Specific peptide-mediated immunity against established melanoma tumors with dendritic cells requires IL-2 and fetal calf serum-free cell culture.
Melanoma, despite its aggressive growth characteristics, is an antigenic tumor expressing several characterized neo- and differentiation antigens. Dendritic cells (DC) when pulsed with defined peptides have been shown to effectively induce melanoma-specific T cell responses in humans and mice. These protect animals from challenge with melanoma, but so far have failed to induce significant tumor regressions. To study the efficacy of DC-based anti-tumor vaccinations, we set up a therapeutic model using C57BL/6J mice with established pulmonary and subcutaneous metastases induced by the B16-melanoma cell line B78-D14. Mice were vaccinated twice with 20,000 antigen-presenting cells, either bone marrow-derived DC or epidermal Langerhans cells (LC), which were loaded with the tyrosinase-related protein 2 (TRP2) peptide. Generally, DC cultured with fetal calf serum (FCS) induced a dominant unspecific response. This was not seen using LC cultured without serum; however, vaccination with TRP2-loaded FCS-free LC alone failed to influence the growth of established B16 tumors. A reproducible reduction of tumor size and weight was only obtained if LC vaccinations with TRP2 were followed by a 5-day treatment of mice with 200,000 IU IL-2 intraperitoneally twice/daily. Omitting the TRP2 peptide abolished the efficacy of this combined treatment, demonstrating the crucial role of priming a melanoma-specific T cell response. Microcytotoxic assays performed with spleen-derived T cells and melanoma as well as congenic fibroblast lines as targets confirmed the TRP2-dependent specificity of LC-induced immune responses. Thus, despite the fact that tumor-specific T cells were primed, an additional IL-2-dependent stimulus was needed to translate this immune response into a therapeutic effect against established tumors.
Eggert
Andreas O
AO
Department of Dermatology, School of Medicine, University of Würzburg, Würzburg, Germany.
Becker
Jürgen C
JC
Ammon
Michael
M
McLellan
Alexander D
AD
Renner
German
G
Merkel
Angela
A
Bröcker
Eva-B
EB
Kämpgen
Eckhart
E
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology* / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000276:immunology; D016895:Culture Media, Serum-Free; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D007167:Immunotherapy; D007376:Interleukin-2 / Q000008:administration & dosage / Q000276:immunology*; D019746:Intramolecular Oxidoreductases / Q000276:immunology* / Q000627:therapeutic use; D008546:Melanoma, Experimental / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D010455:Peptides / Q000276:immunology* / Q000627:therapeutic use; D012710:Serum Albumin, Bovine; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D016895:Culture Media, Serum-Free; D007376:Interleukin-2; D010455:Peptides; D012710:Serum Albumin, Bovine; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase