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Toll-like Receptor-7 Tolerizes Malignant B Cells and Enhances Killing by Cytotoxic Agents

¹ Division of Molecular and Cellular Biology, Research Institute, Sunnybrook Health Sciences Center; ² Toronto-Sunnybrook Regional Cancer Center; Departments of ³ Medicine, ⁴ Medical Biophysics, University of Toronto; ⁵ Immunology Platform, Sanofi-Pasteur, Toronto, Canada; and ⁶ Department of Pharmacology, 3M Pharmaceuticals, 3M Center, St. Paul, Minnesota

Requests for reprints: David Spaner, Division of Molecular and Cellular Biology, Research Institute, S-116A, Research Building, Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Toronto, Ontario, Canada M4N 3M5. Phone: 416-480-6100-2510; Fax: 416-480-5737; E-mail: david.spaner{at}swri.ca.

Chronic activation through Toll-like receptors (TLR) occurs in a number of pathologic settings, but has not been studied to the same extent as primary activation. TLR7, expressed by B cells and some dendritic cells, recognizes molecular patterns associated with viruses that can be mimicked by synthetic imidazoquinolines. In response to primary stimulation with the imidazoquinoline, S28690, human mononuclear cells produced tumor necrosis factor-, but were unable to do so upon restimulation with S28690. This state of "tolerization" lasted at least 5 days. Using chronic lymphocytic leukemia B cells as a model to facilitate biochemical analysis, the tolerized state was found to be associated with altered receptor components, including down-regulated expression of TLR7 mRNA and decreased levels of interleukin-1 receptor-associated kinase 1. Tolerization was characterized by a transcriptionally regulated block in stress-activated protein kinase and nuclear factor B activation, with relatively preserved activation of extracellular signal-regulated kinase (ERK). Tolerized chronic lymphocytic leukemia cells were found to be more sensitive to cytotoxic chemotherapeutic agents, in part through altered stress-activated protein kinase signaling pathways. This property of the TLR7-tolerized state may potentially be exploited in the treatment of B cell cancers. [Cancer Res 2007;67(4):1823–31

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