Dysregulation of TGF-β signaling promotes tumor growth, invasion, metastasis, and a potent immunosuppressive network in pancreas cancer. A strategy for disrupting the tumor-promoting pathway is the silencing of TGF-β by use of small-interfering (si) RNA. Ellermeier and colleagues found that the introduction of a triphosphate group at the 5′ end of siRNA (ppp-siRNA) allowed gene silencing to be combined with immune activation via the cytosolic helicase retinoic acid-inducible gene I (RIG-I), a ubiquitously expressed receptor that recognizes viral RNA.
The investigators validated RIG-I as a therapeutic target by showing that its activation in pancreatic carcinoma cells induced interferon regulatory transcription factor-3 phosphorylation, production of type I interferon, production of chemokine CXCL10, and caspase-9–mediated tumor cell apoptosis. They then generated a bifunctional ppp-siRNA that combined RIG-I activation with gene silencing of TGF-β1 (ppp-TGF-β) and assessed its effects in the orthotopic Panc02 mouse model of pancreatic cancer.
Injection of ppp-TGF-β resulted in reduced systemic and tumor-associated TGF-β levels, high levels of type I interferon and CXCL10 in serum and tumor tissue, increased systemic immune cell activation, and marked tumor cell apoptosis in vivo. Treatment with ppp-TGF-β in mice with established tumors significantly prolonged survival compared with ppp-RNA or TGF-β siRNA treatment alone. Recruitment of activated CD8+ T cells to the tumor was observed along with a reduced frequency of CD11b+ Gr-1+ myeloid cells, with therapeutic efficacy being dependent on levels of CD8+ T cells.
The investigators concluded, “[C]ombining TGF-β gene silencing with RIG-I signaling confers potent antitumor efficacy against pancreatic cancer by breaking tumor-induced CD8+ T cell suppression.” ■
Ellermeier J, Wei J, Duewell P, et al: Therapeutic efficacy of bifunctional siRNA combining TGF-β1 silencing with RIG-I activation in pancreatic cancer. Cancer Res 73:1709-1720, 2013.
Lab Notes is compiled and written for The ASCO Post by Matthew Stenger.