An essential role of antigen-presenting cell/T-helper type 1 cell-cell interactions in draining lymph node during complete eradication of class II-negative tumor tissue by T-helper type 1 cell therapy
An essential role of antigen-presenting cell/T-helper type 1 cell-cell interactions in draining lymph node during complete eradication of class II-negative tumor tissue by T-helper type 1 cell therapy
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DOI：
10.1158/0008-5472.can-05-2246
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发表时间：
2006-02-01
期刊：
影响因子：
11.2
通讯作者：
Nishimura, T
中科院分区：
文献类型：
--
作者：
Chamoto, K;Wakita, D;Nishimura, T
先前的研究已经表明，卵清蛋白（OVA）特异性辅助性T细胞1型（Th 1）转移到携带MHC II类+OVA表达肿瘤细胞（A20-OVA）的小鼠中会导致完全的肿瘤排斥。在这里，我们表明，虽然单独的Th 1细胞疗法对表达MHC II类-OVA的肿瘤细胞（EG-7）无效，但通过静脉内转移Th 1细胞联合静脉内注射治疗已建立的EG-7肿瘤的小鼠，注射模型肿瘤抗原OVA诱导完全肿瘤排斥。转移的Th 1细胞增强了已处理OVA的肿瘤浸润性抗原呈递细胞（APC）向引流淋巴结（DLN）的迁移。尽管转移的Th 1细胞随机分布在DLN、远端LN、脾脏和肿瘤组织中，但Th 1细胞的活跃增殖总是在DLN中启动，其中Th 1细胞与呈递OVA的APC有效地相互作用。平行地，显示EG-7特异性细胞毒性的OVA-四聚体（+）CTL在DLN和局部肿瘤部位中被高度诱导。OVA-四聚体（+）CTL系统性地起作用，因为在治疗一个肿瘤时两个双侧肿瘤块都被完全排斥。此外，在MHC II类缺陷小鼠和LN缺陷Aly/Aly小鼠中，未诱导转移的Th 1细胞的活跃增殖或四聚体（+）CTL的产生。这些结果表明，DLN是启动主动APC/Th 1细胞相互作用的不可或缺的器官，这对于诱导肿瘤特异性CTL完全根除肿瘤块是至关重要的。
Prior studies have shown that transfer of ovalbumin (OVA)-specific T helper type 1 (Th1) cells into mice bearing MHC class II+ OVA-expressing tumor cells (A20-OVA) causes complete tumor rejection. Here we show that, although Th1 cell therapy alone was not effective against MHC class II- OVA-expressing tumor cells (EG-7), treatment of mice bearing established EG-7 tumors by i.v. transfer of Th1 cells combined with i.t. injection of the model tumor antigen OVA induced complete tumor rejection. Transferred Th1 cells enhanced the migration of tumor-infiltrating antigen-presenting cells (APC) that had processed OVA into the draining lymph node (DLN). Although transferred Th1 cells were randomly distributed in DLN, distal LN, spleen, and tumor tissue, active proliferation of Th1 cells always initiated in DLN, where Th1 cells efficiently interacted with APC that presented OVA. In parallel, OVA-tetramer(+) CTLs, showing EG-7-specific cytotoxicity, were highly induced in DLN and the local tumor site. The OVA-tetramer(+) CTL functioned systemically because two bilateral tumor masses were both completely rejected on treatment of one tumor. Furthermore, either active proliferation of transferred Th1 cells or generation of tetramer(+) CTL was not induced in MHC class II-deficient mice and LN-deficient Aly/Aly mice. These results indicate that DLN is an indispensable organ for initiating active APC/Th1 cell interactions, which is critical for inducing complete eradication of tumor mass by tumor-specific CTL.