Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies
Targeting the T cell receptor β-chain constant region for immunotherapy of T cell malignancies
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DOI：
10.1038/nm.4444
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发表时间：
2017-12-01
期刊：
影响因子：
82.9
通讯作者：
Pule, Martin A.
中科院分区：
文献类型：
--
作者：
Maciocia, Paul M.;Wawrzyniecka, Patrycja A.;Pule, Martin A.
成熟T细胞癌通常具有侵袭性，对治疗耐药，且预后较差。由于缺乏区分恶性和健康(正常)T细胞的靶抗原，免疫治疗方法的临床应用一直受到限制。与B细胞枯竭不同，泛T细胞再生障碍性疾病毒性极高。我们报道了一种新的靶向策略，该策略基于T细胞受体β链恒定域1和2(TRBC1和TRBC2)的互斥表达。我们识别了一种具有独特TRBC1特异性的抗体，并用它来证明正常和病毒特异性T细胞群同时包含TRBC1(+)和TRBC2(+)区段，而恶性肿瘤仅限于一个区段。作为抗TRBC免疫治疗的概念验证，我们开发了抗TRBC1嵌合抗原受体(CAR)T细胞，在体外和播散性白血病小鼠模型中识别和杀伤正常和恶性的TRBC1(+)，但不识别和杀伤TRBC2(+)T细胞。与针对整个T细胞群体的非选择性方法不同，TRBC靶向免疫疗法可以根除T细胞恶性肿瘤，同时保留足够的正常T细胞来维持细胞免疫。
Mature T cell cancers are typically aggressive, treatment resistant and associated with poor prognosis. Clinical application of immunotherapeutic approaches has been limited by a lack of target antigens that discriminate malignant from healthy (normal) T cells. Unlike B cell depletion, pan-T cell aplasia is prohibitively toxic. We report a new targeting strategy based on the mutually exclusive expression of T cell receptor beta-chain constant domains 1 and 2 (TRBC1 and TRBC2). We identify an antibody with unique TRBC1 specificity and use it to demonstrate that normal and virus-specific T cell populations contain both TRBC1(+) and TRBC2(+) compartments, whereas malignancies are restricted to only one. As proof of concept for anti-TRBC immunotherapy, we developed anti-TRBC1 chimeric antigen receptor (CAR) T cells, which recognized and killed normal and malignant TRBC1(+), but not TRBC2(+), T cells in vitro and in a disseminated mouse model of leukemia. Unlike nonselective approaches targeting the entire T cell population, TRBC-targeted immunotherapy could eradicate a T cell malignancy while preserving sufficient normal T cells to maintain cellular immunity.