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AuthorsTang H, et al. Show all Journal Gene Ther. 2013 Jul;20(7):770-8. doi: 10.1038/gt.2012.96. Epub 2013 Jan 3. Affiliation 1] University of Pittsburgh Cancer Institute, Departments of Surgery and Immunology, University of Pittsburgh, Pittsburgh, PA, USA  Institute of Clinical and Basic Medical Sciences, The First People's Hospital of Yunnan Province (The Kunhua Affiliated Hospital of Kunming University of Science and Technology), Kunming, Yunnan, China. Abstract 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. PMID 23282955 [PubMed - in process] PMCID PMC3620681 [Available on 2014/1/1] Full text: Nature Publishing Group Related CitationsShow all Induction of the DNA damage response by IAP inhibition triggers natural immunity via upregulation of NKG2D ligands in Hodgkin lymphoma in vitro. Inhibition of Glycogen Synthase Kinase-3 Increases NKG2D Ligand MICA Expression and Sensitivity to NK Cell-Mediated Cytotoxicity in Multiple Myeloma Cells: Role of STAT3. Generation of soluble NKG2D ligands: proteolytic cleavage, exosome secretion, and functional implications. Growth inhibition of different human colorectal cancer xenografts after a single intravenous injection of oncolytic vaccinia virus GLV-1h68. Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: Heterogeneous involvement of the "a disintegrin and metalloproteases" 10 and 17.