Frontiers in Immunology (Mar 2024)
5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation
- Burcu Temizoz,
- Burcu Temizoz,
- Burcu Temizoz,
- Takayuki Shibahara,
- Kou Hioki,
- Tomoya Hayashi,
- Tomoya Hayashi,
- Tomoya Hayashi,
- Kouji Kobiyama,
- Kouji Kobiyama,
- Kouji Kobiyama,
- Michelle Sue Jann Lee,
- Michelle Sue Jann Lee,
- Michelle Sue Jann Lee,
- Naz Surucu,
- Erdal Sag,
- Atsushi Kumanogoh,
- Atsushi Kumanogoh,
- Masahiro Yamamoto,
- Masahiro Yamamoto,
- Mayda Gursel,
- Seza Ozen,
- Etsushi Kuroda,
- Cevayir Coban,
- Cevayir Coban,
- Cevayir Coban,
- Cevayir Coban,
- Ken J. Ishii,
- Ken J. Ishii,
- Ken J. Ishii,
- Ken J. Ishii
Affiliations
- Burcu Temizoz
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Burcu Temizoz
- International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Burcu Temizoz
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan
- Takayuki Shibahara
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Kou Hioki
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Tomoya Hayashi
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Tomoya Hayashi
- International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Tomoya Hayashi
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan
- Kouji Kobiyama
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Kouji Kobiyama
- International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Kouji Kobiyama
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan
- Michelle Sue Jann Lee
- International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Michelle Sue Jann Lee
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan
- Michelle Sue Jann Lee
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Naz Surucu
- Department of Biological Sciences, Middle East Technical University (METU), Ankara, Türkiye
- Erdal Sag
- Department of Pediatric Rheumatology, Hacettepe University, Ankara, Türkiye
- Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan
- Atsushi Kumanogoh
- Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
- Masahiro Yamamoto
- Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
- Masahiro Yamamoto
- Department of Immunoparasitology, Division of Infectious Disease, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
- Mayda Gursel
- 0MG Laboratory on Vaccines and Immunotherapeutics, Basic and Translational Research Program, Izmir Biomedicine and Genome Center, Izmir, Türkiye
- Seza Ozen
- Department of Pediatric Rheumatology, Hacettepe University, Ankara, Türkiye
- Etsushi Kuroda
- 1Department of Immunology, School of Medicine, Hyogo Medical University, Hyogo, Japan
- Cevayir Coban
- International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Cevayir Coban
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan
- Cevayir Coban
- Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Cevayir Coban
- Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
- Ken J. Ishii
- Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
- Ken J. Ishii
- International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan
- Ken J. Ishii
- Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan
- Ken J. Ishii
- Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan
- DOI
- https://doi.org/10.3389/fimmu.2024.1353336
- Journal volume & issue
-
Vol. 15
Abstract
5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA cannot fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative—3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xanthen-9-one (HHMX)—that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.
Keywords
