H₂O₂ production within tumor microenvironment inversely correlated with infiltration of CD56(dim) NK cells in gastric and esophageal cancer: possible mechanisms of NK cell dysfunction

Cancer Immunol Immunother. 2011 Dec;60(12):1801-10. doi: 10.1007/s00262-011-1082-7. Epub 2011 Aug 3.


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.

MeSH terms

  • Aged
  • CD56 Antigen / biosynthesis
  • CD56 Antigen / immunology
  • Carcinoma, Squamous Cell / immunology
  • Carcinoma, Squamous Cell / metabolism
  • Carcinoma, Squamous Cell / pathology
  • Cell Separation
  • Esophageal Neoplasms / immunology*
  • Esophageal Neoplasms / metabolism
  • Esophageal Neoplasms / pathology
  • Female
  • Flow Cytometry
  • Humans
  • Hydrogen Peroxide / metabolism*
  • Immunohistochemistry
  • Killer Cells, Natural / immunology*
  • Lymphocyte Subsets / immunology*
  • Lymphocyte Subsets / metabolism
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Neoplasm Staging
  • Stomach Neoplasms / immunology*
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology
  • Tumor Microenvironment / immunology*


  • CD56 Antigen
  • Hydrogen Peroxide