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* Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland;
Department of Hematology/Oncology, University of Regensburg, Regensburg, Germany;
Dermatologische Klinik, University Hospital Zurich, Zurich, Switzerland;
Transplantation Immunology Unit, University Hospital, Geneva, Switzerland;
¶ II Medizinische Klinik, Krankenhaus Nordwest, Frankfurt, Germany;
|| Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; and
# Medizinische Onkologie, National Center for Tumor Diseases, University Hospital Heidelberg, Germany
The melanocyte differentiation Ag RAB38/NY-MEL-1 was identified by serological expression cloning (SEREX) and is expressed in the vast majority of melanoma lesions. The immunogenicity of RAB38/NY-MEL-1 has been corroborated previously by the frequent occurrence of specific Ab responses in melanoma patients. To elucidate potential CD8 T cell responses, we applied in vitro sensitization with overlapping peptides spanning the RAB38/NY-MEL-1 protein sequence and the reverse immunology approach. The identified peptide RAB38/NY-MEL-150–58 exhibited a marked response in ELISPOT assays after in vitro sensitization of CD8 T cells from HLA-A*0201+ melanoma patients. In vitro digestion assays using purified proteasomes provided evidence of natural processing of RAB38/NY-MEL-150–58 peptide. Accordingly, monoclonal RAB38/NY-MEL-150–58-specific T cell populations were capable of specifically recognizing HLA-A2+ melanoma cell lines expressing RAB38/NY-MEL-1. Applying fluorescent HLA-A2/RAB38/NY-MEL-150–58 multimeric constructs, we were able to document a spontaneously developed memory/effector CD8 T cell response against this peptide in a melanoma patient. To elucidate the Ag-processing pathway, we demonstrate that RAB38/NY-MEL-150–58 is produced efficiently by the standard proteasome and the immunoproteasome. In addition to the identification of a RAB38/NY-MEL-1-derived immunogenic CD8 T cell epitope, this study is instrumental for both the onset and monitoring of future RAB38/NY-MEL-1-based vaccination trials.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by a Swiss National Science Foundation special program and a grant from the Cancer Research Institute/Ludwig Institute for Cancer Research Cancer Vaccine Collaborative; the Terry-Fox, Hanne-Liebermann, and Claudia-von-Schilling Foundation; and the UBS Wealth Management. A.Z., A.G., and S.W. were supported in part by the Emmy-Noether Program (Zi685-2/3) of the Deutsche Forschungsgemeinschaft. F.L. was supported by the Swiss National Foundation and the Cancer Research Institute.
2 S.M.W. and M.G. contributed equally to this work.
3 D.J. and A.Z. contributed equally to this work.
4 Address correspondence and reprint requests to Dr. Alfred Zippelius, Medical Oncology, Department of Internal Medicine, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland. E-mail address: Alfred.zippelius{at}usz.ch
5 Abbreviation used in this paper: DC, dendritic cell.
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