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Dendritic Cell Vaccination with Xenogenic Polypeptide Hormone Induces Tumor Rejection in Neuroendocrine Cancer

Authors' Affiliations: ¹ Endocrine Cancer Center, Department of Endocrinology, Diabetes and Rheumatology, University Hospital Duesseldorf, Duesseldorf, Germany; ² Department of Internal Medicine (Innenstadt), Ludwig-Maximilians-University Muenchen, Muenchen, Germany; ³ INSERM U805; and ⁴ Institute Gustave Roussy, Villejuif, France

Requests for reprints: Matthias Schott, Department of Endocrinology, Diabetes and Rheumatology, University Hospital Duesseldorf, Moorenstr. 5, 40225 Duesseldorf, Germany. Phone: 49-211-8117810; Fax: 49-211-8117860; E-mail: matthias.schott{at}med.uni-duesseldorf.de.

Purpose: No relevant breakthrough has yet been achieved in the identification of tumor antigens in many neuroendocrine cancer types that exist, such as malignant gastrinoma, insulinoma, or medullary thyroid carcinoma. The aim of this study was to proof the concept of dendritic cell immunization with a tumor cell-specific polypeptide hormone as a target molecule in a transgenic mouse model for medullary thyroid carcinoma (Ret/Cal mice).

Experimental Design: Ret/Cal mice were repeatedly immunized for up to 6 months with amino acid–modified (xenogenic) calcitonin-pulsed dendritic cells. Xenogenic calcitonin was chosen for immunization due to its higher immunogenicity as compared with murine calcitonin.

Results: Lymph nodes from control protein-immunized mice did not show any macroscopic abnormalities, whereas tumor peptide-treated mice revealed in general profoundly enlarged lymph nodes. In tetramer analysis of paratumorous lymph nodes, 1.9% to 3.1% of all infiltrating CD8⁺ T cells were specific for one of three tumor epitopes tested. Analysis of the activated IFN--secreting component in splenic cells revealed an average of 2.8% tumor epitope-specific CD8⁺ cells. Immunohistochemistry revealed strong CD8⁺ tumor infiltration in calcitonin-vaccinated mice. In addition, these cells also showed strong in vitro lysis capacity at up to 63.3%. Most importantly, calcitonin-immunized mice revealed largely diminished tumor outgrowth (–74.3%) compared with control mice (P < 0.0001). Likewise, serum calcitonin levels in calcitonin-vaccinated Ret/Cal mice were lower than in the control group.

Conclusion: These results have a major effect, as they are the first to establish a role for xenogenic polypeptide hormones as target molecules for immunotherapy in endocrine malignancies.