1. A pivotal role for CC chemokine receptor 5 in T-cell migration to tumor sites induced by interleukin 12 treatment in tumor-bearing mice.
- Author
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Uekusa Y, Yu WG, Mukai T, Gao P, Yamaguchi N, Murai M, Matsushima K, Obika S, Imanishi T, Higashibata Y, Nomura S, Kitamura Y, Fujiwara H, and Hamaoka T
- Subjects
- Amides pharmacology, Animals, CCR5 Receptor Antagonists, Cell Movement drug effects, Cell Movement immunology, Chemokine CCL3, Chemokine CCL4, Female, Fibrosarcoma chemically induced, Fibrosarcoma drug therapy, Fibrosarcoma immunology, Humans, Lymphocytes, Tumor-Infiltrating cytology, Lymphocytes, Tumor-Infiltrating immunology, Macrophage Inflammatory Proteins biosynthesis, Macrophage Inflammatory Proteins genetics, Macrophage Inflammatory Proteins immunology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Neoplasms, Experimental drug therapy, Neoplasms, Experimental metabolism, Quaternary Ammonium Compounds pharmacology, RNA, Messenger biosynthesis, RNA, Messenger genetics, Receptors, CCR5 biosynthesis, Receptors, CCR5 genetics, Spleen cytology, Spleen immunology, T-Lymphocytes cytology, T-Lymphocytes drug effects, Up-Regulation drug effects, Interleukin-12 pharmacology, Neoplasms, Experimental immunology, Receptors, CCR5 immunology, T-Lymphocytes immunology
- Abstract
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.
- Published
- 2002