title: 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-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.
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33134, USA.
authors.forename: Anugraha
authors.initials: A
authors.lastname: Rajagopalan
authors.affiliation: Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33134, USA.
authors.forename: Alexey
authors.initials: A
authors.lastname: Berezhnoy
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33134, USA.
authors.forename: Brett
authors.initials: B
authors.lastname: Schrand
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33134, USA.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Puplampu-Dove
authors.affiliation: Dodson Interdisciplinary Immunotherapy Institute, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33134, USA; Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33134, USA. Electronic address: egilboa@miami.edu.
authors.forename: Eli
authors.initials: E
authors.lastname: Gilboa
mesh_terms: D000818:Animals; D052157:Aptamers, Nucleotide; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D019496:Cancer Vaccines / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007156:Immunologic Memory / Q000276:immunology; D007167:Immunotherapy; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction
chemical_list: D052157:Aptamers, Nucleotide; D019496:Cancer Vaccines; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D034741:RNA, Small Interfering
keywords: Axin-1; IL-2 receptor; T cell memory; aptamer; siRNA; tumor immunotherapy