Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors
Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors
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DOI：
10.1038/nm1359
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发表时间：
2006-03-01
期刊：
影响因子：
82.9
通讯作者：
Greenberg, PD
中科院分区：
文献类型：
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作者：
Teague, RM;Sather, BD;Greenberg, PD
CD 8（+）T细胞可以介导已建立的肿瘤的根除，目前正在癌症患者中探索通过免疫或体外扩增随后过继转移来扩增肿瘤反应性T细胞数量的策略（1-3）。产生有效的CD 8（+）T细胞介导的对肿瘤的应答通常受到T细胞对相关肿瘤抗原的耐受性的阻碍，因为这些抗原中的大多数也在正常组织中表达。我们研究了这种耐受性T细胞是否可以被拯救并功能恢复，用于治疗已建立的肿瘤。我们使用了转基因T细胞受体（TCR）小鼠模型，其中对候选肿瘤抗原特异性的外周CD 8（+）T细胞也在肝脏中表达是耐受的，不能增殖或分泌白细胞介素（IL）-2以响应抗原（4）。分子和细胞分析表明，这些耐受性T细胞表达IL-15受体α链，并且可以在体外响应于外源性IL-15而被诱导增殖。这种增殖消除了耐受性，并且拯救的细胞在治疗白血病中变得有效。因此，高亲和力的CD 8（+）T细胞不一定会因与外周中的自身抗原相遇而被删除，并且可以潜在地被拯救和扩增以用于肿瘤免疫治疗。
CD8(+) T cells can mediate eradication of established tumors, and strategies to amplify tumor-reactive T-cell numbers by immunization or ex vivo expansion followed by adoptive transfer are currently being explored in individuals with cancer(1-3). Generating effective CD8(+) T cell-mediated responses to tumors is often impeded by T-cell tolerance to relevant tumor antigens, as most of these antigens are also expressed in normal tissues. We examined whether such tolerant T cells could be rescued and functionally restored for use in therapy of established tumors. We used a transgenic T-cell receptor (TCR) mouse model in which peripheral CD8(+) T cells specific for a candidate tumor antigen also expressed in liver are tolerant, failing to proliferate or secrete interleukin (IL)-2 in response to antigen(4). Molecular and cellular analysis showed that these tolerant T cells expressed the IL-15 receptor alpha chain, and could be induced to proliferate in vitro in response to exogenous IL-15. Such proliferation abrogated tolerance and the rescued cells became effective in treating leukemia. Therefore, high-affinity CD8(+) T cells are not necessarily deleted by encounter with self-antigen in the periphery, and can potentially be rescued and expanded for use in tumor immunotherapy.