title: Stimulation of invariant natural killer T cells by α-Galactosylceramide activates the JAK-STAT pathway in endothelial cells and reduces angiogenesis in the 5T33 multiple myeloma model.
abstract: Tumour pathogenesis in multiple myeloma (MM) correlates with a high vascular index. Therefore, targeting angiogenesis is an important therapeutic tool to reduce MM progression. This study aimed to investigate the role of invariant natural killer T (iNKT) cells in angiogenesis and the mechanisms behind the stimulation by α-Galactosylceramide (α-GalCer). We have previously found that α-GalCer could increase the survival of 5T33MM mice and here we demonstrate that α-GalCer reduces the microvessel density. We performed both in vivo and in vitro angiogenic assays to confirm this observation. We found that conditioned medium of α-GalCer stimulated iNKT cells reduced neovascularization in the chick chorioallantoic membrane and in matrigel plug assays. Moreover, we observed a reduction in proliferation, migration and network formation and an induction of apoptosis upon exposure of murine endothelial cell lines to this conditioned medium. We furthermore observed that the JAK-STAT signaling pathway was highly activated in endothelial cells in response to stimulated iNKT cells, indicating the possible role of IFN-γ in the anti-angiogenic process. In conclusion, these results highlight the possibility of recruiting iNKT cells to target MM and angiogenesis. This gives a rationale for combining immunotherapy with conventional anti-tumour treatments in view of increasing their therapeutic potential.
authors.affiliation: Department of Haematology and Immunology, Myeloma Centre Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium; Department of Biology, Faculty of Science and Technology, Hebron University, Hebron, Palestine.
authors.forename: Haneen
authors.initials: H
authors.lastname: Nur
authors.forename: Luigia
authors.initials: L
authors.lastname: Rao
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Frassanito
authors.forename: Hendrik
authors.initials: H
authors.lastname: De Raeve
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Josué Kunjom
authors.initials: JK
authors.lastname: Mfopou
authors.forename: Els
authors.initials: E
authors.lastname: Van Valckenborgh
authors.forename: Elke
authors.initials: E
authors.lastname: De Bruyne
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
mesh_terms: D000818:Animals; D002460:Cell Line; D005699:Galactosylceramides / Q000494:pharmacology*; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D053612:Janus Kinases / Q000276:immunology*; D051379:Mice; D009101:Multiple Myeloma / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D050791:STAT Transcription Factors / Q000276:immunology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology
chemical_list: D005699:Galactosylceramides; D050791:STAT Transcription Factors; C493154:alpha-galactosylceramide; D007371:Interferon-gamma; D053612:Janus Kinases
keywords: JAK-STAT pathway; MM-induced angiogenesis; invariant natural killer T cells; multiple myeloma; α-Galactosylceramide