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Spontaneous CD4⁺ T Cell Responses against TRAG-3 in Patients with Melanoma and Breast Cancers¹

Bratislav Janjic^*, Pedro Andrade^*, Xiao-Fei Wang, Julien Fourcade^*, Christine Almunia, Pavol Kudela^*,, Adam Brufsky^*, Samuel Jacobs^*, David Friedland^*, Ronald Stoller^*, Daniel Gillet, Ronald B. Herberman^*, John M. Kirkwood^*, Bernard Maillere and Hassane M. Zarour^2,*,

^* Department of Medicine and Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovakia; and Protein Engineering and Research Department, CEA-Saclay, Gif-sur-Yvette, France

The taxol resistance gene TRAG-3 was initially isolated from cancer cell lines that became resistant to taxol in vitro. TRAG-3 is a cancer germline Ag expressed by tumors of different histological types including the majority of melanoma, breast, and lung cancers. In the present study, we report that patients with stage IV melanoma and breast cancers developed spontaneous IFN--producing CD4⁺ T cell responses against a single immunodominant and promiscuous peptide epitope from TRAG-3 presented in the context of multiple HLA-DR molecules. The TRAG-3-specific CD4⁺ T cells and clones were expanded in vitro and recognized not only peptide pulsed APCs but also autologous dendritic cells (DCs) loaded with the TRAG-3 protein. All stage IV melanoma patients with TRAG-3-expressing tumors developed spontaneous CD4⁺ T cell responses against TRAG-3, demonstrating its strong immunogenicity. None of these patients had detectable IgG Ab responses against TRAG-3. TCR gene usage studies of TRAG-3-specific CD4⁺ T cell clones from a melanoma patient and a normal donor suggested a restricted TCR repertoire in patients with TRAG-3-expressing tumors. Altogether, our data define a novel profile of spontaneous immune responses to cancer germline Ag-expressing tumors, showing that spontaneous TRAG-3-specific CD4⁺ T cells are directed against a single immunodominant epitope and exist independently of Ab responses. Because of its immunodominance, peptide TRAG-3_34–48 is of particular interest for the monitoring of spontaneous immune responses in patients with TRAG-3-expressing tumors and for the development of cancer vaccines.

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