Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells.
Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells.
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通过淋巴结消除来清除稳态细胞因子下沉，增强了采用转移的肿瘤特异性CD8+ T细胞的功效。
DOI：
10.1084/jem.20050732
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发表时间：
2005-10-03
影响因子：
15.3
通讯作者：
Restifo, Nicholas P
中科院分区：
文献类型：
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作者：
Gattinoni, Luca;Finkelstein, Steven E;Klebanoff, Christopher A;Antony, Paul A;Palmer, Douglas C;Spiess, Paul J;Hwang, Leroy N;Yu, Zhiya;Wrzesinski, Claudia;Heimann, David M;Surh, Charles D;Rosenberg, Steven A;Restifo, Nicholas P
在过继细胞转移（ACT）之前消除免疫元件可以显着提高转移的 CD8+ T 细胞的抗肿瘤功效，但有助于这种增强免疫的具体机制仍不清楚。消除 CD4+CD25+ 调节性 T (T reg) 细胞已被认为是淋巴清除增强基于 ACT 的免疫疗法的关键机制。我们发现，即使在 T reg 细胞遗传性缺失的情况下，非清髓性治疗方案也能显着增强 CD8+ T 细胞对自身组织和肿瘤的反应性。令人惊讶的是，抗肿瘤功效和自身免疫能力的增强是由功能增强而不是肿瘤反应性 T 细胞数量增加引起的，正如稳态机制所预期的那样。 γ C 细胞因子 IL-7 和 IL-15 是增强 T 细胞功能和抗肿瘤活性所必需的。使用抗体或遗传手段去除 γ C 细胞因子反应性内源细胞可增强抗肿瘤反应，类似于非清髓性预处理后所见的效果。这些数据表明，淋巴清除消除了内源性细胞成分，这些细胞成分充当细胞因子的接收器，能够增强自身/肿瘤反应性 CD8+ T 细胞的活性。因此，体内平衡细胞因子的有限可用性可能是外周耐受的一个促成因素，也是肿瘤特异性 T 细胞有效性的有限资源。
Depletion of immune elements before adoptive cell transfer (ACT) can dramatically improve the antitumor efficacy of transferred CD8+ T cells, but the specific mechanisms that contribute to this enhanced immunity remain poorly defined. Elimination of CD4+CD25+ regulatory T (T reg) cells has been proposed as a key mechanism by which lymphodepletion augments ACT-based immunotherapy. We found that even in the genetic absence of T reg cells, a nonmyeloablative regimen substantially augmented CD8+ T cell reactivity to self-tissue and tumor. Surprisingly, enhanced antitumor efficacy and autoimmunity was caused by increased function rather than increased numbers of tumor-reactive T cells, as would be expected by homeostatic mechanisms. The γ C cytokines IL-7 and IL-15 were required for augmenting T cell functionality and antitumor activity. Removal of γ C cytokine–responsive endogenous cells using antibody or genetic means resulted in the enhanced antitumor responses similar to those seen after nonmyeloablative conditioning. These data indicate that lymphodepletion removes endogenous cellular elements that act as sinks for cytokines that are capable of augmenting the activity of self/tumor-reactive CD8+ T cells. Thus, the restricted availability of homeostatic cytokines can be a contributing factor to peripheral tolerance, as well as a limiting resource for the effectiveness of tumor-specific T cells.