BCR-ABL fusion regions as a source of multiple leukemia-specific CD8+ T-cell epitopes
BCR-ABL fusion regions as a source of multiple leukemia-specific CD8+ T-cell epitopes
复制标题
DOI：
10.1038/sj.leu.2404354
复制
发表时间：
2006-10-01
期刊：
影响因子：
11.4
通讯作者：
Melief, C. J. M.
中科院分区：
文献类型：
--
作者：
Kessler, J. H.;Bres-Vloemans, S. A.;Melief, C. J. M.
对于费城阳性白血病患者残留疾病的免疫治疗，BCR-ABL融合区是有吸引力的疾病特异性T细胞靶点。我们分析了这些地区的流行细胞毒性T淋巴细胞（CTL）表位的先进的反向免疫程序。17个新的BCR-ABL融合肽被鉴定为与人淋巴细胞抗原（HLA）-A68、HLA-B51、HLA-B61或HLA-Cw 4 HLA I类分子有效结合。综合酶消化分析表明，28个HLA I类结合融合肽中的10个在其C-末端后被蛋白酶体有效切除，这是有效细胞表面表达的必要条件。因此，这些肽是主要的疫苗候选物。其他肽要么完全缺乏C-末端释放，要么仅被蛋白酶体无效切除，使其不适合或不太适合包含在疫苗中。针对来自BCR-ABL e1 a2融合区的适当加工的HLA-B61表位AEALQRPVA产生的CTL，在急性淋巴细胞白血病（ALL）中表达，特异性识别ALL肿瘤细胞，证明了该表位的细胞表面呈递，其用于免疫治疗的适用性，并强调了我们的表位识别策略的准确性。我们的研究为选择最佳肽段用于抗白血病的免疫原性BCR-ABL疫苗提供了可靠的依据。
For immunotherapy of residual disease in patients with Philadelphia-positive leukemias, the BCR-ABL fusion regions are attractive disease-specific T-cell targets. We analyzed these regions for the prevalence of cytotoxic T lymphocyte ( CTL) epitopes by an advanced reverse immunology procedure. Seventeen novel BCR-ABL fusion peptides were identified to bind efficiently to the human lymphocyte antigen ( HLA)-A68, HLA-B51, HLA-B61 or HLA-Cw4 HLA class I molecules. Comprehensive enzymatic digestion analysis showed that 10 out of the 28 HLA class I binding fusion peptides were efficiently excised after their C-terminus by the proteasome, which is an essential requirement for efficient cell surface expression. Therefore, these peptides are prime vaccine candidates. The other peptides either completely lacked C-terminal liberation or were only inefficiently excised by the proteasome, rendering them inappropriate or less suitable for inclusion in a vaccine. CTL raised against the properly processed HLA-B61 epitope AEALQRPVA from the BCR-ABL e1a2 fusion region, expressed in acute lymphoblastic leukemia ( ALL), specifically recognized ALL tumor cells, proving cell surface presentation of this epitope, its applicability for immunotherapy and underlining the accuracy of our epitope identification strategy. Our study provides a reliable basis for the selection of optimal peptides to be included in immunotherapeutic BCR-ABL vaccines against leukemia.