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T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma
Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim , Heidelberg 69120, Germany
Division of Translational Immunology, German Cancer Center, Heidelberg 69120, Germany
Unit of Environmental Health Sciences, Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Aichi 487-8501, Japan
Department of Dermatology, University Hospital Essen, Essen 45122, Germany
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 27 February 2012; in revised form: 4 April 2012 / Accepted: 18 April 2012 / Published: 26 April 2012
Abstract: Poor response of human malignant melanoma to currently available treatments requires a development of innovative therapeutic strategies. Their evaluation should be based on animal models that resemble human melanoma with respect to genetics, histopathology and clinical features. Here we used a transgenic mouse model of spontaneous skin melanoma, in which the ret transgene is expressed in melanocytes under the control of metallothionein-I promoter. After a short latency, around 25% mice develop macroscopic skin melanoma metastasizing to lymph nodes, bone marrow, lungs and brain, whereas other transgenic mice showed only metastatic lesions without visible skin tumors. We found that tumor lesions expressed melanoma associated antigens (MAA) tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100, which could be applied as targets for the immunotherapy. Upon peptide vaccination, ret transgenic mice without macroscopic melanomas were able to generate T cell responses not only against a strong model antigen ovalbumin but also against typical MAA TRP-2. Although mice bearing macroscopic primary tumors could also display an antigen-specific T cell reactivity, it was significantly down-regulated as compared to tumor-free transgenic mice or non-transgenic littermates. We suggest that ret transgenic mice could be used as a pre-clinical model for the evaluation of novel strategies of melanoma immunotherapy.
Keywords: melanoma; transgenic mouse model; T cells; immunization, cytokines; melanoma associated antigens
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Abschuetz, O.; Osen, W.; Frank, K.; Kato, M.; Schadendorf, D.; Umansky, V. T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma. Cancers 2012, 4, 490-503.
Abschuetz O, Osen W, Frank K, Kato M, Schadendorf D, Umansky V. T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma. Cancers. 2012; 4(2):490-503.
Abschuetz, Oliver; Osen, Wolfram; Frank, Kathrin; Kato, Masashi; Schadendorf, Dirk; Umansky, Viktor. 2012. "T-Cell Mediated Immune Responses Induced in ret Transgenic Mouse Model of Malignant Melanoma." Cancers 4, no. 2: 490-503.