@article{24d560abe632428faa3430acb3116736,
title = "Potentiating tumor immunity using aptamer-targeted RNAi to render CD8+ T cells resistant to TGFβ inhibition",
abstract = "TGFβ 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 TGFβ pathway exhibited at best a modest therapeutic benefit. A likely reason, a common limitation of many cancer drugs, is that the physiologic roles of TGFβ 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 TGFβ may be sufficient to inhibit tumor growth. Here we describe an approach to render vaccine-activated CD8+ T cells transiently resistant to TGFβ inhibition using an siRNA against Smad4 to inhibit a key step in the canonical TGFβ signaling pathway. The siRNA was targeted to vaccine activated CD8+ T cells in the mouse by conjugation to a 4–1BB binding oligonucleotide (ODN) aptamer ligand (4–1BB-Smad4 conjugate). In vitro the 4–1BB-Smad4 conjugate rendered T cells partially resistant to TGFβ inhibition, and treatment of tumor bearing mice with systemically administered 4–1BB-Smad4 conjugate enhanced vaccine- and irradiation-induced antitumor immunity. Limiting the inhibitory effects of TGFβ to tumor-specific T cells will not interfere with its multiple physiologic roles and hence reduce the risk of toxicity.",
keywords = "Aptamers, Cancer immunotherapy, TGFβ, preclinical mouse models, siRNA, tumor targeting",
author = "Yvonne Puplampu-Dove and Tal Gefen and Anugraha Rajagopalan and Darija Muheramagic and Brett Schrand and Eli Gilboa",
note = "Funding Information: EG: Grant PC130382 from the Congressionally Directed Medical Research Program, PC130382 YPD: National Institutes of Health F31CA196258 Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number F31CA196258 to YPD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by grant PC130382 from the Congressionally Directed Medical Research Program to EG, and Initiative for Maximizing Student Development (IMSD) fellowship to YPD. We thank Agata Levay, Iris Castro, Emily Clark and Oliver Umland at the University of Miami for their assistance. Funding Information: EG: Grant PC130382 from the Congressionally Directed Medical Research Program, PC130382 YPD: National Institutes of Health F31CA196258 Funding Information: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number F31CA196258 to YPD. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by grant PC130382 from the Congressionally Directed Medical Research Program to EG, and Initiative for Maximizing Student Development (IMSD) fellowship to YPD. We thank Agata Levay, Iris Castro, Emily Clark and Oliver Umland at the University of Miami for their assistance. Publisher Copyright: {\textcopyright} 2018 Taylor & Francis Group, LLC.",
year = "2018",
month = apr,
day = "3",
doi = "10.1080/2162402X.2017.1349588",
language = "English (US)",
volume = "7",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",
number = "4",
}