Hyporesponsiveness to natural killer T-cell ligand α- galactosylceramide in cancer-bearing state mediated by CD11b+ Gr-1+ cells producing nitric oxide

Kazuhiko Yanagisawa, Mark A. Exley, Xiaofeng Jiang, Nobuhiro Ohkochi, Masaru Taniguchi, Ken Ichiro Seino

    Research output: Contribution to journalArticlepeer-review

    Abstract

    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, α-galactosylceramide (α-GalCer). However, it is known that, in human cancer patients, NKT cells express a degree of hyporesponsiveness to α-GalCer. In this study, we have examined the mechanism by which hyporesponsiveness to α-GalCer can be induced. In cancer-bearing mice, α-GalCer-induced NKT cell expansion, cytokine production, cytotoxicity, and antimetastatic effect in vivo were all significantly impaired. In fact, α-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 α-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 α-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. ©2006 American Association for Cancer Research.
    Original languageEnglish
    Pages (from-to)11441-11446
    Number of pages5
    JournalCancer Research
    Volume66
    Issue number23
    DOIs
    Publication statusPublished - 1 Dec 2006

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