Journal
ONCOIMMUNOLOGY
Volume 7, Issue 4, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/2162402X.2017.1349588
Keywords
Aptamers; Cancer immunotherapy; preclinical mouse models; siRNA; tumor targeting; TGF beta
Categories
Funding
- Congressionally Directed Medical Research Program [PC130382]
- National Institutes of Health [F31CA196258]
- CDMRP [PC130382, 672393] Funding Source: Federal RePORTER
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TGF beta 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 beta 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 beta 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 beta may be sufficient to inhibit tumor growth. Here we describe an approach to render vaccine-activated CD8(+) T cells transiently resistant to TGF beta inhibition using an siRNA against Smad4 to inhibit a key step in the canonical TGF beta 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 TGF beta 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 TGF beta to tumor-specific T cells will not interfere with its multiple physiologic roles and hence reduce the risk of toxicity.
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