In situ immunomodulation of tumors with biosynthetic bacteria promote anti-tumor immunity  

作　　者：Zhongda Lin Fanqiang Meng Yumeng Ma Chi Zhang Zhirang Zhang Zhaoxin Yang Yuan Li Linlin Hou Yuzhong Xu Xin Liang Xudong Zhang 

机构地区：[1]Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases,School of Medicine,Shenzhen Campus of Sun Yat-Sen University,Sun Yat-Sen University,Shenzhen,518107,Guangdong,China [2]Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics,Key Laboratory of Stem Cell and Regenerative Tissue Engineering,School of Basic Medical Sciences,Guangdong Medical University,Dongguan,523808,China [3]Department of Clinical Laboratory,Shenzhen Baoan Hospital,The Second Affiliated Hospital of Shenzhen University,Shenzhen,518101,China

出　　处：《Bioactive Materials》2024年第2期12-27,共16页生物活性材料（英文）

基　　金：supported by grants from Shenzhen Science and Technology Program(Grant No.RCYX20200714114643121);The National Natural Science Foundation of China(31971268,32201084,32371425);Science,Technology&Innovation Commission of Shenzhen Municipality(JCYJ20200109142610136,JCYJ20180507181654186,ZDSYS20220606100803007);Guangdong Basic and Applied Basic Research Foundation(2019A1515010855,2020A1515110166);the Natural Science Foundation of Guangdong Province(No.2020A1515010802,No.2022A1515012289);University of Chinese Academy of Sciences-Shenzhen Hospital Research Funding(HRF-2020004);the Health system scientific research project of Shenzhen Guangming District Science and innovation Bureau(2020R01073,2020R01061);Fundamental Research Funds for the Central Universities(19lgzd453);Special fund for economic development of ShenZhen Guangming District(2021R01128);Doctoral personnel scientific research start-up Fund project of Guangdong Medical University(GDMUB2022037).

摘　　要：Immune checkpoint blockade(ICB)therapy potently revives T cell’s response to cancer.However,patients suffered with tumors that had inadequate infiltrated immune cells only receive limited therapeutic benefits from ICB therapy.Synthetic biology promotes the alternative strategy of harnessing tumor-targeting bacteria to synthesize therapeutics to modulate immunity in situ.Herein,we engineered attenuated Salmonella typhimurium VNP20009 with gene circuits to synthetize granulocyte-macrophage colony-stimulating factor(GM-CSF)and interleukin 7(IL-7)within tumors,which recruited dendritic cells(DCs)and enhanced T cell priming to elicit anti-tumor response.The bacteria-produced GM-CSF stimulated the maturation of bone marrow-derived dendritic cells(BMDCs),while IL-7 promoted the proliferation of spleen isolated T cells and inhibited cytotoxicity T cell apoptosis in vitro.Virtually,engineered VNP20009 prefer to colonize in tumors,and inhibited tumor growth by enhancing DCs and T cell infiltration.Moreover,the tumor-toxic GZMB^(+)CD8^(+)T cell and IFN-γ^(+)CD8^(+)T cell populations conspicuously increased with the treatment of engineered bacteria.The combination of GM-CSF-IL-7-VNP20009 with PD-1 antibody synergistically stunted the tumor progress and metastasis.

关 键 词：SALMONELLA GM-CSF IL-7 Synthetic biology Cancer immunotherapies 

分 类 号：R730.51[医药卫生—肿瘤]