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Endosomal Proteases Influence the Repertoire of MAGE-A3 Epitopes Recognized In vivo by CD4⁺ T Cells

¹ Tumor Immunology Unit, DIBIT, ² Cancer Gene Therapy Unit, ³ Cancer Immunotherapy and Gene Therapy Program, and ⁴ Department of Oncology, Scientific Institute H. San Raffaele; ⁵ Consiglio Nazionale delle Ricerche Istituto di Chimica del Riconoscimento Molecolare, Milan, Italy

Requests for reprints: Maria Pia Protti, Tumor Immunology Unit, Cancer Immunotherapy and Gene Therapy Program, DIBIT, Scientific Institute H. San Raffaele, Via Olgettina 58, 20132 Milan, Italy. Phone: 39-2-2643-4185; Fax: 39-2-2643-4786; E-mail: m.protti{at}hsr.it.

Key Words: MAGE-A3 • CD4+ T-cell epitopes • aspartic and cysteine proteases • antigen processing • tumor immunology

Little is known about the repertoire of MAGE-A3 CD4⁺ T-cell epitopes recognized in vivo by neoplastic patients and how antigen processing influences epitope formation. Here, we first show that MAGE-A3–specific CD4⁺ T cells are present in the blood of advanced melanoma patients. MAGE-A3_111-125, MAGE-A3_191-205, and MAGE-A3_281-300 were recognized by 7, 6, and 5 of the 11 patients tested, respectively. MAGE-A3_146-160 and MAGE-A3_171-185 were also recognized in two and one cases, whereas no recognition of MAGE-A3_161-175 and MAGE-A3_243-258 was observed. Cytokines produced were mainly interleukin 5 and/or granulocyte macrophage colony-stimulating factor, suggesting impairment of productive polarized Th1 responses. Secondly, proteases inhibitors were used to modulate in vitro the recognition by CD4⁺ T-cells clones of dendritic cells loaded with MAGE-A3–expressing cell lysates. We found that formation of MAGE-A3_111-125 depended on both leupeptin-sensitive and pepstatin-sensitive proteases. In contrast, we found that MAGE-A3_161-175, which was never recognized ex vivo, was formed by leupeptin but destroyed by pepstatin-sensitive proteases. Collectively, our results show that (a) anti–MAGE-A3 CD4⁺ T-cell immunity develops in vivo in neoplastic patients and is focused toward immunodominant epitopes, (b) the response in advanced disease is skewed toward a Th2 type, and (c) endosomal/lysosomal proteases in dendritic cells influence the repertoire of the epitopes recognized. [Cancer Res 2008;68(5):1555–62]

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