title: Downregulation of sphingosine kinase-1 induces protective tumor immunity by promoting M1 macrophage response in melanoma.
abstract: 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.
authors.affiliation: Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Molecular Tumorigenesis and Anticancer Pharmacology, EDST, Lebanese University, Hadath, Lebanon.
authors.forename: Marguerite
authors.initials: M
authors.lastname: Mrad
authors.affiliation: Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Imbert
authors.affiliation: Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.
authors.forename: Virginie
authors.initials: V
authors.lastname: Garcia
authors.affiliation: VIB, Center for the Biology of Disease, Leuven, Belgium.
authors.forename: Florian
authors.initials: F
authors.lastname: Rambow
authors.affiliation: Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.
authors.forename: Nicole
authors.initials: N
authors.lastname: Therville
authors.affiliation: Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Carpentier
authors.affiliation: Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Ségui
authors.affiliation: Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Laboratoire de Biochimie Métabolique, Centre Hospitalier Universitaire Toulouse, Toulouse, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Levade
authors.affiliation: Molecular Tumorigenesis and Anticancer Pharmacology, EDST, Lebanese University, Hadath, Lebanon.
authors.forename: Rania
authors.initials: R
authors.lastname: Azar
authors.affiliation: VIB, Center for the Biology of Disease, Leuven, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Marine
authors.affiliation: Molecular Tumorigenesis and Anticancer Pharmacology, EDST, Lebanese University, Hadath, Lebanon.
authors.forename: Mona
authors.initials: M
authors.lastname: Diab-Assaf
authors.affiliation: Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Colacios
authors.affiliation: Université de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.|Inserm 1037, Centre de Recherches en Cancérologie de Toulouse, Equipe Labellisée Ligue Contre le Cancer 2013, Toulouse, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Andrieu-Abadie
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D049109:Cell Proliferation; D015536:Down-Regulation; D006801:Humans; D008264:Macrophages / Q000502:physiology*; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000502:physiology*; D049349:Receptors, Lysosphingolipid / Q000502:physiology; D000081025:Sphingosine-1-Phosphate Receptors; D053773:Transforming Growth Factor beta1 / Q000502:physiology; D000099157:Sphingosine Kinase
chemical_list: D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D000081025:Sphingosine-1-Phosphate Receptors; D053773:Transforming Growth Factor beta1; D000099157:Sphingosine Kinase; C477362:S1PR1 protein, human
keywords: inflammation; macrophage; melanoma; polarization; sphingosine 1-phosphate