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 activa...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.展开更多
基金This work was supported in part by the National Natural Science Foundation of China(21825804)the National Science and Technology Major Project“Key New Drug Creation and Manufacturing Program,”China(2018ZX09711002–019)+2 种基金the Shanghai Municipal Science and Technology Major Project,the Lingang Laboratory(LG202103–02–08)the Shanghai Municipal Science and Technology Major Project,the Natural Science Foundation of China for Innovation Research Group(81821005 to M.G.)the Collaborative Innovation Cluster Project of Shanghai Municipal Commission of Health and Family Planning(2020CXJQ02).A。
文摘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.
