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An Inducible Mouse Model of Melanoma Expressing a Defined Tumor Antigen

¹ Ludwig Institute for Cancer Research and Cellular Genetics Unit, Université catholique de Louvain, Brussels, Belgium; Divisions of ² Molecular Genetics and Centre of Biomedical Genetics and ³ Experimental Animal Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; and ⁴ Centre d'Immunologie de Marseille-Luminy, Centre National de la Recherche Scientifique/Institut National de la Sante et de la Recherche Medicale, Université de la Méditerranée, Marseille, France

Requests for reprints: Benoît J. Van den Eynde, Ludwig Institute for Cancer Research, Avenue Hippocrate 74, UCL 7459, B-1200 Brussels, Belgium. Phone: 32-2-764-7572; Fax: 32-2-764-7590; E-mail: benoit.vandeneynde{at}bru.licr.org.

Cancer immunotherapy based on vaccination with defined tumor antigens has not yet shown strong clinical efficacy, despite promising results in preclinical models. This discrepancy might result from the fact that available preclinical models rely on transplantable tumors, which do not recapitulate the long-term host-tumor interplay that occurs in patients during progressive tumor development and results in tumor tolerance. To create a faithful preclinical model for cancer immunotherapy, we generated a transgenic mouse strain developing autologous melanomas expressing a defined tumor antigen recognized by T cells. We chose the antigen encoded by P1A, a well-characterized murine cancer germ line gene. To transform melanocytes, we aimed at simultaneously activating the Ras pathway and inactivating tumor suppressor Ink4a/Arf, thereby reproducing two genetic events frequently observed in human melanoma. The melanomas are induced by s.c. injection of 4-OH-tamoxifen (OHT). By activating a CreER recombinase expressed from a melanocyte-specific promoter, this treatment induces the loss of the conditional Ink4a/Arf gene in melanocytes. Because the CreER gene itself is also flanked by loxP sites, the activation of CreER also induces the deletion of its own coding sequence and thereby allows melanocyte-specific expression of genes H-ras and P1A, which are located downstream on the same transgene. All melanomas induced in those mice with OHT show activation of the Ras pathway and deletion of gene Ink4a/Arf. In addition, these melanomas express P1A and are recognized by P1A-specific T lymphocytes. This model will allow to characterize the interactions between the immune system and naturally occurring tumors and thereby to optimize immunotherapy approaches targeting a defined tumor antigen. (Cancer Res 2006; 66(6): 3278-86)