Harnessing CD1d-restricted T cells toward antitumor immunity in humans

Natural killer T (NKT) cells are a distinct subset of T cells that recognize lipid antigens in the context of CD1d molecules. There is a considerable body of evidence implicating a role for NKT cells in regulating antitumor immunity in mice. alpha-Galactosylceramide (alpha-GalCer) is a potent agonist ligand for type I NKT cells. We and others have shown that injection of alpha-GalCer-loaded dendritic cells leads to clear expansion of NKT cells in vivo in cancer patients. Preclinical studies suggest the capacity of thalidomide analogues to enhance ligand-dependent NKT activation and provide the rationale for combination approaches that are now being designed. Recently, we demonstrated the presence of CD1d-restricted T cells specific for an inflammation-associated lipid, lysophosphatidylcholine, in patients with advanced myeloma. These studies suggest that type II NKT cells may play a role in sensing and regulating inflammation. Harnessing CD1d-restricted T cells in cancer may depend on regulating the balance between type I and II NKT cells and holds promise as a broad strategy for immune therapy of several cancers.