H2O2 production within tumor microenvironment inversely correlated with infiltration of CD56dim NK cells in gastric and esophageal cancer: possible mechanisms of NK cell dysfunction

Human NK cells can be divided into two subsets, CD56(dim)CD16(+)NK and CD56(bright)CD16(-)NK cells, based on their expression of CD56 and CD16. In the present study, we analyzed the relationship between CD56(dim)/CD56(bright) NK cells and H2O2 in tumor-infiltrating NK cells in patients with gastric (n = 50) and esophageal (n = 35) cancer. The ratio of CD56(dim) NK cells infiltrating tumors gradually decreased according to disease progression. H2O2 was abundantly produced within tumor microenvironments, and there was an inverse correlation between CD56(dim) NK cell infiltration and H2O2 production. CD56(dim) NK cells are more sensitive to apoptosis induced by physiological levels of H2O2 than CD56(bright) NK cells. Furthermore, the exposure of NK cells to H2O2 resulted in the impairment of ADCC activity. In conclusion, H2O2 produced within tumor microenvironments inversely correlated with the infiltration of CD56(dim) NK cells, possibly due to their preferentially induced cell death. These observations may explain one of the mechanisms behind NK cell dysfunction frequently observed in tumor microenvironments.