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Final Antigenic Melan-A Peptides Produced Directly by the Proteasomes Are Preferentially Selected for Presentation by HLA-A*0201 in Melanoma Cells¹

Laurence Chapatte^*, Catherine Servis^*,,¶, Danila Valmori, Odile Burlet-Schiltz, Johanna Dayer^*, Bernard Monsarrat, Pedro Romero^,¶ and Frédéric Lévy^2,*,¶

^* Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; Division of Clinical Onco-Immunology, Ludwig Institute for Cancer Research, Lausanne Branch, University Hospital, Lausanne, Switzerland; Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche ScientifiqueS, Toulouse, France; Department of Biochemistry, University of Lausanne, Epalinges, Switzerland; and ^¶ National Center of Competence in Research-Molecular Oncology, Epalinges, Switzerland

The melanoma-associated protein Melan-A contains the immunodominant CTL epitope Melan-A_26/27–35/HLA-A*0201 against which a high frequency of T lymphocytes has been detected in many melanoma patients. In this study we show that the in vitro degradation of a polypeptide encompassing Melan-A_26/27–35 by proteasomes produces both the final antigenic peptide and N-terminally extended intermediates. When human melanoma cells expressing the corresponding fragments were exposed to specific CTL, those expressing the minimal antigenic sequence were recognized more efficiently than those expressing the N-terminally extended intermediates. Using a tumor-reactive CTL clone, we confirmed that the recognition of melanoma cells expressing an N-terminally extended intermediate of Melan-A is inefficient. We demonstrated that the inefficient cytosolic trimming of N-terminally extended intermediates could offer a selective advantage for the preferred presentation of Melan-A peptides directly produced by the proteasomes. These results imply that both the proteasomes and postproteasomal peptidases limit the availability of antigenic peptides and that the efficiency of presentation may be affected by conditions that alter the ratio between fully and partially processed proteasomal products.

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