title: Skin-depigmenting agent monobenzone induces potent T-cell autoimmunity toward pigmented cells by tyrosinase haptenation and melanosome autophagy.
abstract: In this study, we report the previously unknown mechanism of inducing robust anti-melanoma immunity by the vitiligo-inducing compound monobenzone. We show monobenzone to increase melanocyte and melanoma cell immunogenicity by forming quinone-haptens to the tyrosinase protein and by inducing the release of tyrosinase- and melanoma antigen recognized by T cells-1 (MART-1)-containing CD63+ exosomes following melanosome oxidative stress induction. Monobenzone further augments the processing and shedding of melanocyte-differentiation antigens by inducing melanosome autophagy and enhanced tyrosinase ubiquitination, ultimately activating dendritic cells, which induced cytotoxic human melanoma-reactive T cells. These T cells effectively eradicate melanoma in vivo, as we have reported previously. Monobenzone thereby represents a promising and readily applicable compound for immunotherapy in melanoma patients.
authors.affiliation: Department of Dermatology and The Netherlands Institute for Pigment Disorders, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Jasper G
authors.initials: JG
authors.lastname: van den Boorn
authors.forename: Daisy I
authors.initials: DI
authors.lastname: Picavet
authors.forename: Paul F
authors.initials: PF
authors.lastname: van Swieten
authors.forename: Henk A
authors.initials: HA
authors.lastname: van Veen
authors.forename: Debby
authors.initials: D
authors.lastname: Konijnenberg
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.forename: Toni
authors.initials: T
authors.lastname: van Capel
authors.forename: Esther C de
authors.initials: EC
authors.lastname: Jong
authors.forename: Eric A
authors.initials: EA
authors.lastname: Reits
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Jan D
authors.initials: JD
authors.lastname: Bos
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Rosalie M
authors.initials: RM
authors.lastname: Luiten
mesh_terms: D015551:Autoimmunity / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D003713:Dendritic Cells / Q000276:immunology; D006684:HLA-DR Antigens / Q000032:analysis; D006241:Haptens / Q000378:metabolism*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D008247:Lysosomes / Q000378:metabolism; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000187:drug effects* / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D020460:Melanosomes / Q000187:drug effects* / Q000502:physiology; D014442:Monophenol Monooxygenase / Q000276:immunology / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012880:Skin Pigmentation / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D054875:Ubiquitination
chemical_list: D006684:HLA-DR Antigens; D006241:Haptens; D006873:Hydroquinones; D008543:Melanins; D017382:Reactive Oxygen Species; C006429:monobenzone; D014442:Monophenol Monooxygenase