Aptamer-Targeted Attenuation of IL-2 Signaling in CD8⁺ T Cells Enhances Antitumor Immunity.

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-2R?) 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 ?-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.

SUBMITTER: Rajagopalan A 

PROVIDER: S-EPMC5363184 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature