TCL1: a shared tumor-associated antigen for immunotherapy against B-cell lymphomas.
TCL1: a shared tumor-associated antigen for immunotherapy against B-cell lymphomas.
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DOI：
10.1182/blood-2011-09-382838
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发表时间：
2011-11
期刊：
影响因子：
20.3
通讯作者：
Jinsheng Weng;S. Rawal;F. Chu;H. Park;Rakesh K Sharma;David A. Delgado;L. Fayad;M. Fanale;J. Romaguera;A. Luong;L. Kwak;S. Neelapu
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文献类型：
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作者：
Jinsheng Weng;S. Rawal;F. Chu;H. Park;Rakesh K Sharma;David A. Delgado;L. Fayad;M. Fanale;J. Romaguera;A. Luong;L. Kwak;S. Neelapu
治疗性独特型疫苗的免疫治疗为B细胞恶性肿瘤的治疗提供了希望。然而，新的免疫原性淋巴瘤相关抗原，普遍表达的鉴定是必要的，以克服患者特异性独特型疫苗的障碍。在这里，我们确定了由TCL 1基因编码的T细胞白血病/淋巴瘤1（TCL 1）癌蛋白是否可以作为B细胞恶性肿瘤免疫治疗的靶点。我们发现，TCL 1 mRNA和蛋白质选择性表达于正常B细胞，但在多种人类B细胞淋巴瘤，包括滤泡性淋巴瘤，慢性淋巴细胞白血病，套细胞淋巴瘤，弥漫性大B细胞淋巴瘤，脾边缘区B细胞淋巴瘤显着过表达。我们证明了TCL 1特异性CD 8（+）T细胞可以从HLA-A*0201（HLA-A2）（+）正常供体产生，并鉴定了TCL 1（71-78）（LLPIMWQL）为这些T细胞识别的最小表位。更重要的是，TCL 1（71-78）肽特异性T细胞存在于淋巴瘤患者的外周血和肿瘤浸润淋巴细胞中，可以在体外扩增，并以HLA-A2限制性方式裂解自体肿瘤细胞，但不裂解正常B细胞。我们的研究结果表明，TCL 1是自然加工和淋巴瘤细胞的表面上提出的细胞毒性T细胞的识别，可以作为一个新的目标，针对常见的B细胞淋巴瘤的免疫策略的发展。
Immunotherapy with therapeutic idiotype vaccines offers promise for treatment of B-cell malignancies. However, identification of novel immunogenic lymphoma-associated antigens that are universally expressed is necessary to overcome the barriers of patient-specific idiotype vaccines. Here, we determined whether T-cell leukemia/lymphoma 1 (TCL1) oncoprotein encoded by the TCL1 gene could be a target for immunotherapy of B-cell malignancies. We show that TCL1 mRNA and protein are selectively expressed in normal B cells but markedly hyperexpressed in multiple human B-cell lymphomas, including follicular lymphoma, chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B-cell lymphoma, and splenic marginal zone B-cell lymphoma. We demonstrated that TCL1-specific CD8(+) T cells can be generated from HLA-A*0201 (HLA-A2)(+) normal donors and identified TCL1(71-78) (LLPIMWQL) as the minimal epitope recognized by these T cells. More importantly, TCL1(71-78) peptide-specific T cells were present in the peripheral blood and tumor-infiltrating lymphocytes of lymphoma patients, could be expanded in vitro, and lysed autologous tumor cells but not normal B cells in an HLA-A2-restricted manner. Our results suggest that TCL1 is naturally processed and presented on the surface of lymphoma cells for recognition by cytotoxic T cells and can serve as a novel target for development of immunotherapeutic strategies against common B-cell lymphomas.