TLR9 and STING agonists synergistically induce innate and adaptive type-II IFN
| Autor: | Burcu Temizoz, Ken Ishii, Kouji Kobiyama, Taiki Aoshi, Etsushi Kuroda, Koji Ozasa, Nao Jounai, Keiichi Ohata |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
CpG ODN
CpG Oligodeoxynucleotide medicine.medical_treatment Interferon Regulatory Factor-7 Immunology Pharmacology Biology Interferon-gamma Mice Immune system Adjuvants Immunologic TLR Cell Line Tumor Neoplasms medicine Immunology and Allergy Cytotoxic T cell Animals IFN-γ Adjuvant Mice Knockout TLR9 Membrane Proteins hemic and immune systems Drug Synergism Interleukin-12 eye diseases Innate Immunity Mice Inbred C57BL Sting Oligodeoxyribonucleotides cGAMP Immunoglobulin G Toll-Like Receptor 9 Interferon Type I Myeloid Differentiation Factor 88 Female Interferon Regulatory Factor-3 Nucleotides Cyclic IRF3 CD8 STING T-Lymphocytes Cytotoxic |
| Zdroj: | European Journal of Immunology |
| ISSN: | 1521-4141 0014-2980 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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