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Cyclic-di-GMP based immune stimulatory formulations as novel vaccine adjuvants and anti-cancer agents

Soner Yildiz1*, Esin Alpdundar1, Banu Bayyurt2, Mine Ozcan1, Gozde Gucluler2, Defne Bayik2, Bilgi Gungor1, Ihsan Gursel2 and Mayda Gursel1
  • 1 Middle East Technical University, Department of Biological Sciences, Türkiye
  • 2 Bilkent University, Molecular Biology and Genetics, Türkiye

3´,5´-Cyclic diguanylic acid (c-di-GMP) is a bacterial derived small cyclic dinucleotide that functions as the universal bacterial secondary messenger[1]. To date, studies concerning its immunostimulatory effects revealed that cytosolic sensing of c-di-GMP by the innate immune receptor STING[2], induces a robust type-I interferon production in antigen presenting cells[3], leading to their maturation[4]. However, the chemical structure and the anionic nature of c-di-GMP limit its efficient entry through cellular membranes, requiring its transfection to cytosol. Here, we present a simple molecular complexation strategy that improves the intracellular delivery and boosts the immunostimulatory activity of c-di-GMP. Moreover, we also show that bacteria derived membrane vesicles (MV) can be utilized as vesicular carriers of this cyclic dinucleotide. Vaccination of mice using model antigen OVA adjuvanted with c-di-GMP/nonaarginine peptide complexes or c-di-GMP encapsulated in bacterial MVs, induced significantly higher levels of antigen-specific total IgG when compared to OVA or OVA+free c-di-GMP immunized groups. In contrast to OVA immunized mice, OVA+c-di-GMP/nonaarginine and OVA+c-di-GMP/bacterial MV adjuvanted groups showed complete protection from EG.7 tumor challenge. Consistent with the ability of these formulations to induce anti-tumorimmunity, ex-vivo re-stimulation of spleen cells harvested from immunized mice with the SIINFEKL peptide resulted in 8 to 10 fold increase in IFN-γ production. These findings suggest that c-di-GMP/nonarginine complexes or c-di-GMP/bacterial MVs are effective vaccine adjuvants and can generate tumor-specific CD8 T cell responses.

References

[1] Yan H, Chen W. 3',5'-Cyclic diguanylic acid: a small nucleotide that makes big impacts. Chem Soc Rev. 2010 Aug;39
[2] Dara L. Burdette, Kathryn M. Monroe, Katia Sotelo-Troha, Jeff S. Iwig, Barbara Eckert, Mamoru Hyodo, Yoshihiro Hayakawa, Russell E. Vance STING is a direct innate immune sensor of cyclic-di-GMP. Nature. Author manuscript; available in PMC 2012 April 27
[3] Whirter SM, Barbalat R, Monroe KM, Fontana MF, Hyodo M, Joncker NT, Ishii KJ, Akira S, Colonna M, Chen ZJ, Fitzgerald KA, Hayakawa Y, Vance RE. A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. J Exp Med. 2009 Aug 31
[4] Karaolis DK, Means TK, Yang D, Takahashi M, Yoshimura T, Muraille E, Philpott D, Schroeder JT, Hyodo M, Hayakawa Y, Talbot BG, Brouillette E, Malouin F. Bacterial c-di-GMP is an immunostimulatory molecule. J Immunol. 2007 Feb 15

Keywords: cylic-di-GMP, complexation, vaccine adjuvant, anti-tumor agent, cationic peptides, bacterial membrane vesicles

Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.

Presentation Type: Abstract

Topic: Translational immunology and immune intervention

Citation: Yildiz S, Alpdundar E, Bayyurt B, Ozcan M, Gucluler G, Bayik D, Gungor B, Gursel I and Gursel M (2013). Cyclic-di-GMP based immune stimulatory formulations as novel vaccine adjuvants and anti-cancer agents. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00117

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Received: 11 Mar 2013; Published Online: 22 Aug 2013.

* Correspondence: Mr. Soner Yildiz, Middle East Technical University, Department of Biological Sciences, ANKARA, 06800, Türkiye, e153181@metu.edu.tr