate (S1P), in melanoma. The present study aimed at defining the role of tumor SK1 in the recruitment and differentiation of macrophages in melanoma. Herein, we show that downregulation of SK1 in melanoma cells causes a reduction in the percentage of CD206highMHCIIlow M2 macrophages in favor of an increased proportion of CD206lowMHCIIhigh M1 macrophages into the tumor. This macrophage differentiation orchestrates T lymphocyte recruitment as well as tumor rejection through the expression of Th1 cytokines and chemokines. In vitro experiments indicated that macrophage migration is triggered by the binding of tumor S1P to S1PR1 receptors present on macrophages whereas macrophage differentiation is stimulated by SK1-induced secretion of TGF-β1. Finally, RNA-seq analysis of human melanoma tumors revealed a positive correlation between SK1 and TGF-β1 expression. Altogether, our findings demonstrate that melanoma SK1 plays a key role in the recruitment and phenotypic shift of the tumor macrophages that promote melanoma growth.
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