Hyporesponsiveness to natural killer T-cell ligand alpha-galactosylceramide in cancer-bearing state mediated by CD11b+ Gr-1+ cells producing nitric oxide.
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.
Yanagisawa
Kazuhiko
K
Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
Exley
Mark A
MA
Jiang
Xiaofeng
X
Ohkochi
Nobuhiro
N
Taniguchi
Masaru
M
Seino
Ken-ichiro
K
D000818:Animals; D039481:CD11b Antigen / Q000032:analysis* / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005699:Galactosylceramides / Q000276:immunology / Q000494:pharmacology*; D007371:Interferon-gamma / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019707:Receptors, Chemokine / Q000032:analysis* / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014212:Tretinoin / Q000276:immunology / Q000494:pharmacology
D039481:CD11b Antigen; D005699:Galactosylceramides; C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; C493154:alpha-galactosylceramide; D015847:Interleukin-4; D009569:Nitric Oxide; D014212:Tretinoin; D007371:Interferon-gamma