Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side eff...Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8+T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8+T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.展开更多
Aggregation-Induced Emission luminogen(AIEgen)possess great potential in enhancing bioimaging-guided radiotherapeutic effects and radioimmunotherapy to improve the therapeutic effects of the tumor with good biosafety....Aggregation-Induced Emission luminogen(AIEgen)possess great potential in enhancing bioimaging-guided radiotherapeutic effects and radioimmunotherapy to improve the therapeutic effects of the tumor with good biosafety.Bacteria as a natural carrier have demonstrated great advantages in tumor targeted delivery and penetration to tumor.Herein,we construct a delivery platform that Salmonella VNP20009 act as an activated bacteria vector loaded the as-prepared novel AIEgen(TBTP-Au,VNP@TBTP-Au),which showed excellent radioimmunotherapy.VNP@TBTP-Au could target and retain AIEgen at the tumor site and deliver it into tumor cells specially,upon X-ray irradiation,much ROS was generated to induce immunogenic cell death via cGAS-STING signaling pathway to evoke immune response,thus achieving efficient radioimmunotherapy of the primary tumor with good biosafety.More importantly,the radioimmunotherapy with VNP@TBTP-Au formatted good abscopal effect that was able to suppress the growth of distant tumor.Our strategy pioneer a novel and simple strategy for the organic combination of bacteria and imaging-guided radiotherapy,and also pave the foundation for the combination with immunotherapy for better therapeutic effects.展开更多
Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains unsolved.In this report,the active involvement of the host immune response...Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains unsolved.In this report,the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts.Since flagella are key inducers of the host immune response during bacterial infection,flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy.The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects,even when more bacteria were administered to offset the difference in invasion efficiency.Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5(TLR5)signalling pathway.Indeed,we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma.Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy,thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.展开更多
Tumor growth is an angiogenesis-dependent process and accompanied by the formation of hypoxic areas.Tumstatin is a tumor-specific angiogenesis inhibitor that suppresses the proliferation and induces the apoptosis of t...Tumor growth is an angiogenesis-dependent process and accompanied by the formation of hypoxic areas.Tumstatin is a tumor-specific angiogenesis inhibitor that suppresses the proliferation and induces the apoptosis of tumorous vascular endothelial cells.VNP20009,an attenuated Salmonella typhimurium strain,preferentially accumulates in the hypoxic areas of solid tumors.In this study,a novel Salmonella-mediated targeted expression system of tumstatin(VNP-Tum5)was developed under the control of the hypoxia-induced J23100 promoter to obtain anti-tumor efficacy in mice.Treatment with VNP-Tum5 effectively suppressed tumor growth and prolonged survival in the mouse model of B16F10 melanoma.VNP-Tum5 exhibited a higher efficacy in inhibiting the proliferation and inducing the necrosis and apoptosis of B16F10 cells in vitro and in vivo compared with VNP(control).VNP-Tum5 significantly inhibited the proliferation and migration of mouse umbilical vascular endothelial cells to impede angiogenesis.VNP-Tum5 downregulated the expression of anti-vascular endothelial growth factor A,platelet endothelial cell adhesion molecule-1,phosphorylated phosphoinositide 3 kinase,and phosphorylated protein kinase B and upregulated the expression of cleaved-caspase 3 in tumor tissues.This study is the first to use tumstatin-transformed VNP20009 as a tumor-targeted system for treatment of melanoma by combining anti-tumor and anti-angiogenic effects.展开更多
基金supported in part by grants from the National Natural Sciences Foundation of China (82130106)Jiangsu Provincial Department of Science and Technology (BK20192005, China)+1 种基金Changzhou Bureau of Science and Technology (CJ20210024, CZ20210010, China)Jiangsu TargetPharma Laboratories Inc., China
文摘Bacterial antitumor therapy has great application potential given its unique characteristics,including genetic manipulation, tumor targeting specificity and immune system modulation. However,the nonnegligible side effects and limited efficacy of clinical treatment limit their biomedical applications. Engineered bacteria for therapeutic applications ideally need to avoid their accumulation in normal organs and possess potent antitumor activity. Here, we show that macrophage-mediated tumor-targeted delivery of Salmonella typhimurium VNP20009 can effectively reduce the toxicity caused by administrating VNP20009 alone in a melanoma mouse model. This benefits from tumor-induced chemotaxis for macrophages combined with their slow release of loaded strains. Inspired by changes in the tumor microenvironment, including a decrease in intratumoral dysfunctional CD8+T cells and an increase in PDL1 on the tumor cell surface, macrophages were loaded with the engineered strain VNP-PD1nb, which can express and secrete anti-PD1 nanoantibodies after they are released from macrophages. This novel triple-combined immunotherapy significantly inhibited melanoma tumors by reactivating the tumor microenvironment by increasing immune cell infiltration, inhibiting tumor cell proliferation, remodeling TAMs to an M1-like phenotype and prominently activating CD8+T cells. These data suggest that novel combination immunotherapy is expected to be a breakthrough relative to single immunotherapy.
