Uekusa Yasuhiro, Yu Wen-Gong, Mukai Takao, Gao Ping, Yamaguchi Nobuya, Murai Masako, Matsushima Kouji, Obika Satoshi, Imanishi Takeshi, Higashibata Yuji, Nomura Shintaro, Kitamura Yukihiko, Fujiwara Hiromi, Hamaoka Toshiyuki
Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Suita, Japan.
Cancer Res. 2002 Jul 1;62(13):3751-8.
Interleukin (IL) 12 treatment in the CSA1M and OV-HM, but not in Meth A tumor models,induces tumor regression that is associated with T-cell migration to tumor sites.Here, we investigated the role of the CC chemokine receptor (CCR)5 in T-cell migration induced after IL-12 treatment. In the two IL-12-responsive tumor models (CSA1M and OV-HM), IL-12 treatment up-regulated the mRNA expression of CCR5 in splenic T cells as well as ligands for CCR5, such as macrophage inflammatory protein (MIP) 1alpha and MIP-1beta in tumor masses. In contrast, the expression of CCR5 in spleens and MIP-1alpha/MIP-1beta in tumor masses was marginally induced before and even after IL-12 treatment in the Meth A model in which T-cell migration is not observed. T cells infiltrating tumor masses in the former two IL-12-responsive models expressed CCR5. Administration of a synthetic CCR5 antagonist TAK-779 to tumor-bearing mice during IL-12 immunotherapy prevented T-cell migration and tumor regression. Furthermore, anti-CCR5 antibody was found to inhibit T-cell migration in the lymphoid cell migration assay. Namely, although splenic T cells prepared from IL-12-treated CSA1M or OV-HM-bearing mice migrated into the corresponding tumor masses in recipient mice, the migration was inhibited when donor T cells were treated with anti-CCR5 antibody before the injection. These results indicate a critical role for CCR5 in the induction of T-cell migration to tumor sites after IL-12 treatment.
白细胞介素（IL）12治疗在CSA1M和OV - HM肿瘤模型中可诱导肿瘤消退，且这与T细胞向肿瘤部位迁移有关，但在Meth A肿瘤模型中却并非如此。在此，我们研究了CC趋化因子受体（CCR）5在IL - 12治疗后诱导的T细胞迁移中的作用。在两种对IL - 12有反应的肿瘤模型（CSA1M和OV - HM）中，IL - 12治疗上调了脾T细胞中CCR5的mRNA表达以及CCR5的配体，如肿瘤块中的巨噬细胞炎性蛋白（MIP）1α和MIP - 1β的表达。相比之下，在未观察到T细胞迁移的Meth A模型中，无论在IL - 12治疗前还是治疗后，脾中CCR5的表达以及肿瘤块中MIP - 1α/MIP - 1β的表达仅有轻微诱导。在前两种对IL - 12有反应的模型中浸润肿瘤块的T细胞表达CCR5。在IL - 12免疫治疗期间给荷瘤小鼠施用合成的CCR5拮抗剂TAK - 779可阻止T细胞迁移和肿瘤消退。此外，发现在淋巴细胞迁移试验中抗CCR5抗体可抑制T细胞迁移。也就是说，虽然从经IL - 治疗的CSA1M或OV - HM荷瘤小鼠制备的脾T细胞可迁移到受体小鼠相应的肿瘤块中，但在注射前用抗CCR5抗体处理供体T细胞时，迁移会受到抑制。这些结果表明CCR5在IL - 12治疗后诱导T细胞向肿瘤部位迁移中起关键作用。
