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Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway
The stimulator of interferon genes (STING) protein is an important and promising innate immune target for tumor therapy. However, the instability of the agonists of STING and their tendency to cause systemic immune activation is a hurdle. The STING activator, cyclic di-adenosine monophosphate (CDA),...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
AAAS
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10065788/ https://www.ncbi.nlm.nih.gov/pubmed/37011280 http://dx.doi.org/10.34133/research.0102 |
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author | Jiang, Yu Li, Xiyuan Qian, Fenghui Sun, Bingbing Wang, Xiyuan Zhang, Yan Zhang, Deqiang Geng, Meiyu Xie, Zuoquan Yang, Sheng |
author_facet | Jiang, Yu Li, Xiyuan Qian, Fenghui Sun, Bingbing Wang, Xiyuan Zhang, Yan Zhang, Deqiang Geng, Meiyu Xie, Zuoquan Yang, Sheng |
author_sort | Jiang, Yu |
collection | PubMed |
description | The stimulator of interferon genes (STING) protein is an important and promising innate immune target for tumor therapy. However, the instability of the agonists of STING and their tendency to cause systemic immune activation is a hurdle. The STING activator, cyclic di-adenosine monophosphate (CDA), produced by the modified Escherichia coli Nissle 1917, shows high antitumor activity and effectively reduces the systemic effects of the “off-target” caused by the activation of the STING pathway. In this study, we used synthetic biological approaches to optimize the translation levels of the diadenylate cyclase that catalyzes CDA synthesis in vitro. We developed 2 engineered strains, CIBT4523 and CIBT4712, for producing high levels of CDA while keeping their concentrations within a range that did not compromise the growth. Although CIBT4712 exhibited stronger induction of the STING pathway corresponding to in vitro CDA levels, it had lower antitumor activity than CIBT4523 in an allograft tumor model, which might be related to the stability of the surviving bacteria in the tumor tissue. CIBT4523 exhibited complete tumor regression, prolonged survival of mice, and rejection of rechallenged tumors, thus, offering new possibilities for more effective tumor therapy. We showed that the appropriate production of CDA in engineered bacterial strains is essential for balancing antitumor efficacy and self-toxicity. |
format | Online Article Text |
id | pubmed-10065788 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | AAAS |
record_format | MEDLINE/PubMed |
spelling | pubmed-100657882023-04-01 Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway Jiang, Yu Li, Xiyuan Qian, Fenghui Sun, Bingbing Wang, Xiyuan Zhang, Yan Zhang, Deqiang Geng, Meiyu Xie, Zuoquan Yang, Sheng Research (Wash D C) Research Article The stimulator of interferon genes (STING) protein is an important and promising innate immune target for tumor therapy. However, the instability of the agonists of STING and their tendency to cause systemic immune activation is a hurdle. The STING activator, cyclic di-adenosine monophosphate (CDA), produced by the modified Escherichia coli Nissle 1917, shows high antitumor activity and effectively reduces the systemic effects of the “off-target” caused by the activation of the STING pathway. In this study, we used synthetic biological approaches to optimize the translation levels of the diadenylate cyclase that catalyzes CDA synthesis in vitro. We developed 2 engineered strains, CIBT4523 and CIBT4712, for producing high levels of CDA while keeping their concentrations within a range that did not compromise the growth. Although CIBT4712 exhibited stronger induction of the STING pathway corresponding to in vitro CDA levels, it had lower antitumor activity than CIBT4523 in an allograft tumor model, which might be related to the stability of the surviving bacteria in the tumor tissue. CIBT4523 exhibited complete tumor regression, prolonged survival of mice, and rejection of rechallenged tumors, thus, offering new possibilities for more effective tumor therapy. We showed that the appropriate production of CDA in engineered bacterial strains is essential for balancing antitumor efficacy and self-toxicity. AAAS 2023-03-30 2023 /pmc/articles/PMC10065788/ /pubmed/37011280 http://dx.doi.org/10.34133/research.0102 Text en https://creativecommons.org/licenses/by/4.0/Exclusive Licensee Science and Technology Review Publishing House. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY 4.0) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Jiang, Yu Li, Xiyuan Qian, Fenghui Sun, Bingbing Wang, Xiyuan Zhang, Yan Zhang, Deqiang Geng, Meiyu Xie, Zuoquan Yang, Sheng Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway |
title | Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway |
title_full | Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway |
title_fullStr | Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway |
title_full_unstemmed | Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway |
title_short | Fine-tuning Bacterial Cyclic di-AMP Production for Durable Antitumor Effects Through the Activation of the STING Pathway |
title_sort | fine-tuning bacterial cyclic di-amp production for durable antitumor effects through the activation of the sting pathway |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10065788/ https://www.ncbi.nlm.nih.gov/pubmed/37011280 http://dx.doi.org/10.34133/research.0102 |
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