Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells
Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells
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DOI：
10.1172/jci24480
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发表时间：
2005-06-01
影响因子：
15.9
通讯作者：
Restifo, NP
中科院分区：
文献类型：
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作者：
Gattinoni, L;Klebanoff, CA;Restifo, NP
T细胞分化是一个以表型和功能变化为特征的渐进过程。通过将肿瘤特异性CD8(+) T细胞转移到处于不同分化阶段的荷瘤小鼠体内，我们评估了它们对过继免疫治疗的疗效。我们发现给药幼稚和早期效应T细胞，结合主动免疫和IL-2，导致根除大的，已建立的肿瘤。尽管体外抗肿瘤特性增强，但分化程度更高的效应T细胞在体内肿瘤治疗中效果较差。几个事件可能是这种矛盾现象的基础：(a)淋巴归巢和共刺激分子的下调；(b)不能产生IL-2和获取稳态细胞因子；(c)进入促凋亡和复制性衰老状态。虽然最终效应物的逐渐获得的特点是在体外显著的肿瘤杀伤，但体内T细胞的激活、增殖和存活却逐渐受损。这些发现表明，目前选择T细胞进行转移的方法是不充分的，并为过继免疫治疗的最佳淋巴细胞群的产生和筛选提供了新的标准。
T cell differentiation is a progressive process characterized by phenotypic and functional changes. By transferring tumor-specific CD8(+) T cells into tumor-bearing mice at various stages of differentiation, we evaluated their efficacy for adoptive immunotherapy. We found that administration of naive and early effector T cells, in combination with active immunization and IL-2, resulted in the eradication of large, established tumors. Despite enhanced in vitro antitumor properties, more-differentiated effector T cells were less effective for in vivo tumor treatment. Several events may underlie this paradoxical phenomenon: (a) downregulation of lymphoid-homing and costimulatory molecules; (b) inability to produce IL-2 and access homeostatic cytokines; and (c) entry into a proapoptotic and replicative senescent state. While the progressive acquisition of terminal effector properties is characterized by pronounced in vitro tumor killing, in vivo T cell activation, proliferation, and survival are progressively impaired. These findings suggest that the current methodology for selecting T cells for transfer is inadequate and provide new criteria for the generation and the screening of optimal lymphocyte populations for adoptive immunotherapy.