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

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, alpha-galactosylceramide (alpha-GalCer). However, it is known that, in human cancer patients, NKT cells express a degree of hyporesponsiveness to alpha-GalCer. In this study, we have examined the mechanism by which hyporesponsiveness to alpha-GalCer can be induced. In cancer-bearing mice, alpha-GalCer-induced NKT cell expansion, cytokine production, cytotoxicity, and antimetastatic effect in vivo were all significantly impaired. In fact, alpha-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 alpha-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 alpha-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.

• Authors: Kazuhiko Yanagisawa, Mark A Exley, Xiaofeng Jiang, Nobuhiro Ohkochi, Masaru Taniguchi, Ken-ichiro Seino
• Journal: Cancer research (Cancer Res) Vol. 66 Issue 23 Pg. 11441-6 (Dec 01 2006) ISSN: 0008-5472 [Print] United States
• PMID: 17145891 (Publication Type: Journal Article)

Chemical References

• CD11b Antigen
• Galactosylceramides
• Gr-1 protein, mouse
• Receptors, Chemokine
• alpha-galactosylceramide
• Interleukin-4
• Nitric Oxide
• Tretinoin
• Interferon-gamma

Topics

• Animals
• CD11b Antigen (analysis, immunology)
• Carcinoma, Lewis Lung (immunology, pathology, prevention & control)
• Cell Line, Tumor
• Enzyme-Linked Immunosorbent Assay
• Galactosylceramides (immunology, pharmacology)
• Interferon-gamma (analysis)
• Interleukin-4 (analysis)
• Killer Cells, Natural (drug effects, immunology, metabolism)
• Male
• Melanoma, Experimental (immunology, pathology, prevention & control)
• Mice
• Mice, Inbred C57BL
• Neoplasms, Experimental (immunology, pathology, prevention & control)
• Nitric Oxide (biosynthesis)
• Receptors, Chemokine (analysis, immunology)
• Spleen (cytology, drug effects, metabolism)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Time Factors
• Tretinoin (immunology, pharmacology)