The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to γδ T-cell cytotoxicity
The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to γδ T-cell cytotoxicity
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DOI：
10.1182/blood-2009-08-237123
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发表时间：
2010-03-25
期刊：
影响因子：
20.3
通讯作者：
Silva-Santos, Bruno
中科院分区：
文献类型：
--
作者：
Lanca, Telma;Correia, Daniel V.;Silva-Santos, Bruno
在造血肿瘤的成功免疫治疗的道路上，γ δ T细胞提供了巨大的希望，因为它们的人白细胞抗原（HLA）-不受限制地靶向各种白血病/淋巴瘤。然而，γ δ T细胞识别淋巴瘤的分子机制仍不清楚。在这里，我们表明，UL 16结合蛋白1（ULBP 1）的表达水平决定淋巴瘤的易感性γ δ T细胞介导的细胞溶解。与此一致的是，阻断NKG 2D（所有V γ 9+ T细胞上表达的ULBP 1受体）可显着抑制淋巴瘤细胞杀伤。特定的功能丧失研究表明ULBP 1的作用是非冗余的，突出了迄今为止γ δ T细胞对肿瘤识别的独特生理相关性。重要的是，我们在淋巴瘤和白血病患者的原发性活检中观察到非常广泛的ULBP 1表达水平。我们认为这将影响对基于γ δ T细胞的免疫疗法的反应性，因此建议将ULBP 1用作即将进行的临床试验中的白血病/淋巴瘤生物标志物。（血。2010;115：2407-2411）
On the path to successful immunotherapy of hematopoietic tumors, gamma delta T cells offer great promise because of their human leukocyte antigen (HLA)-unrestricted targeting of a wide variety of leukemias/lymphomas. However, the molecular mechanisms underlying lymphoma recognition by gamma delta T cells remain unclear. Here we show that the expression levels of UL16-binding protein 1 (ULBP1) determine lymphoma susceptibility to gamma delta T cell-mediated cytolysis. Consistent with this, blockade of NKG2D, the receptor for ULBP1 expressed on all V gamma 9+ T cells, significantly inhibits lymphoma cell killing. Specific loss-of-function studies demonstrate that the role of ULBP1 is nonredundant, highlighting a thus far unique physiologic relevance for tumor recognition by gamma delta T cells. Importantly, we observed a very wide spectrum of ULBP1 expression levels in primary biopsies obtained from lymphoma and leukemia patients. We suggest this will impact on the responsiveness to gamma delta T cell-based immunotherapy, and therefore propose ULBP1 to be used as a leukemia/lymphoma biomarker in upcoming clinical trials. (Blood. 2010;115:2407-2411)