Potential for enhanced therapeutic activity of biological cancer therapies with doxycycline combination

Gene Ther. 2013 Jul;20(7):770-8. doi: 10.1038/gt.2012.96. Epub 2013 Jan 3.


Despite significant strides made in the clinical translation of adoptive immune cell therapies, it is apparent that many tumors incorporate strategies to avoid recognition by receptors expressed on the immune cells, such as NKG2D. Strategies that stabilize the expression of ligands for these receptors may enhance the therapeutic potential of these and related therapies. Doxycycline inhibits matrix metalloproteinases (MMPs) that act to cleave the extracellular domain of MICA/B, ligands for the NKG2D receptor. Doxycycline treatment blocked shedding of MICA/B from a panel of human tumor cells, but also acted to increase their expression and cell surface translocation, possibly through its action on ATM. This meant that many tumor cells displayed increased MICA/B expression and enhanced susceptibility to CIK cells. Interestingly, doxycycline also selectively enhanced the replication of oncolytic vaccinia in many tumor cell lines, leading to increased sensitivity to these therapies. Combination (CIK-oncolytic vaccinia) therapies used in conjunction with doxycycline led to increased anti-tumor effects. The unexpected and pleiotropic beneficial anti-tumor effects of doxycycline on both immune cell and oncolytic viral therapies make it an excellent candidate for rapid clinical testing.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cell Line, Tumor
  • Combined Modality Therapy
  • Cytotoxicity, Immunologic
  • Doxycycline / administration & dosage*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Immunotherapy, Adoptive*
  • NK Cell Lectin-Like Receptor Subfamily K / genetics*
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Neoplasms / drug therapy*
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Oncolytic Virotherapy*
  • Translational Research, Biomedical
  • Vaccinia virus / genetics


  • Histocompatibility Antigens Class I
  • KLRK1 protein, human
  • MHC class I-related chain A
  • NK Cell Lectin-Like Receptor Subfamily K
  • Doxycycline