A pivotal role for CC chemokine receptor 5 in T-cell migration to tumor sites induced by interleukin 12 treatment in tumor-bearing mice

• Published in: Cancer research (Chicago, Ill.) Ill.), 2002-07, Vol.62 (13), p.3751-3758
• Main Authors: UEKUSA, Yasuhiro, YU, Wen-Gong, NOMURA, Shintaro, KITAMURA, Yukihiko, FUJIWARA, Hiromi, HAMAOKA, Toshiyuki, MUKAI, Takao, PING GAO, YAMAGUCHI, Nobuya, MURAI, Masako, MATSUSHIMA, Kouji, OBIKA, Satoshi, IMANISHI, Takeshi, HIGASHIBATA, Yuji
• Format: Article
• Language: English
• Subjects: Amides - pharmacology; Animals; Antineoplastic agents; Biological and medical sciences; CCR5 Receptor Antagonists; Cell Movement - drug effects; Cell Movement - immunology; Chemokine CCL3; Chemokine CCL4; Female; Fibrosarcoma - chemically induced; Fibrosarcoma - drug therapy; Fibrosarcoma - immunology; Humans; Immunotherapy; Interleukin-12 - pharmacology; Lymphocytes, Tumor-Infiltrating - cytology; Lymphocytes, Tumor-Infiltrating - immunology; Macrophage Inflammatory Proteins - biosynthesis; Macrophage Inflammatory Proteins - genetics; Macrophage Inflammatory Proteins - immunology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred C57BL; Neoplasms, Experimental - drug therapy; Neoplasms, Experimental - immunology; Neoplasms, Experimental - metabolism; Pharmacology. Drug treatments; Quaternary Ammonium Compounds - pharmacology; Receptors, CCR5 - biosynthesis; Receptors, CCR5 - genetics; Receptors, CCR5 - immunology; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Spleen - cytology; Spleen - immunology; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Up-Regulation - drug effects
• ISSN: 0008-5472

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.