5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation

Burcu Temizoz; Takayuki Shibahara; Kou Hioki; Tomoya Hayashi; Kouji Kobiyama; Michelle Sue Jann Lee; Naz Surucu; Erdal Sag; Atsushi Kumanogoh; Masahiro Yamamoto; Mayda Gursel; Seza Ozen; Etsushi Kuroda; Cevayir Coban; Ken J Ishii

doi:10.3389/fimmu.2024.1353336

5,6-dimethylxanthenone-4-acetic acid (DMXAA), a partial STING agonist, competes for human STING activation

Front Immunol. 2024 Mar 12:15:1353336. doi: 10.3389/fimmu.2024.1353336. eCollection 2024.

Authors

Burcu Temizoz^#^{1

2

3}, Takayuki Shibahara^#⁴, Kou Hioki¹, Tomoya Hayashi^{1

2

3}, Kouji Kobiyama^{1

2

3}, Michelle Sue Jann Lee^{2

3

5}, Naz Surucu⁶, Erdal Sag⁷, Atsushi Kumanogoh^{4

8}, Masahiro Yamamoto^{8

9}, Mayda Gursel¹⁰, Seza Ozen⁷, Etsushi Kuroda¹¹, Cevayir Coban^{2

3

5

8}, Ken J Ishii^{1

2

3

8}

Affiliations

¹ Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
² International Vaccine Design Center (VDesC), The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan.
³ Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo, Japan.
⁴ Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Osaka, Japan.
⁵ Division of Malaria Immunology, Department of Microbiology and Immunology, The Institute of Medical Science (IMSUT), The University of Tokyo, Tokyo, Japan.
⁶ Department of Biological Sciences, Middle East Technical University (METU), Ankara, Türkiye.
⁷ Department of Pediatric Rheumatology, Hacettepe University, Ankara, Türkiye.
⁸ Immunology Frontier Research Center (IFReC), Osaka University, Osaka, Japan.
⁹ Department of Immunoparasitology, Division of Infectious Disease, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
¹⁰ MG Laboratory on Vaccines and Immunotherapeutics, Basic and Translational Research Program, Izmir Biomedicine and Genome Center, Izmir, Türkiye.
¹¹ Department of Immunology, School of Medicine, Hyogo Medical University, Hyogo, Japan.

^# Contributed equally.

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: DMXAA derivative; HHMX; SAVI; STING; partial agonist.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Leukocytes, Mononuclear / metabolism
Lung / metabolism
Lung Neoplasms*
Membrane Proteins* / metabolism
Mice
Xanthones*

Substances

vadimezan
Membrane Proteins
Xanthones

Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. BT was supported by the Grant-in-Aid for Early-Career Scientists (grant no. 19K1683322K15437). This research was partly supported by MUFJ Vaccine Development Grant (CC and ML) of the IMSUT, the University of Tokyo. KI and CC were supported partly by the grant from Japan Agency for Science and Technology (JST) Core Research for Evolutionary Science and Technology (grant number: JPMJCR18H1) and partly by AMED Strategic Center of Biomedical Advanced Vaccine Research and Development for Preparedness and Response (SCARDA) grants (grants no JP223fa627001 (UTOPIA), 223fa727001 and JP223fa727002). EK was supported by the Japan Society for the Promotion of Science (JSPS), Regional Innovation Strategy Support Program, a Grant-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT), (MEXT/JSPS KAKENHI grant no. JP24591145 and JP16H05256); the Takeda Science Foundation; and the Mochida Memorial Foundation for Medical and Pharmaceutical Research. This study was partly supported by a Grant from International Joint Usage/Research Center, the IMSUT (CC and KI).