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 TCR alpha chain specific for the MHC class I-like CD1d protein. These invarian t NK T cells can regulate diverse immune responses in mice, including antit umor responses, through mechanisms including rapid production of IL-4 and I FN-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. I nvariant NK T cells from healthy donors produced high levels of both IFN-ga mma and IL-4. In contrast, whereas invariant NK T cells from prostate cance r 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 can cer patients produced normal levels of IFN-gamma and IL-4. These findings s upport an immunoregulatory function for invariant NK T cells in humans medi ated by differential production of Th1 vs Th2 cytokines. They further indic ate that antitumor responses may be suppressed by the marked Th2 bias of in variant NK T cells in advanced cancer patients.