Loss of IFN-γ Production by Invariant NK T Cells in Advanced Cancer

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Abstract
Invariant NK T cells express certain NK cell receptors and an invariant TCRα 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-γ, 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 (α-galactosylceramide) was diminished compared with healthy donors. Invariant NK T cells from healthy donors produced high levels of both IFN-γ and IL-4. In contrast, whereas invariant NK T cells from prostate cancer patients also produced IL-4, they had diminished IFN-γ production and a striking decrease in their IFN-γ:IL-4 ratio. The IFN-γ deficit was specific to the invariant NK T cells, as bulk T cells from prostate cancer patients produced normal levels of IFN-γ 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.