title: Amino acid-modified calcitonin immunization induces tumor epitope-specific immunity in a transgenic mouse model for medullary thyroid carcinoma.
abstract: Up to now, no relevant tumor antigen has been identified in medullary thyroid carcinoma (MTC). The aim of the present study was to prove the concept of an immunization with an amino acid-modified calcitonin (CT) for the treatment of MTC in a transgenic mouse model. Amino acid-modified (human) CT has been chosen for vaccination because of its higher binding affinity to the murine H2-Kb-MHC molecule. Mice were immunized over 6 months with monthly injections of amino acid-modified CT-pulsed dendritic cells. For enumeration of tumor epitope-specific CD8+ cytotoxic T cells, tetramer analyses were performed. CT peptide-treated mice revealed a mean 0.73 +/- 0.45 and 0.91 +/- 0.59% positive cells, depending on the two tetramers tested, whereas no increase was seen in control protein-immunized mice (0.08-0.12% tetramer-positive cells). Importantly, the subset of CT-specific CD8+ T cells also showed a high expression of interferon-gamma. In line with these results, CT-immunized mice also showed an intratumor infiltration with CD8+ T lymphocytes. Importantly, we also found a diminished tumor outgrowth of -57% and a decrease of the serum CT levels (2.0 +/- 0.1 pg/ml) compared with control protein-immunized Ret/Cal mice (3.0 +/- 0.4 pg/ml). In summary, we show that amino acid-modified CT is recognized from the immune system leading to a specific antitumor immune response and a diminished tumor outgrowth in transgenic MTC mice. The results are of potential importance because they might be applicable to patients with metastatic spread of a MTC.
authors.affiliation: Endocrine Cancer Center, Department of Endocrinology, Diabetology and Rheumatology, University Hospital Duesseldorf, 40225 Duesseldorf, Germany.
authors.forename: Margret
authors.initials: M
authors.lastname: Wuttke
authors.forename: Claudia
authors.initials: C
authors.lastname: Papewalis
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Meyer
authors.forename: Caroline
authors.initials: C
authors.lastname: Kessler
authors.forename: Benedikt
authors.initials: B
authors.lastname: Jacobs
authors.forename: Holger S
authors.initials: HS
authors.lastname: Willenberg
authors.forename: Sven
authors.initials: S
authors.lastname: Schinner
authors.forename: Christine
authors.initials: C
authors.lastname: Kouatchoua
authors.forename: Thomas
authors.initials: T
authors.lastname: Baehring
authors.forename: Werner A
authors.initials: WA
authors.lastname: Scherbaum
authors.forename: Matthias
authors.initials: M
authors.lastname: Schott
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D000918:Antibody Specificity; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002116:Calcitonin / Q000737:chemistry / Q000276:immunology*; D018276:Carcinoma, Medullary / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007114:Immunization / Q000379:methods; D016233:Immunotherapy, Active; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000276:immunology; D013964:Thyroid Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D047368:Tumor Burden
chemical_list: D000596:Amino Acids; D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D002116:Calcitonin