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* Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne, Switzerland;
Swiss Institute of Bioinformatics, Lausanne, Switzerland;
Multidisciplinary Oncology Center, Lausanne University Hospital, Lausanne, Switzerland; and
Ludwig Institute for Cancer Research, Lausanne Branch, Epalinges, Switzerland
HLA-A2-restricted cytolytic T cells specific for the immunodominant human tumor Ag Melan-AMART-1 can kill most HLA-matched melanoma cells, through recognition of two naturally occurring antigenic variants, i.e., Melan-A nonamer AAGIGILTV and decamer EAAGIGILTV peptides. Several previous studies have suggested a high degree of TCR cross-reactivity to the two peptides. In this study, we describe for the first time that some T cell clones are exclusively nonamer specific, because they are not labeled by A2/decamer-tetramers and do not recognize the decamer when presented endogenously. Functional assays with peptides gave misleading results, possibly because decamers were cleaved by exopeptidases. Interestingly, nonapeptide-specific T cell clones were rarely V
2.1 positive (only 1 of 19 clones), in contrast to the known strong bias for V2.1-positive TCRs found in decamer-specific clones (59 of 69 clones). Molecular modeling revealed that nonapeptide-specific TCRs formed unfavorable interactions with the decapeptide, whereas decapeptide-specific TCRs productively created a hydrogen bond between CDR1 and glutamic acid (E) of the decapeptide. Ex vivo analysis of T cells from melanoma metastases demonstrated that both nonamer and decamer-specific T cells were enriched to substantial frequencies in vivo, and representative clones showed efficient tumor cell recognition and killing. We conclude that the two peptides should be regarded as distinct epitopes when analyzing tumor immunity and developing immunotherapy against melanoma.
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 and sponsored by the Ludwig Institute for Cancer Research, the Swiss Cancer League/Oncosuisse, the Swiss National Science Foundation, and the Swiss National Center of Competence in Research Molecular Oncology. P.R. was funded in part by a grant from the European Community FP6, Cancer Immunotherapy.
2 Address correspondence and reprint requests to Dr. Daniel E. Speiser, Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Hôpital Orthopédique, Niveau 5 Est, Avenue Pierre-Decker 4, CH-1005 Lausanne, Switzerland. E-mail address: daniel.speiser{at}hospvd.ch
3 Abbreviations used in this paper: TIL, tumor infiltrating lymphocyte; TILN, tumor-infiltrated lymph node cell; p-MHC, peptide-MHC.
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  V. Voelter, N. Rufer, S. Reynard, G. Greub, R. Brookes, P. Guillaume, F. Grosjean, T. Fagerberg, O. Michelin, S. Rowland-Jones, et al. Characterization of Melan-A reactive memory CD8+ T cells in a healthy donor Int. Immunol., August 1, 2008; 20(8): 1087 - 1096. [Abstract] [Full Text] [PDF]
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