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Hyporesponsiveness to Natural Killer T-Cell Ligand -Galactosylceramide in Cancer-Bearing State Mediated by CD11b⁺ Gr-1⁺ Cells Producing Nitric Oxide

¹ Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan; ² Division of Hematology/Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts; ³ Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan; ⁴ PRESTO, Japan Science and Technology Agency, Kawaguchi, Saitama, Japan; and ⁵ Laboratory for Molecular Therapy, Institute of Medical Science, St. Marianna University School of Medicine, Kanagawa, Japan

Requests for reprints: Ken-ichiro Seino, Laboratory for Molecular Therapy, Institute of Medical Science, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan. Phone: 81-44-977-8165; Fax: 81-44-977-8165; E-mail: seino{at}marianna-u.ac.jp.

CD1d-restricted natural killer T (NKT) cells are a potential therapeutic target for cancer, for which several clinical trials have already been reported. NKT cells are specifically activated by a synthetic glycolipid, -galactosylceramide (-GalCer). However, it is known that, in human cancer patients, NKT cells express a degree of hyporesponsiveness to -GalCer. In this study, we have examined the mechanism by which hyporesponsiveness to -GalCer can be induced. In cancer-bearing mice, -GalCer-induced NKT cell expansion, cytokine production, cytotoxicity, and antimetastatic effect in vivo were all significantly impaired. In fact, -GalCer could eliminate metastatic disease in naive animals but failed to protect cancer-bearing mice. CD11b⁺ Gr-1⁺ cells were particularly increased in cancer-bearing mice and were necessary and sufficient for the suppression of the -GalCer response in a nitric oxide–mediated fashion. Administration of a retinoic acid to cancer-bearing mice reduced the population of CD11b⁺ Gr-1⁺ cells and effectively restored -GalCer-induced protection. These results show a novel feature of NKT cell function in cancer. Furthermore, our data suggest a new strategy to enhance NKT cell-mediated anticancer immune responses by suppressing CD11b⁺ Gr-1⁺ cell functions. (Cancer Res 2006; 66(23): 11441-6)

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