An inducible mouse model of melanoma expressing a defined tumor antigen.
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.
Huijbers
Ivo J
IJ
Ludwig Institute for Cancer Research and Cellular Genetics Unit, Université Catholique de Louvain, Brussels, Belgium.
Krimpenfort
Paul
P
Chomez
Patrick
P
van der Valk
Martin A
MA
Song
Ji-Ying
JY
Inderberg-Suso
Else-Marit
EM
Schmitt-Verhulst
Anne-Marie
AM
Berns
Anton
A
Van den Eynde
Benoît J
BJ
D000818:Animals; D000951:Antigens, Neoplasm / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D011995:Recombination, Genetic; D013629:Tamoxifen / Q000031:analogs & derivatives; D025803:Tumor Suppressor Protein p14ARF / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
D000951:Antigens, Neoplasm; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; C507749:cancer-testis antigen P1A, mouse; D013629:Tamoxifen; C016601:afimoxifene; D018631:ras Proteins