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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 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 Citation Map 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. Related Collections Immunobiology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Bortezomib treatment and regulatory T-cell depletion enhance the antitumor effects of adoptively infused NK cells Andreas Lundqvist1,2, Hisayuki Yokoyama1, Aleah Smith1, Maria Berg1, and Richard Childs1 1 Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 2 Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet, Stockholm, Sweden 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 antitumor effects of syngeneic NK-cell infusions in tumor-bearing animals; this effect is further enhanced in regulatory T cell (Treg cell)–depleted hosts. In vitro, bortezomib-treated tumors had higher tumor necrosis factor–related apoptosis-inducing ligand (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 with 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 Treg cells were eradicated with anti-CD25 antibody before infusing NK cells compared with mice without Treg-cell ablation (tumor doubling time, 16.7 vs 4.9 days, respectively; P = .02). These findings suggest that depletion of Treg cells 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? Related Article in Blood Online: Reinforcing natural killers Helmut Rainer Salih and Alexander Steinle Blood 2009 113: 6042-6043. [Full Text] [PDF] 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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