Abstract
Immune responses elicited against cancer using existing therapies such as vaccines or immune stimulatory antibodies are often not curative. One way to potentiate antitumor immunity is to enhance the long-term persistence of anti-tumor CD8+ T cells. Studies have shown that the persistence of activated CD8+ T cells is negatively impacted by the strength of interleukin 2 (IL-2) signaling. Here, we used small interfering RNAs (siRNAs) against CD25 (IL-2Rα) to attenuate IL-2 signaling in CD8+ T cells. The siRNAs were targeted to 4-1BB-expressing CD8+ T cells by conjugation to a 4-1BB-binding oligonucleotide aptamer. Systemic administration of the 4-1BB aptamer-CD25 siRNA conjugate downregulated CD25 mRNA only in 4-1BB-expressing CD8+ T cells promoting their differentiation into memory cells. Treatment with the 4-1BB aptamer-CD25 siRNA conjugates enhanced the antitumor response of a cellular vaccine or local radiation therapy. Indicative of the generality of this approach, 4-1BB aptamer-targeted delivery of an Axin-1 siRNA, a rate-limiting component of the β-catenin destruction complex, enhanced CD8+ T cell memory development and antitumor activity. These findings show that aptamer-targeted siRNA therapeutics can be used to modulate the function of circulating CD8+ T cells, skewing their development into long-lasting memory CD8+ T cells, and thereby potentiating antitumor immunity.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 54-61 |
| Number of pages | 8 |
| Journal | Molecular Therapy |
| Volume | 25 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 4 2017 |
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Keywords
- aptamer
- Axin-1
- IL-2 receptor
- siRNA
- T cell memory
- tumor immunotherapy
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery
Cite this
Aptamer-Targeted Attenuation of IL-2 Signaling in CD8+ T Cells Enhances Antitumor Immunity. / Rajagopalan, Anugraha; Berezhnoy, Alexey; Schrand, Brett; Puplampu-Dove, Yvonne; Gilboa, Eli.
In: Molecular Therapy, Vol. 25, No. 1, 04.01.2017, p. 54-61.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Aptamer-Targeted Attenuation of IL-2 Signaling in CD8+ T Cells Enhances Antitumor Immunity
AU - Rajagopalan, Anugraha
AU - Berezhnoy, Alexey
AU - Schrand, Brett
AU - Puplampu-Dove, Yvonne
AU - Gilboa, Eli
PY - 2017/1/4
Y1 - 2017/1/4
N2 - Immune responses elicited against cancer using existing therapies such as vaccines or immune stimulatory antibodies are often not curative. One way to potentiate antitumor immunity is to enhance the long-term persistence of anti-tumor CD8+ T cells. Studies have shown that the persistence of activated CD8+ T cells is negatively impacted by the strength of interleukin 2 (IL-2) signaling. Here, we used small interfering RNAs (siRNAs) against CD25 (IL-2Rα) to attenuate IL-2 signaling in CD8+ T cells. The siRNAs were targeted to 4-1BB-expressing CD8+ T cells by conjugation to a 4-1BB-binding oligonucleotide aptamer. Systemic administration of the 4-1BB aptamer-CD25 siRNA conjugate downregulated CD25 mRNA only in 4-1BB-expressing CD8+ T cells promoting their differentiation into memory cells. Treatment with the 4-1BB aptamer-CD25 siRNA conjugates enhanced the antitumor response of a cellular vaccine or local radiation therapy. Indicative of the generality of this approach, 4-1BB aptamer-targeted delivery of an Axin-1 siRNA, a rate-limiting component of the β-catenin destruction complex, enhanced CD8+ T cell memory development and antitumor activity. These findings show that aptamer-targeted siRNA therapeutics can be used to modulate the function of circulating CD8+ T cells, skewing their development into long-lasting memory CD8+ T cells, and thereby potentiating antitumor immunity.
AB - Immune responses elicited against cancer using existing therapies such as vaccines or immune stimulatory antibodies are often not curative. One way to potentiate antitumor immunity is to enhance the long-term persistence of anti-tumor CD8+ T cells. Studies have shown that the persistence of activated CD8+ T cells is negatively impacted by the strength of interleukin 2 (IL-2) signaling. Here, we used small interfering RNAs (siRNAs) against CD25 (IL-2Rα) to attenuate IL-2 signaling in CD8+ T cells. The siRNAs were targeted to 4-1BB-expressing CD8+ T cells by conjugation to a 4-1BB-binding oligonucleotide aptamer. Systemic administration of the 4-1BB aptamer-CD25 siRNA conjugate downregulated CD25 mRNA only in 4-1BB-expressing CD8+ T cells promoting their differentiation into memory cells. Treatment with the 4-1BB aptamer-CD25 siRNA conjugates enhanced the antitumor response of a cellular vaccine or local radiation therapy. Indicative of the generality of this approach, 4-1BB aptamer-targeted delivery of an Axin-1 siRNA, a rate-limiting component of the β-catenin destruction complex, enhanced CD8+ T cell memory development and antitumor activity. These findings show that aptamer-targeted siRNA therapeutics can be used to modulate the function of circulating CD8+ T cells, skewing their development into long-lasting memory CD8+ T cells, and thereby potentiating antitumor immunity.
KW - aptamer
KW - Axin-1
KW - IL-2 receptor
KW - siRNA
KW - T cell memory
KW - tumor immunotherapy
UR - http://www.scopus.com/inward/record.url?scp=85016265970&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85016265970&partnerID=8YFLogxK
U2 - 10.1016/j.ymthe.2016.10.021
DO - 10.1016/j.ymthe.2016.10.021
M3 - Article
C2 - 28129128
AN - SCOPUS:85016265970
VL - 25
SP - 54
EP - 61
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 1
ER -