期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 104, 期 25, 页码 10299-10304出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0703824104
关键词
antigen presentation; CD1; alpha-galactosylceramide
alpha-Galactosylceramide (alpha-GalCer), a glycolipid that stimulates natural killer T (NKT) cells to produce both T helper (Th)1 and Th2 cytokines, has shown antitumor effects in mice but failed in clinical trials. We evaluated 16 analogs of alpha-GalCer for their CD1-mediated T cell receptor (TCR) activation of naive human NKT cells and their anticancer efficacy. In vitro, glycolipids containing an aromatic ring in their acyl tail or sphingosine tail were more effective than alpha-GalCer in inducing Th1 cytokines/chemokines, TCR activation, and human NKT cell expansion. None of these glycolipids could directly stimulate human dendritic cell maturation, except for a glycolipid with an aromatic ring on the sphingosine tail. Here, we show that glycolipids activated the TCR of NKT cells with phosphorylation of CD3 epsilon, ERK1/2, or CREB, which correlated with their induction of Th1 cytokines. Notably, the extent of NKT cell activation when glycolipid was presented by antigen-presenting cells was greater than when glycolipid was presented by non-antigen-presenting cells. In vivo, in mice bearing breast or lung cancers, the glycolipids that induced more Th1-biased cytokines and ClD8/CD4 T cells displayed significantly greater anticancer potency than alpha-GalCer. These findings indicate that alpha-GalCer analogs can be designed to favor Th1-biased immunity, with greater anticancer efficacy and other immune-enhancing activities than alpha-GalCer itself.
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