Loss of IFN-gamma production by invariant NK T cells in advanced cancer.
Invariant NK T cells express certain NK cell receptors and an invariant TCRalpha chain specific for the MHC class I-like CD1d protein. These invariant NK T cells can regulate diverse immune responses in mice, including antitumor responses, through mechanisms including rapid production of IL-4 and IFN-gamma, but their physiological functions remain uncertain. Invariant NK T cells were markedly decreased in peripheral blood from advanced prostate cancer patients, and their ex vivo expansion with a CD1d-presented lipid Ag (alpha-galactosylceramide) was diminished compared with healthy donors. Invariant NK T cells from healthy donors produced high levels of both IFN-gamma and IL-4. In contrast, whereas invariant NK T cells from prostate cancer patients also produced IL-4, they had diminished IFN-gamma production and a striking decrease in their IFN-gamma:IL-4 ratio. The IFN-gamma deficit was specific to the invariant NK T cells, as bulk T cells from prostate cancer patients produced normal levels of IFN-gamma and IL-4. These findings support an immunoregulatory function for invariant NK T cells in humans mediated by differential production of Th1 vs Th2 cytokines. They further indicate that antitumor responses may be suppressed by the marked Th2 bias of invariant NK T cells in advanced cancer patients.
Tahir
S M
SM
Cancer Biology Program, Hematology/Oncology Division, Department of Medicine, Beth Israel-Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA.
Cheng
O
O
Shaulov
A
A
Koezuka
Y
Y
Bubley
G J
GJ
Wilson
S B
SB
Balk
S P
SP
Exley
M A
MA
D002478:Cells, Cultured; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D011471:Prostatic Neoplasms / Q000175:diagnosis / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D007371:Interferon-gamma