title: DAI (DLM-1/ZBP1) as a genetic adjuvant for DNA vaccines that promotes effective antitumor CTL immunity.
abstract: DNA vaccination is an attractive approach to induce antigen-specific cytotoxic CD8(+) T lymphocytes (CTLs), which can mediate protective antitumor immunity. The potency of DNA vaccines encoding weakly immunogenic tumor-associated antigens (TAAs) can be enhanced by codelivering gene-encoded adjuvants. Pattern recognition receptors (PRRs) that sense intracellular DNA could potentially be used to harness intrinsic immune-stimulating properties of plasmid DNA vaccines. Consequently, the cytosolic DNA sensor, DNA-dependent activator of interferon (IFN) regulatory factors (DAI), was used as a genetic adjuvant. In vivo electroporation (EP) of mice with a DAI-encoding plasmid (pDAI) promoted transcription of genes encoding type I IFNs, proinflammatory cytokines, and costimulatory molecules. Coimmunization with pDAI and antigen-encoding plasmids enhanced in vivo antigen-specific proliferation, and induction of effector and memory CTLs. Moreover, codelivery of pDAI effectively promoted CTL and CD4(+) Th1 responses to the TAA survivin. The DAI-enhanced CTL induction required nuclear factor κB (NF-κB) activation and type I IFN signaling, but did not involve the IFN regulatory factor 3 (IRF3). Codelivery of pDAI also increased CTL responses to the melanoma-associated antigen tyrosinase-related protein-2 (TRP2), enhanced tumor rejection and conferred long-term protection against B16 melanoma challenge. This study constitutes "proof-of-principle" validating the use of intracellular PRRs as genetic adjuvants to enhance DNA vaccine potency.
authors.affiliation: Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden. Alvaro.Lladser@gmail.com
authors.forename: Alvaro
authors.initials: A
authors.lastname: Lladser
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Mougiakakos
authors.forename: Helena
authors.initials: H
authors.lastname: Tufvesson
authors.forename: Maarten A
authors.initials: MA
authors.lastname: Ligtenberg
authors.forename: Andrew Fg
authors.initials: AF
authors.lastname: Quest
authors.forename: Rolf
authors.initials: R
authors.lastname: Kiessling
authors.forename: Karl
authors.initials: K
authors.lastname: Ljungberg
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000276:Adjuvants, Immunologic / Q000235:genetics*; D000818:Animals; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology; D019746:Intramolecular Oxidoreductases / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000276:immunology*; D010957:Plasmids / Q000235:genetics / Q000276:immunology; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000276:immunology; D016019:Survival Analysis; D000077022:Survivin; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D019444:Vaccines, DNA / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C117749:Birc5 protein, mouse; D006023:Glycoproteins; D051034:Inhibitor of Apoptosis Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D000077022:Survivin; D019444:Vaccines, DNA; C402632:Zbp1 protein, mouse; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase