Abstract
Deregulated TGF-β 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-β 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-β1 (ppp-TGF-β) and studied its therapeutic efficacy in the orthotopic Panc02 mouse model of pancreatic cancer. Intravenous injection of ppp-TGF-β reduced systemic and tumor-associated TGF-β 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-β significantly prolonged survival as compared with ppp-RNA or TGF-β 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-β gene silencing with RIG-I signaling confers potent antitumor efficacy against pancreatic cancer by breaking tumor-induced CD8(+) T cell suppression.
Highlights
Pancreatic cancer is the fourth leading cause of cancerrelated death and is characterized by early metastasis and resistance to chemotherapy and irradiation
Pancreatic carcinoma cells express functional retinoic acid-inducible gene I (RIG-I) RIG-I expression was studied in human PanIN lesions, primary pancreatic adenocarcinomas, and metastases by immunohistochemistry
We found strong cytosolic staining for RIG-I in premalignant lesions and in tumor cells in 10 of 10 specimens (Supplementary Fig. S1)
Summary
Pancreatic cancer is the fourth leading cause of cancerrelated death and is characterized by early metastasis and resistance to chemotherapy and irradiation. The identification of deregulated molecular pathways in pancreatic cancer and the development of novel targeted therapies had so far little impact on clinical outcome [1]. Prognosis of patients with pancreatic cancer has remained extremely poor with a 5-year. Authors' Affiliations: 1Medizinische Klinik und Poliklinik IV, Klinikum der Universita€t Mu€nchen; 2Center for Integrated Protein Sciences Munich and Division of Clinical Pharmacology, Medizinische Klinik und Poliklinik IV, Klinikum der Universita€t Mu€nchen; 3Pathologisches Institut der LMU Mu€nchen; 4Medizinische Klinik, Universita€tsklinikum Rechts der Isar, Technische Universita€t, Mu€nchen; 5Institut fu€r Klinische Chemie und Klinische Pharmakologie, Universita€tsklinikum, Bonn, Germany; and 6Medical School of Nanjing University, Nanjing, China. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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