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Cyclin D1–Specific Cytotoxic T Lymphocytes Are Present in the Repertoire of Cancer Patients: Implications for Cancer Immunotherapy

Authors' Affiliations: ¹ Molecular Tumor Biology and Tumor Immunology, 1st Department of Internal Medicine, ² Max-Eder-Nachwuchsgruppe der Deutschen Krebshilfe, and ³ Institute of Pathology, University Hospital of Cologne, Cologne, Germany; ⁴ Department of Pediatric Hematology/Oncology, Hannover Medical School, Hannover, Germany; ⁵ Department of Adult Oncology, Dana-Farber Cancer Institute; ⁶ Department of Medicine, Brigham and Women's Hospital; ⁷ Department of Medicine, Harvard Medical School, Boston, Massachusetts; and ⁸ Laboratory for Genomics and Immunoregulation, University of Bonn, Bonn, Germany

Requests for reprints: Michael S. von Bergwelt-Baildon, Max-Eder Nachwuchsgruppe, Molecular Tumor Biology and Tumor Immunology, University Hospital of Cologne, Joseph-Stelzmann Strasse 9/Haus 16, 50924 Cologne, Germany. Phone: 49-221-476-7438; Fax: 49-221-476-7782; E-mail: michael.bergwelt{at}uk-koeln.de.

Purpose: Cyclin D1, a key cell cycle regulator, is overexpressed in multiple types of cancer. Such tumor-associated genes may be useful targets for cancer immunotherapy. Nevertheless, it had previously been suggested that efficient T cells recognizing cyclin D1-derived epitopes are absent from the repertoire because of thymic deletion. We attempted to induce autologous CTL from healthy donors and patients with cyclin D1-overexpressing tumors using a highly efficient T-cell expansion system based on CD40-activated B cells as antigen-presenting cells.

Experimental Design: Cyclin D1-derived, HLA-A*0201–restricted epitopes were predicted by multiple computer algorithms, screened in HLA-A2-binding assays, and used for T-cell stimulation. The generated CTL lines and clones were analyzed by IFN- enzyme-linked immunosorbent spot assay or cytolysis assay.

Results: After screening, at least two naturally processed and presented HLA-A*0201–binding cyclin D1 epitopes were identified. CTL specific for these epitopes could be successfully generated from HLA-A2⁺ donors. T cells efficiently recognized target cells pulsed with the cognate peptide and cyclin D1-expressing tumor cell lines in an HLA-A*0201–restricted manner. More importantly, HLA-A*0201–matched, primary cyclin D1⁺ tumor cells were efficiently recognized by cyclin D1-specific CTL. These CTL could be generated from patients with mantle cell lymphoma and cyclin D1⁺ colon cancer.

Conclusions: These results underscore that cyclin D1 needs to be considered as a target for broad-based antitumor immunotherapy.