%0 Journal Article
%T Potentiating tumor immunity using aptamer-targeted RNAi to render CD8+ T cells resistant to TGF¦Â inhibition
%A Anugraha Rajagopalan
%A Brett Schrand
%A Darija Muheramagic
%A Eli Gilboa
%A Tal Gefen
%A Yvonne Puplampu-Dove
%J Archive of "Oncoimmunology".
%D 2018
%R 10.1080/2162402X.2017.1349588
%X TGF¦Â secreted by tumor cells and/or tumor infiltrating stromal cells is a key mediator of tumor growth and immune suppression at the tumor site. Nonetheless, clinical trials in cancer patients targeting the TGF¦Â pathway exhibited at best a modest therapeutic benefit. A likely reason, a common limitation of many cancer drugs, is that the physiologic roles of TGF¦Â in tissue homeostasis, angiogenesis, and immune regulation precluded the dose escalation necessary to achieve a profound clinical response. Murine studies have suggested that countering immune suppressive effects of TGF¦Â may be sufficient to inhibit tumor growth. Here we describe an approach to render vaccine-activated CD8+ T cells transiently resistant to TGF¦Â inhibition using an siRNA against Smad4 to inhibit a key step in the canonical TGF¦Â signaling pathway. The siRNA was targeted to vaccine activated CD8+ T cells in the mouse by conjugation to a 4¨C1BB binding oligonucleotide (ODN) aptamer ligand (4¨C1BB-Smad4 conjugate). In vitro the 4¨C1BB-Smad4 conjugate rendered T cells partially resistant to TGF¦Â inhibition, and treatment of tumor bearing mice with systemically administered 4¨C1BB-Smad4 conjugate enhanced vaccine- and irradiation-induced antitumor immunity. Limiting the inhibitory effects of TGF¦Â to tumor-specific T cells will not interfere with its multiple physiologic roles and hence reduce the risk of toxicity
%K Aptamers
%K Cancer immunotherapy
%K preclinical mouse models
%K siRNA
%K tumor targeting
%K TGF¦Â
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889204/