Immunological visibility: posttranscriptional regulation of human NKG2D ligands by the EGF receptor pathway

Sci Transl Med. 2014 Apr 9;6(231):231ra49. doi: 10.1126/scitranslmed.3007579.


Human cytolytic T lymphocytes and natural killer cells can limit tumor growth and are being increasingly harnessed for tumor immunotherapy. One way cytolytic lymphocytes recognize tumor cells is by engagement of their activating receptor, NKG2D, by stress antigens of the MICA/B and ULBP families. This study shows that surface up-regulation of NKG2D ligands by human epithelial cells in response to ultraviolet irradiation, osmotic shock, oxidative stress, and growth factor provision is attributable to activation of the epidermal growth factor receptor (EGFR). EGFR activation causes intracellular relocalization of AUF1 proteins that ordinarily destabilize NKG2D ligand mRNAs by targeting an AU-rich element conserved within the 3' ends of most human, but not murine, NKG2D ligand genes. Consistent with these findings, NKG2D ligand expression by primary human carcinomas positively correlated with EGFR expression, which is commonly hyperactivated in such tumors, and was reduced by clinical EGFR inhibitors. Therefore, stress-induced activation of EGFR not only regulates cell growth but also concomitantly regulates the cells' immunological visibility. Thus, therapeutics designed to limit cancer cell growth should also be considered in terms of their impact on immunosurveillance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • AU Rich Elements / genetics
  • Animals
  • Cell Death / radiation effects
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Cell Membrane / radiation effects
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / metabolism*
  • Gene Expression Regulation* / radiation effects
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Histocompatibility Antigens Class I / genetics
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Ligands
  • Mice
  • Models, Biological
  • NK Cell Lectin-Like Receptor Subfamily K / genetics*
  • RNA Stability / radiation effects
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / genetics*
  • Signal Transduction / radiation effects
  • Stress, Physiological / radiation effects
  • Transcription, Genetic* / radiation effects
  • Ultraviolet Rays
  • Up-Regulation / radiation effects


  • 3' Untranslated Regions
  • Histocompatibility Antigens Class I
  • KLRK1 protein, human
  • Ligands
  • MHC class I-related chain A
  • NK Cell Lectin-Like Receptor Subfamily K
  • RNA, Messenger
  • Epidermal Growth Factor
  • EGFR protein, human
  • ErbB Receptors