title: Evaluation of genetic melanoma vaccines in cdk4-mutant mice provides evidence for immunological tolerance against authochthonous melanomas in the skin.
abstract: We evaluated the efficacy of a candidate melanoma vaccine approach in mice genetically prone to develop melanoma due to the introduction of an oncogenic mutation (R24C) in the germline sequence of the cyclin-dependent kinase 4 (cdk4), a protein critically involved in cell cycle regulation. Melanomas were induced in cdk4-mutant mice by chemical carcinogenesis and UVB irradiation. A genetic prime-boost strategy targeting the clinically relevant differentiation antigen tyrosinase-related protein 2 (TRP2) was performed which was able to stimulate a melanocyte-specific cellular immune response associated with localized autoimmune vitiligo-like depigmentation. However, significant destruction of carcinogen-induced autochthonous melanocytic neoplasms in the skin was not observed following immunization. We provide evidence that autochthonous melanomas expressed TRP2 but not the MHC molecule H2-Kb and are immunologically tolerated in the skin. Our results highlight the importance of assessing melanoma vaccines in genetic mouse models that more adequately represent the expected clinical situation in order to identify strategies, which eventually may be of benefit for melanoma patients.
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology, University of Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Steitz
authors.forename: Stefanie
authors.initials: S
authors.lastname: Büchs
authors.forename: Damia
authors.initials: D
authors.lastname: Tormo
authors.forename: Aleix
authors.initials: A
authors.lastname: Ferrer
authors.forename: Jörg
authors.initials: J
authors.lastname: Wenzel
authors.forename: Christoph
authors.initials: C
authors.lastname: Huber
authors.forename: Thomas
authors.initials: T
authors.lastname: Wölfel
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.forename: Marcos
authors.initials: M
authors.lastname: Malumbres
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
mesh_terms: D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D002273:Carcinogens; D002453:Cell Cycle / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D007108:Immune Tolerance; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D008545:Melanoma / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D019496:Cancer Vaccines; D002273:Carcinogens; D051358:Cyclin-Dependent Kinase 4; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase