An inducible mouse model of melanoma expressing a defined tumor antigen

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 6; pp. 3278 - 3286
• Main Authors: HUIJBERS, Ivo J, KRIMPENFORT, Paul, CHOMEZ, Patrick, VAN DER VALK, Martin A, SONG, Ji-Ying, INDERBERG-SUSO, Else-Marit, SCHMITT-VERHULST, Anne-Marie, BERNS, Anton, VAN DEN EYNDE, Benoit J
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.03.2006
• Subjects: Animals; Antigens, Neoplasm - biosynthesis; Antigens, Neoplasm - genetics; Antigens, Neoplasm - immunology; Antineoplastic agents; Biological and medical sciences; CD8-Positive T-Lymphocytes - immunology; Cyclin-Dependent Kinase Inhibitor p16 - antagonists & inhibitors; Cyclin-Dependent Kinase Inhibitor p16 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Dermatology; Disease Models, Animal; Immunology; Life Sciences; Medical sciences; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Mice; Mice, Transgenic; Pharmacology. Drug treatments; ras Proteins - genetics; Recombination, Genetic; Tamoxifen - analogs & derivatives; Tumor Suppressor Protein p14ARF - antagonists & inhibitors; Tumor Suppressor Protein p14ARF - biosynthesis; Tumor Suppressor Protein p14ARF - genetics; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; Animal model; Vertebrata; Mammalia; Tumor associated antigen; Mouse; Rodentia; Malignant melanoma; Malignant tumor; Gene expression
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-3216

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.