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Detection of Spontaneous CD4⁺ T-Cell Responses in Melanoma Patients against a Tyrosinase-Related Protein-2–Derived Epitope Identified in HLA-DRB1*0301 Transgenic Mice

Authors' Affiliations: ¹ Skin Cancer Unit of the German Cancer Research Center Heidelberg, University Hospital Mannheim; ² Institute of Transfusion Medicine and Immunology, Mannheim, Germany; ³ Gesellschaft für Schwerionenforschung, Darmstadt, Germany; ⁴ Basel Institute for Immunology; ⁵ Roche Center for Medical Genomics; ⁶ Non-Clinical Immunology, Pharmaceutical Research, Basel, Switzerland; and ⁷ Department of Hematology and Oncology, Clinics of the University of Munich, Munich, Germany

Requests for reprints: Annette Paschen, Skin Cancer Unit of the German Cancer Research Center Heidelberg (Dermato-Oncology), University Hospital Mannheim, House 24, Theodor Kutzer Ufer 1, 68135 Mannheim, Germany. Phone: 49-621-383-2177; Fax: 49-621-383-2163; E-mail: a.paschen{at}dkfz.de.

Purpose: The frequently expressed differentiation antigen tyrosinase-related protein-2 (TRP-2) has repeatedly been described as a target of spontaneous cytotoxic T-cell responses in melanoma patients, suggesting that it might be an ideal candidate antigen for T cell–based immunotherapy. As a prerequisite for immunization, T-cell epitopes have to be identified. Whereas a number of HLA class I–presented TRP-2–derived epitopes are known, information about HLA class II–presented antigenic ligands recognized by CD4⁺ T helper (Th) cells is limited.

Experimental Design: The search for TRP-2–derived Th epitopes was carried out by competitive in vitro peptide binding studies with predicted HLA-DRB1*0301 ligands in combination with peptide and protein immunizations of HLA-DRB1*0301 transgenic mice. In vivo selected candidate epitopes were subsequently verified for their immunogenicity in human T-cell cultures.

Results: This strategy led to the characterization of TRP-2_60-74 as an HLA-DRB1*0301–restricted Th epitope. Importantly, TRP-2_60-74–reactive human CD4⁺ Th cell lines, specifically recognizing target cells loaded with recombinant TRP-2 protein, could be established by repeated peptide stimulation of peripheral blood lymphocytes from several HLA-DRB1*03⁺ melanoma patients. Even short-term peptide stimulation of patients' peripheral blood lymphocytes showed the presence of TRP-2_60-74–reactive T cells, suggesting that these T cells were already activated in vivo.

Conclusion: Peptide TRP-2_60-74 might be a useful tool for the improvement of immunotherapy and immune monitoring of melanoma patients.

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