Evaluation of genetic melanoma vaccines in cdk4-mutant mice provides evidence for immunological tolerance against authochthonous melanomas in the skin.
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.
Steitz
Julia
J
Laboratory of Experimental Dermatology, Department of Dermatology, University of Bonn, Germany.
Büchs
Stefanie
S
Tormo
Damia
D
Ferrer
Aleix
A
Wenzel
Jörg
J
Huber
Christoph
C
Wölfel
Thomas
T
Barbacid
Mariano
M
Malumbres
Marcos
M
Tüting
Thomas
T
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
D019496:Cancer Vaccines; D002273:Carcinogens; D051358:Cyclin-Dependent Kinase 4; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase