title: TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN.
abstract: Agonists for TLR9 and Stimulator of IFN Gene (STING) act as vaccine adjuvants that induce type-1 immune responses. However, currently available CpG oligodeoxynucleotide (ODN) (K-type) induces IFNs only weakly and STING ligands rather induce type-2 immune responses, limiting their potential therapeutic applications. Here, we show a potent synergism between TLR9 and STING agonists. Together, they make an effective type-1 adjuvant and an anticancer agent. The synergistic effect between CpG ODN (K3) and STING-ligand cyclic GMP-AMP (cGAMP), culminating in NK cell IFN-γ (type-II IFN) production, is due to the concurrent effects of IL-12 and type-I IFNs, which are differentially regulated by IRF3/7, STING, and MyD88. The combination of CpG ODN with cGAMP is a potent type-1 adjuvant, capable of inducing strong Th 1-type responses, as demonstrated by enhanced antigen-specific IgG2c and IFN-γ production, as well as cytotoxic CD8(+) T-cell responses. In our murine tumor models, intratumoral injection of CpG ODN and cGAMP together reduced tumor size significantly compared with the singular treatments, acting as an antigen-free anticancer agent. Thus, the combination of CpG ODN and a STING ligand may offer therapeutic application as a potent type-II IFN inducer.
authors.affiliation: Laboratory of Vaccine Science, WPI Immunology Frontier Research Center (iFReC), Osaka University, Osaka, Japan.
authors.forename: Burcu
authors.initials: B
authors.lastname: Temizoz
authors.forename: Etsushi
authors.initials: E
authors.lastname: Kuroda
authors.forename: Keiichi
authors.initials: K
authors.lastname: Ohata
authors.forename: Nao
authors.initials: N
authors.lastname: Jounai
authors.forename: Koji
authors.initials: K
authors.lastname: Ozasa
authors.forename: Kouji
authors.initials: K
authors.lastname: Kobiyama
authors.forename: Taiki
authors.initials: T
authors.lastname: Aoshi
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Ishii
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000276:immunology; D018664:Interleukin-12 / Q000378:metabolism; D008565:Membrane Proteins / Q000819:agonists*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D009369:Neoplasms / Q000628:therapy*; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D000099197:STING Protein
chemical_list: D000276:Adjuvants, Immunologic; D007074:Immunoglobulin G; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007370:Interferon Type I; D007371:Interferon-gamma; D018664:Interleukin-12; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D009712:Nucleotides, Cyclic; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; C408982:CPG-oligonucleotide; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C507780:Myd88 protein, mouse; C530855:Sting1 protein, mouse; D000099197:STING Protein; C495370:Tlr9 protein, mouse; C584311:cyclic guanosine monophosphate-adenosine monophosphate
keywords: Adjuvant; CpG ODN; IFN-γ; STING; TLR; cGAMP