title: Modulation of Acid Sphingomyelinase in Melanoma Reprogrammes the Tumour Immune Microenvironment.
abstract: The inflammatory microenvironment induces tumours to acquire an aggressive and immunosuppressive behaviour. Since acid sphingomyelinase (A-SMase) downregulation in melanoma was shown to determine a malignant phenotype, we aimed here to elucidate the role of A-SMase in the regulation of tumour immunogenic microenvironment using in vivo melanoma models in which A-SMase was either downregulated or maintained at constitutively high levels. We found high levels of inflammatory factors in low A-SMase expressing tumours, which also displayed an immunosuppressive/protumoural microenvironment: high levels of myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs), as well as low levels of dendritic cells (DCs). In contrast, the restoration of A-SMase in melanoma cells not only reduced tumour growth and immunosuppression, but also induced a high recruitment at tumour site of effector immune cells with an antitumoural function. Indeed, we observed a poor homing of MDSCs and Tregs and the increased recruitment of CD8(+) and CD4(+) T lymphocytes as well as the infiltration of DCs and CD8(+)/CD44(high) T lymphocytes. This study demonstrates that change of A-SMase expression in cancer cells is sufficient per se to tune in vivo melanoma growth and that A-SMase levels modulate immune cells at tumour site. This may be taken into consideration in the setting of therapeutic strategies.
authors.affiliation: Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy ; Division of Molecular Oncology, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Assi
authors.affiliation: Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), University Hospital "Luigi Sacco", Università di Milano, 20157 Milan, Italy ; Department for Innovation in Biological, Agro-Food and Forest Systems (DIBAF), Università della Tuscia, 01100 Viterbo, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Cervia
authors.affiliation: Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy ; Department of Oncology, Università di Torino and Laboratory of Neurovascular Biology, Candiolo Cancer Institute, 10060 Candiolo, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Bizzozero
authors.affiliation: Division of Regenerative Medicine, San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Annalisa
authors.identifier: 0000-0002-0271-6323
authors.initials: A
authors.lastname: Capobianco
authors.affiliation: Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), University Hospital "Luigi Sacco", Università di Milano, 20157 Milan, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: Pambianco
authors.affiliation: Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), University Hospital "Luigi Sacco", Università di Milano, 20157 Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Morisi
authors.affiliation: Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), University Hospital "Luigi Sacco", Università di Milano, 20157 Milan, Italy.
authors.forename: Clara
authors.initials: C
authors.lastname: De Palma
authors.affiliation: Unit of Morphology, Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), Università di Milano, 20157 Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Moscheni
authors.affiliation: Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), University Hospital "Luigi Sacco", Università di Milano, 20157 Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Pellegrino
authors.affiliation: Scientific Institute IRCCS Eugenio Medea, 23842 Bosisio Parini, Italy ; Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), University Hospital "Luigi Sacco", Università di Milano, 20157 Milan, Italy.
authors.forename: Emilio
authors.identifier: 0000-0001-7333-8270
authors.initials: E
authors.lastname: Clementi
authors.affiliation: Unit of Clinical Pharmacology, National Research Council-Institute of Neuroscience, Department of Biomedical and Clinical Sciences "Luigi Sacco" (DIBIC), University Hospital "Luigi Sacco", Università di Milano, 20157 Milan, Italy.
authors.forename: Cristiana
authors.identifier: 0000-0001-6680-4536
authors.initials: C
authors.lastname: Perrotta
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D065150:Cellular Reprogramming; D005260:Female; D007108:Immune Tolerance; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D013108:Sphingomyelin Phosphodiesterase / Q000502:physiology*; D059016:Tumor Microenvironment
chemical_list: D013108:Sphingomyelin Phosphodiesterase