Tumor cell apoptosis induces tumor-specific immunity in a CC chemokine receptor 1-and 5-dependent manner in mice
Tumor cell apoptosis induces tumor-specific immunity in a CC chemokine receptor 1-and 5-dependent manner in mice
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DOI：
10.1189/jlb.1107791
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发表时间：
2008-10-01
影响因子：
5.5
通讯作者：
Mukaida, Naofumi
中科院分区：
文献类型：
--
作者：
Lida, Noriho;Nakamoto, Yasunari;Mukaida, Naofumi
肿瘤免疫产生的第一步是树突状细胞（DCs）向凋亡肿瘤的迁移，这被认为是由各种趋化因子介导的。为了阐明趋化因子的作用，我们使用自杀基因疗法诱导细胞凋亡，并研究肿瘤细胞凋亡后的免疫反应。我们用HSV-胸苷激酶（tk）基因转染的小鼠肝癌细胞系BNL 1 ME A.7R.1（BNL）注射小鼠，然后用更昔洛韦（GCV）治疗动物。GCV治疗诱导大量肿瘤细胞凋亡，伴有肿瘤内DC浸润。肿瘤浸润DC表达趋化因子受体CCR 1和CCR 5，T细胞和巨噬细胞表达CCL 3，CCR 1和CCR 5的配体。此外，肿瘤凋亡增加了DC迁移到引流淋巴结的数量，并最终产生针对BNL细胞的特异性细胞毒性细胞群。尽管GCV完全根除了CCR 1-、CCR 5-或CCL 3-缺陷小鼠中HSV-tk转染的BNL细胞，但在这些小鼠中肿瘤内和结内DC浸润以及随后的细胞毒性产生减弱。当通过GCV治疗完全根除原发性肿瘤后再次注射亲本细胞时，野生型小鼠完全排斥再激发的细胞，但缺陷型小鼠表现出排斥受损。因此，我们提供了明确的证据表明，CCR 1和CCR 5及其配体CCL 3发挥了至关重要的作用，在调节肿瘤内DC的积累和随后建立肿瘤免疫诱导肿瘤细胞凋亡的自杀基因。
The first step in the generation of tumor immunity is the migration of dendritic cells (DCs) to the apoptotic tumor, which is presumed to be mediated by various chemokines. To clarify the roles of chemokines, we induced apoptosis using suicide gene therapy and investigated the immune responses following tumor apoptosis. We injected mice with a murine hepatoma cell line, BNL 1ME A.7R.1 (BNL), transfected with HSV-thymidine kinase (tk) gene and then treated the animals with ganciclovir (GCV). GCV treatment induced massive tumor cell apoptosis accompanied with intratumoral DC infiltration. Tumor-infiltrating DCs expressed chemokine receptors CCR1 and CCR5, and T cells and macrophages expressed CCL3, a ligand for CCR1 and CCR5. Moreover, tumor apoptosis increased the numbers of DCs migrating into the draining lymph nodes and eventually generated a specific cytotoxic cell population against BNL cells. Although GCV completely eradicated HSV-tk-transfected BNL cells in CCR1-, CCR5-, or CCL3-deficient mice, intratumoral and intranodal DC infiltration and the subsequent cytotoxicity generation were attenuated in these mice. When parental cells were injected again after complete eradication of primary tumors by GCV treatment, the wild-type mice completely rejected the rechallenged cells, but the deficient mice exhibited impairment in rejection. Thus, we provide definitive evidence indicating that CCR1 and CCR5 and their ligand CCL3 play a crucial role in the regulation of intratumoral DC accumulation and the subsequent establishment of tumor immunity following induction of tumor apoptosis by suicide genes.