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A Pivotal Role for CC Chemokine Receptor 5 in T-Cell Migration to Tumor Sites Induced by Interleukin 12 Treatment in Tumor-bearing Mice¹

Department of Oncology, Biomedical Research Center, Osaka University Graduate School of Medicine, Osaka 565-0871 [Y. U., W-G. Y., T. M., P. G., N. Y., H. F., T. H.]; Department of Molecular Preventive Medicine, Tokyo University School of Medicine, Tokyo 113-0033 [M. M., K. M.]; Department of Bioorganic Chemistry, Graduate School of Pharmaceutical Sciences Osaka University, Osaka 565-0871 [S. O., T. I.]; and Department of Pathology, Osaka University Graduate School of Medicine, Osaka 565-0871 [Y. H., S. N., Y. K.], Japan

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) 1 and MIP-1ß in tumor masses. In contrast, the expression of CCR5 in spleens and MIP-1/MIP-1ß 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.

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