Spontaneous CD8 T cell responses against the melanocyte differentiation antigen RAB38/NY-MEL-1 in melanoma patients

Senta M Walton, Marco Gerlinger, Olga de la Rosa, Natko Nuber, Ashley Knights, Asma Gati, Monika Laumer, Laura Strauss, Carolin Exner, Niklaus Schäfer, Mirjana Urosevic, Reinhard Dummer, Jean-Marie Tiercy, Andreas Mackensen, Elke Jaeger, Frédéric Lévy, Alexander Knuth, Dirk Jäger, Alfred Zippelius

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

Abstract

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-1(50-58) 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-1(50-58) peptide. Accordingly, monoclonal RAB38/NY-MEL-1(50-58)-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-1(50-58) 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-1(50-58) 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.

Original languageEnglish
Pages (from-to)8212-8
Number of pages7
JournalThe Journal of Immunology
Volume177
Issue number11
Publication statusPublished - 1 Dec 2006
Externally publishedYes

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