Decreased invariant Natural Killer T cell-mediated anti-tumor immune response in patients with gastric cancer.

Gastric cancer (GC) is the third most common cause of cancer-related death worldwide. Invariant natural killer T (iNKT) cells are innate-like cytotoxic T lymphocytes involved in tumor immune surveillance. They can be activated either through CD1d-presented glycolipid antigens recognized by their invariant T cell receptor, cytokines or by sensing tumor-associated stress-induced ligands through NKG2D receptor. Although the number and functionality of iNKT cells may be decreased in several types of cancer, here we show that GC patients presented a mild increase in iNKT cell frequencies and numbers in the blood compared with healthy donors. In GC patients, iNKT cells, expanded in vitro with alpha-Galactosyl Ceramide and stimulated with PMA and Ionomycin, produced higher levels of IL-2 and TGF-beta, while their capacity to degranulate remained preserved. Since tumor-derived EpCAM-positive epithelial cells did not display surface CD1d, and NKG2D ligands (NKG2DL) were detected in the gastric tumor milieu, we envisioned a role for NKG2D on iNKT cell functions. Peripheral iNKT cells from GC patients and controls presented similar levels of NKG2D; nevertheless, the percentages of IFN-gamma-producing and CD107a-positive iNKT cells from patients were reduced upon challenge with CD1d-negative, NKG2DL-positive K562 cells, suggesting a compromised response by iNKT cells in GC patients, which may not result from impaired NKG2D/NKG2DL signaling. The decreased response of iNKT cells may explain the fact that higher frequencies of circulating iNKT cells did not confer a survival benefit for GC patients. Therefore, iNKT cells functional impairment in GC may contribute to tumor immune escape and favor disease progression.