Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal.
Blood. 2010 Mar 25;115(12):2407-11. doi: 10.1182/blood-2009-08-237123. Epub 2010 Jan 25.
On the path to successful immunotherapy of hematopoietic tumors, gammadelta 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 gammadelta T cells remain unclear. Here we show that the expression levels of UL16-binding protein 1 (ULBP1) determine lymphoma susceptibility to gammadelta T cell-mediated cytolysis. Consistent with this, blockade of NKG2D, the receptor for ULBP1 expressed on all Vgamma9(+) 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 gammadelta 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 gammadelta T cell-based immunotherapy, and therefore propose ULBP1 to be used as a leukemia/lymphoma biomarker in upcoming clinical trials.
在成功进行造血系统肿瘤的免疫治疗的道路上，γδ T 细胞因其 HLA 非限制性地靶向多种白血病/淋巴瘤而具有巨大的应用前景。然而，γδ T 细胞识别淋巴瘤的分子机制仍不清楚。在此，我们发现 UL16 结合蛋白 1（ULBP1）的表达水平决定了淋巴瘤对 γδ T 细胞介导的细胞溶解的易感性。与此一致，阻断 NKG2D，即所有 Vγ9(+)T 细胞表达的 ULBP1 的受体，可显著抑制淋巴瘤细胞的杀伤。特异性的功能丧失研究表明，ULBP1 的作用是不可或缺的，这突出了 γδ T 细胞识别肿瘤的独特生理相关性。重要的是，我们在从淋巴瘤和白血病患者获得的原发性活检中观察到非常广泛的 ULBP1 表达水平。我们认为这将影响对 γδ T 细胞为基础的免疫治疗的反应性，因此建议将 ULBP1 用作即将进行的临床试验中的白血病/淋巴瘤的生物标志物。
