Wang M, Sun L, Qian J, Han X, Zhang L, Lin P, Cai Z, Yi Q
Division of Cancer Medicine, Department of Lymphoma and Myeloma, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Leukemia. 2009 Jul;23(7):1320-8. doi: 10.1038/leu.2009.19. Epub 2009 Feb 19.
Mantle cell lymphoma (MCL) accounts for 5-10% of all non-Hodgkin lymphomas and has the worst prognosis among all lymphomas. The hallmark of MCL is a t(11;14) translocation that results in overexpression of cyclin D1 by tumor cells of virtually all patients. In this study, we examined whether cyclin D1 could be an effective tumor-associated antigen for immunotherapy. We identified cyclin D1 peptides for HLA-A()0201 and generated peptide-specific CD8(+) T-cell lines from HLA-A()0201(+) blood donors and MCL patients. These cell lines proliferated in response to cyclin D1 peptide-pulsed stimulatory cells. Moreover, the T cells efficiently lysed peptide-pulsed but not unpulsed T2 cells and autologous dendritic cells; cyclin D1(+) and HLA-A()0201(+) human MCL lines MINO, SP53, Jeko-1 and Granta 519; and more importantly, HLA-A()0201(+) primary lymphoma cells from MCL patients. No killing was observed with HLA-A()0201(-) primary lymphoma cells or HLA-A()0201(+) normal blood cells, including B cells. These results indicate that these T cells are potent cytotoxic T cells and recognize cyclin D1 peptides naturally presented by patient lymphoma cells in the context of HLA-A(*)0201 molecules. Taken together, our work identifies cyclin D1 as a potentially important antigen for immunotherapy of MCL.
套细胞淋巴瘤（MCL）占所有非霍奇金淋巴瘤的5%-10%，是所有淋巴瘤中预后最差的。MCL的标志是t(11;14)易位，几乎所有患者的肿瘤细胞都会因此导致细胞周期蛋白D1过表达。在本研究中，我们检测了细胞周期蛋白D1是否可能是免疫治疗有效的肿瘤相关抗原。我们鉴定了针对HLA-A()0201的细胞周期蛋白D1肽段，并从HLA-A()0201(+)献血者和MCL患者中产生了肽特异性CD8(+) T细胞系。这些细胞系在细胞周期蛋白D1肽脉冲刺激细胞的作用下增殖。此外，这些T细胞能有效裂解经肽脉冲处理而非未经处理的T2细胞和自体树突状细胞；细胞周期蛋白D1(+)且HLA-A()0201(+)的人MCL细胞系MINO、SP53、Jeko-1和Granta 519；更重要的是，能裂解来自MCL患者的HLA-A()0201(+)原发性淋巴瘤细胞。用HLA-A()0201(-)原发性淋巴瘤细胞或HLA-A()0201(+)正常血细胞（包括B细胞）未观察到杀伤作用。这些结果表明，这些T细胞是有效的细胞毒性T细胞，并且在HLA-A(*)0201分子的背景下识别患者淋巴瘤细胞自然呈递的细胞周期蛋白D1肽段。综上所述，我们的工作将细胞周期蛋白D1鉴定为MCL免疫治疗的潜在重要抗原。
