Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells
Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells
复制标题
DOI：
10.1073/pnas.0503726102
复制
发表时间：
2005-07-05
影响因子：
11.1
通讯作者：
Restifo, NP
中科院分区：
文献类型：
--
作者：
Klebanoff, CA;Gattinoni, L;Restifo, NP
中枢记忆性CD 8 + T细胞（T-cm）和效应记忆性CD 8（+）T细胞（T-EM）存在于人类和小鼠中;然而，它们对宿主免疫的相对贡献最近才在体内进行了研究。此外，Tcm治疗已建立的肿瘤或感染的能力还有待评估。为了解决不同的肿瘤反应性CD 8 + T细胞记忆亚群的治疗潜力，我们使用了建立的模型，分别通过使用IL-15和IL-2体外产生Tcm和TEm。当与肿瘤抗原疫苗接种和外源性IL-2结合时，连续转移的Tcm表现出强有力的体内回忆反应，导致大的已建立肿瘤的根除。相比之下，T-EM在每个细胞的基础上效果要差得多。微阵列分析显示，体内高效抗肿瘤T细胞的特征包括负责运输到次级淋巴组织的基因的过表达。该基因表达谱正确预测了肿瘤反应性T细胞的体外和体内淋巴归巢属性。此外，我们发现归巢到次级淋巴组织是最佳肿瘤治疗所必需的。我们的研究结果表明，体内高效的抗肿瘤T细胞是那些最初靶向次级淋巴组织，而不是肿瘤部位，如以前所假设的。因此，具有Tcm的表型和功能属性的肿瘤反应性CD 8（+）T细胞群体可能上级于使用伴随的肿瘤抗原疫苗接种的过继免疫疗法的T-EM/效应T细胞。
Central memory CD8+ T cells (T-cm) and effector memory CD8(+) T cells (T-EM) are found in humans and mice; however, their relative contributions to host immunity have only recently been examined in vivo. Further, the ability of Tcm to treat an established tumor or infection has yet to be evaluated. To address the therapeutic potential of different tumor-reactive CD8+ T cell memory subsets, we used an established model for the in vitro generation of Tcm and TEm by using IL-15 and IL-2, respectively. Adoptively transferred Tcm exhibited a potent in vivo recall response when combined with tumor-antigen vaccination and exogenous IL-2, leading to the eradication of large established tumors. By contrast, T-EM were far less effective on a per-cell basis. Microarray analysis revealed that the signature of highly in vivo effective antitumor T cells included the overexpression of genes responsible for trafficking to secondary lymphoid tissues. This gene expression profile correctly predicted the in vitro and in vivo lymphoid-homing attributes of tumor-reactive T cells. Furthermore, we found that homing to secondary lymphoid tissue is required for optimal tumor treatment. Our findings indicated that highly in vivo effective antitumor T cells were those that initially targeted secondary lymphoid tissue, rather than tumor sites, as had previously been postulated. Thus, tumor-reactive CD8(+) T cell populations with the phenotypic and functional attributes of Tcm may be superior to T-EM/effector T cells for adoptive immunotherapies using concomitant tumor-antigen vaccination.