Therapeutic Efficacy of Bifunctional siRNA Combining TGF-β1 Silencing with RIG-I Activation in Pancreatic Cancer

被引:127
作者
Ellermeier, Jonathan [1 ]
Wei, Jiwu [1 ,7 ]
Duewell, Peter [1 ]
Hoves, Sabine [1 ]
Stieg, Mareike R. [1 ]
Adunka, Tina [1 ]
Noerenberg, Daniel [1 ]
Anders, Hans-Joachim [1 ]
Mayr, Doris [4 ]
Poeck, Hendrik [5 ]
Hartmann, Gunther [6 ]
Endres, Stefan [2 ,3 ]
Schnurr, Max [1 ]
机构
[1] Klinikum Univ Munchen, Med Klin & Poliklin 4, Munich, Germany
[2] Klinikum Univ Munchen, Ctr Integrated Prot Sci Munich, Munich, Germany
[3] Klinikum Univ Munchen, Med Klin & Poliklin 4, Div Clin Pharmacol, Munich, Germany
[4] LMU Munchen, Inst Pathol, Munich, Germany
[5] Tech Univ Munich, Univ Klinikum Rechts Isar, Med Klin, D-80290 Munich, Germany
[6] Univ Klinikum, Inst Klin Chem & Klin Pharmakol, Bonn, Germany
[7] Nanjing Univ, Sch Med, Nanjing 210008, Jiangsu, Peoples R China
关键词
TGF-BETA; ANTIVIRAL RESPONSES; DENDRITIC CELLS; T-CELLS; RNA; GROWTH; ADENOCARCINOMAS; RECOGNITION; INTERFERONS; INHIBITION;
D O I
10.1158/0008-5472.CAN-11-3850
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Deregulated TGF-beta signaling in pancreatic cancer promotes tumor growth, invasion, metastasis, and a potent immunosuppressive network. A strategy for disrupting this tumor-promoting pathway is silencing TGF-beta by siRNA. By introducing a triphosphate group at the 5' end of siRNA (ppp-siRNA), gene silencing can be combined with immune activation via the cytosolic helicase retinoic acid-inducible gene I (RIG-I), a ubiquitously expressed receptor recognizing viral RNA. We validated RIG-I as a therapeutic target by showing that activation of RIG-I in pancreatic carcinoma cells induced IRF-3 phosphorylation, production of type I IFN, the chemokine CXCL10, as well as caspase-9-mediated tumor cell apoptosis. Next, we generated a bifunctional ppp-siRNA that combines RIG-I activation with gene silencing of TGF-beta(1) (ppp-TGF-beta) and studied its therapeutic efficacy in the orthotopic Panc02 mouse model of pancreatic cancer. Intravenous injection of ppp-TGF-beta reduced systemic and tumor-associated TGF-beta levels. In addition, it induced high levels of type I IFN and CXCL10 in serum and tumor tissue, systemic immune cell activation, and profound tumor cell apoptosis in vivo. Treatment of mice with established tumors with ppp-TGF-beta significantly prolonged survival as compared with ppp-RNA or TGF-beta siRNA alone. Furthermore, we observed the recruitment of activated CD8(+) T cells to the tumor and a reduced frequency of CD11b(+) Gr-1(+) myeloid cells. Therapeutic efficacy was dependent on CD8(+) T cells, whereas natural killer cells were dispensable. In conclusion, combing TGF-beta gene silencing with RIG-I signaling confers potent antitumor efficacy against pancreatic cancer by breaking tumor-induced CD8(+) T cell suppression. Cancer Res; 73(6); 1709-20. (c) 2013 AACR.
引用
收藏
页码:1709 / 1720
页数:12
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