title: Therapeutic efficacy of antigen-specific vaccination and toll-like receptor stimulation against established transplanted and autochthonous melanoma in mice.
abstract: Malignant melanoma is an attractive model disease for the development of antigen-specific immunotherapy because many antigens recognized by tumor-specific T cells have been identified. In C57BL/6 mice, genetic immunization with recombinant adenovirus encoding xenogeneic human tyrosinase-related protein 2 (Ad-hTRP2) induces protective but not therapeutic cellular immunity against growth of transplanted B16 melanoma cells. Here, we additionally applied CpG DNA and synthetic double-stranded RNA, which activate the innate immune system via Toll-like receptors (TLR). Both adenoviral vaccination and peritumoral injections of TLR ligands were required for rejection of established B16 melanoma in the skin. To more closely mimic the clinical situation in patients with melanoma, we evaluated this combined immunotherapeutic strategy in genetically modified mice, which overexpress hepatocyte growth factor (HGF) and carry an oncogenic mutation in the cyclin-dependent kinase 4 (CDK4)(R24C). HGF x CDK4(R24C) mice rapidly develop multiple invasive melanomas in the skin following neonatal carcinogen treatment, which spontaneously metastasize to lymph nodes and lungs. Vaccination with Ad-hTRP2 followed by injections of TLR ligands resulted in delayed growth of autochthonous primary melanomas in the skin and reduction in the number of spontaneous lung metastases but did not induce tumor regression. Carcinogen-treated HGF x CDK4(R24C) mice bearing multiple autochthonous melanomas did not reject transplanted B16 melanoma despite treatment with Ad-hTRP2 and TLR ligands, suggesting the development of tumor immunotolerance. Further investigations in our novel genetic melanoma model may help to better understand the role of the immune system in the pathogenesis and treatment of this life-threatening disease.
authors.affiliation: Laboratory of Experimental Dermatology, Department of Dermatology, University of Bonn, Bonn, Germany.
authors.forename: Damia
authors.initials: D
authors.lastname: Tormo
authors.forename: Aleix
authors.initials: A
authors.lastname: Ferrer
authors.forename: Pilar
authors.initials: P
authors.lastname: Bosch
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.forename: Etiena
authors.initials: E
authors.lastname: Basner-Tschakarjan
authors.forename: Jörg
authors.initials: J
authors.lastname: Wenzel
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D018899:CpG Islands / Q000235:genetics / Q000276:immunology; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D000939:Epitopes; D005260:Female; D017228:Hepatocyte Growth Factor / Q000235:genetics; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology*; D008175:Lung Neoplasms / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011070:Poly I-C / Q000494:pharmacology; D012878:Skin Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051193:Toll-Like Receptors / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology / Q000494:pharmacology*
chemical_list: D019496:Cancer Vaccines; D000939:Epitopes; D051193:Toll-Like Receptors; D019444:Vaccines, DNA; D017228:Hepatocyte Growth Factor; D051358:Cyclin-Dependent Kinase 4; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase; D011070:Poly I-C