Mutated regions of nucleophosmin 1 elicit both CD4+ and CD8+ T-cell responses in patients with acute myeloid leukemia
Mutated regions of nucleophosmin 1 elicit both CD4+ and CD8+ T-cell responses in patients with acute myeloid leukemia
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DOI：
10.1182/blood-2011-11-394395
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发表时间：
2012-08-09
期刊：
影响因子：
20.3
通讯作者：
Schmitt, Michael
中科院分区：
文献类型：
--
作者：
Greiner, Jochen;Ono, Yoko;Schmitt, Michael
核磷蛋白基因突变 (NPM1(mut)) 是急性髓系白血病 (AML) 中最常见的分子改变之一，免疫反应可能有助于 NPM1(mut) AML 患者的良好预后。在本研究中，我们能够证明 CD4(+) 和 CD8(+) T 细胞对 NPM1(mut) 的反应。对 33 名健康志愿者和 27 名 AML 患者的 10 种源自野生型 NPM1 和 NPM1(mut) 的肽进行了 ELISPOT 分析。针对最有趣的表位进行了四聚体测定，并使用 Cr-51 释放测定来显示肽特异性 T 细胞的细胞毒性。此外，HLA-DR结合表位用于测试CD4(+) T细胞在NPM1免疫原性中的作用。源自 NPM1(mut) 的两个表位（表位 #1 和 #3）诱导 CD8(+) T 细胞反应。总共 33% 的 NPM1(mut) AML 患者表现出针对表位 #1 的免疫反应，44% 的患者表现出针对表位 #3 的免疫反应。检测到白血病细胞的特异性裂解。为了获得针对肿瘤细胞的强大免疫反应，CD4(+) T细胞的激活至关重要。因此，在 ELISPOT 分析中分析重叠 (OL) 肽，发现 OL8 能够激活 CD8(+) 和 CD4(+) T 细胞。本研究结果表明，NPM1（mut）诱导CD4（+）和CD8（+）T细胞的特异性T细胞反应，因此是AML特异性免疫治疗的有希望的靶标。 （血。2012；120(6):1282-1289）
Mutations in the nucleophosmin gene (NPM1(mut)) are one of the most frequent molecular alterations in acute myeloid leukemia (AML), and immune responses may contribute to the favorable prognosis of AML patients with NPM1(mut). In the present study, we were able to demonstrate both CD4(+) and CD8(+) T-cell responses against NPM1(mut). Ten peptides derived from wild-type NPM1 and NPM1(mut) were subjected to ELISPOT analysis in 33 healthy volunteers and 27 AML patients. Tetramer assays against the most interesting epitopes were performed and Cr-51-release assays were used to show the cytotoxicity of peptide-specific T cells. Moreover, HLA-DR-binding epitopes were used to test the role of CD4(+) T cells in NPM1 immunogenicity. Two epitopes (epitopes #1 and #3) derived from NPM1(mut) induced CD8(+) T-cell responses. A total of 33% of the NPM1(mut) AML patients showed immune responses against epitope #1 and 44% against epitope #3. Specific lysis of leukemic blasts was detected. To obtain robust immune responses against tumor cells, the activation of CD4(+) T cells is crucial. Therefore, overlapping (OL) peptides were analyzed in ELISPOT assays and OL8 was able to activate both CD8(+) and CD4(+) T cells. The results of the present study show that NPM1(mut) induces specific T-cell responses of CD4(+) and CD8(+) T cells and therefore is a promising target for specific immunotherapies in AML. (Blood. 2012;120(6):1282-1289)