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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6120-6127. Prepublished online as a Blood First Edition Paper on February 6, 2009; DOI 10.1182/blood-2008-11-190421. This Article Full Text (PDF) All Versions of this Article: blood-2008-11-190421v1 113/24/6120    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Lundqvist, A. Articles by Childs, R. Search for Related Content PubMed PubMed Citation Articles by Lundqvist, A. Articles by Childs, R. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 19, 2008 Accepted January 27, 2009 Bortezomib treatment and regulatory T-cell depletion enhance the anti-tumor effects of adoptively infused NK cells Andreas Lundqvist, Hisayuki Yokoyama, Aleah Smith, Maria Berg, and Richard Childs* Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States * Corresponding author; email: childsr{at}nih.gov. Ligation of inhibitory receptors renders natural killer (NK) cells inactive against autologous tumors. Recently the proteasome inhibitor bortezomib was shown to sensitize tumors to autologous NK cell cytotoxicity in vitro. Here we show bortezomib augments the anti-tumor effects of syngeneic NK cell infusions in tumor-bearing animals with this effect being further enhanced in regulatory T-cell (Tregs) depleted hosts. In vitro, bortezomib treated tumors had higher TRAIL and perforin/granzyme-mediated caspase-8 activity, which enhanced their susceptibility to NK cell lysis. Bioluminescence imaging of mice with established tumors showed treatment with bortezomib and syngeneic NK cells reduced tumor growth and prolonged survival compared to controls receiving bortezomib or NK cells alone. In contrast, tumor progression was not delayed when animals received bortezomib and perforin-deficient NK cells showing drug-induced augmentation in NK cell cytotoxicity was mediated through perforin/granzyme. Furthermore, tumor growth was slower in bortezomib-treated recipients when host Tregs were eradicated with an anti-CD25 antibody prior to infusing NK cells compared to mice without Treg ablation (tumor doubling time 16.7 vs. 4.9 days respectively, p=0.02). These findings suggest that depletion of Tregs followed by bortezomib-induced tumor sensitization to autologous NK cells could be used as a novel strategy to treat cancer. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. R. Salih and A. Steinle Reinforcing natural killers Blood, June 11, 2009; 113(24): 6042 - 6043. [Full Text] [PDF]

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