CD1d-restricted T cells in patients wth oesophageal cancer

Oesophageal cancer (OC) causes over 0.5 million deaths worldwide each year. Current therapeutic regimens focus on chemo-radiotherapy prior to surgery, however, only 20-30% of patients respond to treatment. Therefore, new treatments are badly needed. Natural killer T (NKT) cells are innate T cells that recognize lipid antigens presented by CD1d molecules. We enumerated circulating NKT cells in OC patients and control subjects by flow cytometry using monoclonal antibodies and CD1d tetramers loaded with glycolipid antigens.
This allowed for the detection of invariant NKT cells, which possess invariant T cell receptor (TCR) α-chains reactive with α-galactosylceramide and mediate anti-tumour immunity in mice and humans, as well as novel NKT cells that recognise other glycolipids. We found that invariant NKT cells were depleted and functionally-impaired in patients with OC. In contrast, NKT cells reactive against sulfatide and tetramyristoyl-cardiolipin (TCL) were present in significantly higher numbers in OC patients compared to controls. Most of these cells expressed γδ TCRs, specifically the Vδ1 subset. TCL induced the production of transforming growth factor-β by expanded Vδ1 T cells in vitro in a CD1d dependant manner. Supernatants of Vδ1 T cells activated with sulfatide or TCL inhibited degranulation by invariant NKT cells. These data suggest that invariant NKT cells protect against OC but other CD1d-restricted NKT cells may promote tumorigenesis in these patients. These findings have important implications for cellular therapies involving invariant NKT cells, which are currently being tested in clinical trials for multiple cancer types.