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

Yasuhiro Uekusa, Wen Gong Yu, Takao Mukai, Ping Gao, Nobuya Yamaguchi, Masako Murai, Kouji Matsushima, Satoshi Obika, Takeshi Imanishi, Yuji Higashibata, Shintaro Nomura, Yukihiko Kitamura, Hiromi Fujiwara, Toshiyuki Hamaoka

Research output: Contribution to journalArticle

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

Original languageEnglish (US)
Pages (from-to)3751-3758
Number of pages8
JournalCancer Research
Volume62
Issue number13
StatePublished - Jul 1 2002
Externally publishedYes

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CCR5 Receptors
Interleukin-12
Cell Movement
T-Lymphocytes
Macrophage Inflammatory Proteins
Neoplasms
Therapeutics
Anti-Idiotypic Antibodies
Cell Migration Assays
Immunotherapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Uekusa, Y., Yu, W. G., Mukai, T., Gao, P., Yamaguchi, N., Murai, M., ... Hamaoka, T. (2002). A pivotal role for CC chemokine receptor 5 in T-cell migration to tumor sites induced by interleukin 12 treatment in tumor-bearing mice. Cancer Research, 62(13), 3751-3758.

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

In: Cancer Research, Vol. 62, No. 13, 01.07.2002, p. 3751-3758.

Research output: Contribution to journalArticle

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 & Hamaoka, T 2002, 'A pivotal role for CC chemokine receptor 5 in T-cell migration to tumor sites induced by interleukin 12 treatment in tumor-bearing mice', Cancer Research, vol. 62, no. 13, pp. 3751-3758.
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. / A pivotal role for CC chemokine receptor 5 in T-cell migration to tumor sites induced by interleukin 12 treatment in tumor-bearing mice. In: Cancer Research. 2002 ; Vol. 62, No. 13. pp. 3751-3758.
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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) 1α and MIP-1β in tumor masses. In contrast, the expression of CCR5 in spleens and MIP-1α/MIP-1β 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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AU - Murai, Masako

AU - Matsushima, Kouji

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AU - Imanishi, Takeshi

AU - Higashibata, Yuji

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AU - Kitamura, Yukihiko

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