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Reinstalling Antitumor Immunity by Inhibiting Tumor-Derived Immunosuppressive Molecule IDO through RNA Interference¹

Xiufen Zheng^*, James Koropatnick^*,¶, Mu Li, Xusheng Zhang, Fengjun Ling^*, Xiubao Ren^||, Xishan Hao^||, Hongtao Sun^*, Costin Vladau^*, Jacob A. Franek^*, Biao Feng^*, Bradley L. Urquhart^*, Robert Zhong^*,,,, David J. Freeman^*, Bertha Garcia^* and Wei-Ping Min^2,*,,,

^* Department of Surgery, Pathology, Oncology, Microbiology, and Immunology and Multi-Organ Transplant Program, London Health Science Centre, London, Ontario, Canada; Lawson Health Research Institute, London, Ontario, Canada; Robarts Research Institute, London, Ontario, Canada; ^¶ London Regional Cancer Program, London, Ontario, Canada; and ^|| Tianjin Medical University, Tianjin, People’s Republic of China

Tumor-derived immune suppression is a major impediment to successful immune/gene cancer therapy. In the present study, we describe a novel strategy to disrupt tumor-derived immune suppression by silencing a tolerogenic molecule of tumor origin, IDO, using small interfering RNA (siRNA). Silencing of IDO in B16F10 cells in vitro using IDO-siRNA prevented catabolism of tryptophan and inhibited apoptosis of T cells. IDO-siRNA treatment of B16F10 cells in vitro inhibited subsequent growth, tumor formation, and the size of tumor formed, by those cells when transplanted into host mice. In vivo treatment of B16F10 tumor-bearing mice successfully postponed tumor formation time and significantly decreased tumor size. Furthermore, in vivo IDO-siRNA treatment resulted in recovery of T cells responses and enhancement of tumor-specific killing. Thus, silencing IDO may break tumor-derived immune suppression. These data indicate that RNA interference has potential to enhance cancer therapy by reinstalling anticancer immunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study is partially supported by the Internal Research Fund Grant from Lawson Health Research Institute.

² Address correspondence and reprints requests to Dr. Wei-Ping Min, 339 Windermere Road, London Health Science Centre-University Campus C9-136, London, Ontario N6A 5A5, Canada. E-mail address: mweiping{at}uwo.ca

³ Abbreviations used in this paper: DC, dendritic cell; KLH, keyhole limpet hemocyanin; 1-MT, 1-methyl-tryptophan; pDC, plasmacytoid DC; RNAi, RNA interference; siRNA, small interfering RNA.

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