γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs
γ9 and δ2CDR3 domains regulate functional avidity of T cells harboring γ9δ2TCRs
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DOI：
10.1182/blood-2012-05-432427
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发表时间：
2012-12-20
期刊：
影响因子：
20.3
通讯作者：
Kuball, Juergen
中科院分区：
文献类型：
--
作者：
Gruender, Cordula;van Dorp, Suzanne;Kuball, Juergen
利用先天免疫细胞的免疫疗法作为癌症患者的一种新的治疗选择最近引起了广泛的兴趣。特别地，γ 9 δ 2 T细胞作为具有高频率和强抗肿瘤反应性的先天细胞群体出现，这使得它们及其受体成为免疫干预的有希望的候选者。然而，迄今为止，临床试验仅报道了过继转移的γ 9 δ 2 T细胞对肿瘤的有限控制。作为这种缺乏功效的潜在解释，我们发现在生理性人γ 9 δ 2 T细胞库内肿瘤识别的出乎意料的高变异性，其基本上由单个γ 9 δ 2 TCR的CDR 3结构域调节。在本研究中，我们证明了所报道的CDR 3结构域与靶细胞相互作用的分子要求形成了生理性γ 9 δ 2 T细胞库，并且很可能限制了γ 9 δ 2 T细胞的保护性和治疗性抗肿瘤功效。基于这些发现，我们提出组合γ δ TCR链交换作为设计高亲和力γ 9 δ 2 TCR的有效方法，所述高亲和力γ 9 δ 2 TCR在体外和体内人源化小鼠模型中在α β T细胞中表达时介导改善的抗肿瘤应答。（血。2012; 120（26）：5153-5162）
Immunotherapy with innate immune cells has recently evoked broad interest as a novel treatment option for cancer patients. gamma 9 delta 2T cells in particular are emerging as an innate cell population with high frequency and strong antitumor reactivity, which makes them and their receptors promising candidates for immune interventions. However, clinical trials have so far reported only limited tumor control by adoptively transferred gamma 9 delta 2T cells. As a potential explanation for this lack of efficacy, we found unexpectedly high variability in tumor recognition within the physiologic human gamma 9 delta 2T-cell repertoire, which is substantially regulated by the CDR3 domains of individual gamma 9 delta 2TCRs. In the present study, we demonstrate that the reported molecular requirements of CDR3 domains to interact with target cells shape the physiologic gamma 9 delta 2T-cell repertoire and, most likely, limit the protective and therapeutic antitumor efficacy of gamma 9 delta 2T cells. Based on these findings, we propose combinatorial-gamma delta TCR-chain exchange as an efficient method for designing high-affinity gamma 9 delta 2TCRs that mediate improved antitumor responses when expressed in alpha beta T cells both in vitro and in vivo in a humanized mouse model. (Blood. 2012; 120(26): 5153-5162)