Cord Blood T Cells Retain Early Differentiation Phenotype Suitable for Immunotherapy After TCR Gene Transfer to Confer EBV Specificity
Cord Blood T Cells Retain Early Differentiation Phenotype Suitable for Immunotherapy After TCR Gene Transfer to Confer EBV Specificity
复制标题
DOI：
10.1111/j.1600-6143.2012.04286.x
复制
发表时间：
2013-01-01
影响因子：
8.8
通讯作者：
Chen, F. E.
中科院分区：
文献类型：
--
作者：
Frumento, G.;Zheng, Y.;Chen, F. E.
过继T细胞治疗对移植后EB病毒(EBV)相关的淋巴增生性疾病和黑色素瘤有效。将高亲和力的TCR基因导入T淋巴细胞是一种提高肿瘤特异性T细胞效力和特异性的新兴方法。然而，这两种方法都需要在体外进行淋巴细胞增殖，产生高度分化的效应细胞，在输注后表现出降低的存活率和抗肿瘤效果。据报道，从外周血中分离的幼稚淋巴细胞转导TCR可以提供更好的体内存活和功能。我们利用脐带血(CB)淋巴细胞，主要由幼稚细胞组成，用于转导EBV特异性TCR。TCR在成体细胞和CB细胞中的表达相似，但后者表达的分化特征较早。进一步的抗原驱动刺激使成人淋巴细胞偏向与免疫衰竭相关的晚期分化表型。相反，CB T细胞在抗原刺激后仍保持较低分化表型，仍为CD57阴性，但仍能表达抗原特异性多功能细胞因子，并对EBV抗原产生细胞毒作用。CB T细胞也保留了更长的端粒，通常具有更高的端粒酶活性，表明有更大的增殖潜力。因此，CB淋巴细胞具有延长存活期和有利于免疫治疗的效应功能，特别是在供者淋巴细胞无法获得的情况下，如在实体器官和CB移植中。
Adoptive T cell therapy can be effective for EpsteinBarr virus (EBV)-associated posttransplant lymphoproliferative disease and melanoma. Transducing high-affinity TCR genes into T lymphocytes is an emerging method to improve potency and specificity of tumor-specific T cells. However, both methods necessitate in vitro lymphocyte proliferation, generating highly differentiated effector cells that display reduced survival and antitumor efficacy postinfusion. TCR-transduction of naive lymphocytes isolated from peripheral blood is reported to provide superior in vivo survival and function. We utilized cord blood (CB) lymphocytes, which comprise mainly naive cells, for transducing EBV-specific TCR. Comparable TCR expression was achieved in adult and CB cells, but the latter expressed an earlier differentiation profile. Further antigen-driven stimulation skewed adult lymphocytes to a late differentiation phenotype associated with immune exhaustion. In contrast, CB T cells retained a less differentiated phenotype after antigen stimulation, remaining CD57-negative but were still capable of antigen-specific polyfunctional cytokine expression and cytotoxicity in response to EBV antigen. CB T cells also retained longer telomeres and in general possessed higher telomerase activity indicative of greater proliferative potential. CB lymphocytes therefore have qualities indicating prolonged survival and effector function favorable to immunotherapy, especially in settings where donor lymphocytes are unavailable such as in solid organ and CB transplantation.