基金the National Natural Science Foundation of China(82102904)the Science,Technology&Innovation Commission of Shenzhen Municipality(Nos.JCYJ20190807144605514,JCYJ20210324113405014,JCYJ20210324113810029 and JCYJ20190808154213097)+4 种基金Guangdong Basic and Applied Basic Research Foundation(No.2022A1515110534)Medical Science and Technology Foundation of Guangdong Province(No.A2022122)Scientific research project of Guangdong Bureau of traditional Chinese Medicine(20231002)Science and Technology Program of Guangzhou(No.2023A04J0535)Start-up Funding for the National Natural Project of Guangdong Provincial People’s Hospital in 2022(No.8220070617).
文摘Aggregation-Induced Emission luminogen(AIEgen)possess great potential in enhancing bioimaging-guided radiotherapeutic effects and radioimmunotherapy to improve the therapeutic effects of the tumor with good biosafety.Bacteria as a natural carrier have demonstrated great advantages in tumor targeted delivery and penetration to tumor.Herein,we construct a delivery platform that Salmonella VNP20009 act as an activated bacteria vector loaded the as-prepared novel AIEgen(TBTP-Au,VNP@TBTP-Au),which showed excellent radioimmunotherapy.VNP@TBTP-Au could target and retain AIEgen at the tumor site and deliver it into tumor cells specially,upon X-ray irradiation,much ROS was generated to induce immunogenic cell death via cGAS-STING signaling pathway to evoke immune response,thus achieving efficient radioimmunotherapy of the primary tumor with good biosafety.More importantly,the radioimmunotherapy with VNP@TBTP-Au formatted good abscopal effect that was able to suppress the growth of distant tumor.Our strategy pioneer a novel and simple strategy for the organic combination of bacteria and imaging-guided radiotherapy,and also pave the foundation for the combination with immunotherapy for better therapeutic effects.
基金supported by grants from the Jiangsu Provincial Nature Science Foundation(BK20192005,China)National Natural Science Foundation of China(81630092,81903143,81802338,and 82072646)+1 种基金Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(LR21H160001)Start-up Grant of HZNU(4125C5021820470,China)。
文摘Salmonella:mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models,but the detailed mechanism remains unsolved.In this report,the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts.Since flagella are key inducers of the host immune response during bacterial infection,flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy.The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects,even when more bacteria were administered to offset the difference in invasion efficiency.Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5(TLR5)signalling pathway.Indeed,we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma.Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy,thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.
基金supported in part by grants from the National Natural Sciences Foundation of China(No.82130106)the Jiangsu Provincial Department of Science and Technology(No.BK20192005).
文摘Tumor growth is an angiogenesis-dependent process and accompanied by the formation of hypoxic areas.Tumstatin is a tumor-specific angiogenesis inhibitor that suppresses the proliferation and induces the apoptosis of tumorous vascular endothelial cells.VNP20009,an attenuated Salmonella typhimurium strain,preferentially accumulates in the hypoxic areas of solid tumors.In this study,a novel Salmonella-mediated targeted expression system of tumstatin(VNP-Tum5)was developed under the control of the hypoxia-induced J23100 promoter to obtain anti-tumor efficacy in mice.Treatment with VNP-Tum5 effectively suppressed tumor growth and prolonged survival in the mouse model of B16F10 melanoma.VNP-Tum5 exhibited a higher efficacy in inhibiting the proliferation and inducing the necrosis and apoptosis of B16F10 cells in vitro and in vivo compared with VNP(control).VNP-Tum5 significantly inhibited the proliferation and migration of mouse umbilical vascular endothelial cells to impede angiogenesis.VNP-Tum5 downregulated the expression of anti-vascular endothelial growth factor A,platelet endothelial cell adhesion molecule-1,phosphorylated phosphoinositide 3 kinase,and phosphorylated protein kinase B and upregulated the expression of cleaved-caspase 3 in tumor tissues.This study is the first to use tumstatin-transformed VNP20009 as a tumor-targeted system for treatment of melanoma by combining anti-tumor and anti-angiogenic effects.
