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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),...

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Autores principales: Jiang, Yu, Li, Xiyuan, Qian, Fenghui, Sun, Bingbing, Wang, Xiyuan, Zhang, Yan, Zhang, Deqiang, Geng, Meiyu, Xie, Zuoquan, Yang, Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: AAAS 2023
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.
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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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