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Original Article

¹ Ludwig Institute for Cancer Research and Cellular Genetics Unit, Université de Louvain, B-1200 Brussels, Belgium
² Institut de Pharmacologie et de Biologie Structurale, Centre National de la Recherche Scientifique, F-31077 Toulouse Cedex, France
³ Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico H.S. Raffaele, I-20132 Milano, Italy
⁴ Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, CH-1066 Epalinges, Switzerland

Address correspondence to P. van der Bruggen, Ludwig Institute for Cancer Research, 74 Ave., Hippocrate UCL 74.59, B-1200 Brussels, Belgium. Phone: 322-764-7431; Fax: 322-762-9405; E-mail: pierre.vanderbruggen{at}bru.licr.org

By stimulating human CD8⁺ T lymphocytes with autologous dendritic cells infected with an adenovirus encoding MAGE-3, we obtained a cytotoxic T lymphocyte (CTL) clone that recognized a new MAGE-3 antigenic peptide, AELVHFLLL, which is presented by HLA-B40. This peptide is also encoded by MAGE-12. The CTL clone recognized MAGE-3–expressing tumor cells only when they were first treated with IFN-. Since this treatment is known to induce the exchange of the three catalytic subunits of the proteasome to form the immunoproteasome, this result suggested that the processing of this MAGE-3 peptide required the immunoproteasome. Transfection experiments showed that the substitution of ß5i (LMP7) for ß5 is necessary and sufficient for producing the peptide, whereas a mutated form of ß5i (LMP7) lacking the catalytically active site was ineffective. Mass spectrometric analyses of in vitro digestions of a long precursor peptide with either proteasome type showed that the immunoproteasome produced the antigenic peptide more efficiently, whereas the standard proteasome more efficiently introduced cleavages destroying the antigenic peptide. This is the first example of a tumor-specific antigen exclusively presented by tumor cells expressing the immunoproteasome.

Key Words: ß5i • proteasome • mass spectrometry • tumor • HLA-B40

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