Negative regulation of natural killer cell in tumor tissue and peripheral blood of oral squamous cell carcinoma

Cytokine. 2015 Dec;76(2):123-130. doi: 10.1016/j.cyto.2015.09.006. Epub 2015 Sep 12.


Natural killer (NK) cells are the key lymphocytes in solid tumors. Its activity is regulated by both germline encoded receptors and cytokine microenvironment. We conducted a case-control study to investigate the activation status of NK cell in oral squamous cell carcinoma (OSCC). NK cell activation was assessed in context of NK cell cytotoxicity and transcript expression of NK cell receptors (NKp46 and KIRs) and NK cell associated cytokines (IL-1β, IL-2, IL-10, IL-12β, IL-15, IL-18, IL-21, IFN-γ, TNF-α and TGF-β). The results revealed possible mechanisms involved in reduced NK cell activation in peripheral circulation: quantitative deficiency of NK cell number and lowered cytotoxicity together with qualitative NK impairments caused by--(1) decreased expression of NK activating receptor NKp46, (2) increased expression of NK suppressive cytokines--IL-10 and TGF-β and (3) induction of FOXP3(+)CTLA4(+) suppressor cells. On the other hand, in the tumor tissue, escape of NK immune surveillance appeared to be modulated by upregulation of TGF-β and IL-10 together with downregulation of NK cell activating cytokines (IL-2, IL-12β, IL-15, IL-18, IL-21 and IFN-γ) and NK receptors (NKp46 and KIRs). In addition, our study supported the earlier contention that TNF-α and IL-1β expression levels may be used as markers of malignant transformation in oral leukoplakia. In conclusion, the study provided an insight into the negative regulation of NK cell in tumor tissue and peripheral blood of OSCC patients, which can be exploited to boost the current NK cell and cytokine based immunotherapy for the treatment of oral cancer.

Keywords: Cytokine; Cytotoxic T-Lymphocyte-Associated Antigen 4; Forkhead Box P3; Killer cell immunoglobulin-like receptor; Natural killer cell; Oral squamous cell carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / blood
  • CTLA-4 Antigen / genetics
  • Carcinoma, Squamous Cell / blood
  • Carcinoma, Squamous Cell / immunology*
  • Carcinoma, Squamous Cell / physiopathology
  • Case-Control Studies
  • Cytokines / blood
  • Cytokines / genetics
  • Female
  • Forkhead Transcription Factors / genetics
  • Humans
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Mouth Neoplasms / blood
  • Mouth Neoplasms / immunology*
  • Mouth Neoplasms / physiopathology
  • Natural Cytotoxicity Triggering Receptor 1 / genetics
  • Receptors, KIR / genetics
  • Transforming Growth Factor beta / biosynthesis
  • Tumor Necrosis Factor-alpha / blood*
  • Tumor Necrosis Factor-alpha / genetics


  • Biomarkers, Tumor
  • CTLA-4 Antigen
  • Cytokines
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Natural Cytotoxicity Triggering Receptor 1
  • Receptors, KIR
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha