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

被引:16
|
作者
Kondo, Eisei [1 ,2 ]
Maecker, Britta [4 ]
Weihrauch, Martin R. [1 ,2 ]
Wickenhauser, Claudia [3 ]
Zeng, WanYong [5 ]
Nadler, Lee M. [5 ,6 ,7 ]
Schultze, Joachim L. [8 ]
von Bergwelt-Baildon, Michael S. [1 ,2 ]
机构
[1] Univ Hosp Cologne, Dept Internal Med 1, D-50924 Cologne, Germany
[2] Univ Hosp Cologne, Max Eder Nachwuchsgrp Deutschen Krebshilfe, D-50924 Cologne, Germany
[3] Univ Hosp Cologne, Inst Pathol, D-50924 Cologne, Germany
[4] Hannover Med Sch, Dept Pediat Hematol Oncol, D-3000 Hannover, Germany
[5] Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA 02115 USA
[6] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA
[7] Harvard Univ, Sch Med, Dept Med, Boston, MA USA
[8] Univ Bonn, Lab Genom & Immunoregulat, D-5300 Bonn, Germany
关键词
D O I
10.1158/1078-0432.CCR-08-0825
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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-gamma 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.
引用
收藏
页码:6574 / 6579
页数:6
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