Prognostic significance and functional implication of immune activating receptor NKG2D in gastric cancer

NKG2D, an activating receptor expressed on CD8⁺ T lymphocytes, serves as a co-stimulation molecule by engagement with its ligands MICA/B and ULBPs to trigger immune activation against tumors. Currently, the biological function and clinical significance of NKG2D in gastric cancer remains unexplored. The study aims to investigate the expression of NKG2D in gastric cancer in association with clinical prognosis and its biological function. Real-time PCR was used to analyze NKG2D expression in paired cancer and adjacent non-malignant tissues in 139 gastric cancer patients between 2007 and 2010 in Shanghai Cancer Center. NKG2D expression showed no association with any clinical characteristic parameters. High NKG2D level was significantly associated with better outcome (P = 0.018 for OS, P = 0.041 for DFS). Using univariate Cox regression model, high NKG2D mRNA resulted in 43% risk reduction in gastric cancer patients (HR = 0.57, CI (0.36-0.91), P = 0.019). High NKG2D level displayed a significant association with longer OS in the multivariate analysis (HR = 0.59, CI (0.363-0.96), P = 0.034), independent of other prognostic factors including Lauren classification, neural infiltration, vascular/lymphatic invasion, TNM stage. Upon co-incubation with cancer cells, NKG2D expression in CD8⁺ T cells was markedly down-regulated. Functional study suggested that either blocking NKG2D or its ligand ULBP-2 could suppress tumor-killing activity of CD8⁺ T cells. Our data showed that NKG2D receptor could be an independent favorable prognostic indicator for gastric cancer. Furthermore, decreased NKG2D expression might be the mechanism underlying immune evasion by tumors in gastric cancer.