Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella
Abstract Synergistic combinations of immunotherapeutic agents can improve the performance of anti-cancer therapies but may lead to immune-mediated adverse effects. These side-effects can be overcome by using a tumor-specific delivery system. Here, we report a method of targeted immunotherapy using a...
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Nature Portfolio
2024-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-50950-5 |
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| author | Dinh-Huy Nguyen Sung-Hwan You Hien Thi-Thu Ngo Khuynh Van Nguyen Khang Vuong Tran Tan-Huy Chu So-young Kim Sang-Jun Ha Yeongjin Hong Jung-Joon Min |
| author_facet | Dinh-Huy Nguyen Sung-Hwan You Hien Thi-Thu Ngo Khuynh Van Nguyen Khang Vuong Tran Tan-Huy Chu So-young Kim Sang-Jun Ha Yeongjin Hong Jung-Joon Min |
| author_sort | Dinh-Huy Nguyen |
| collection | DOAJ |
| description | Abstract Synergistic combinations of immunotherapeutic agents can improve the performance of anti-cancer therapies but may lead to immune-mediated adverse effects. These side-effects can be overcome by using a tumor-specific delivery system. Here, we report a method of targeted immunotherapy using an attenuated Salmonella typhimurium (SAM-FC) engineered to release dual payloads: cytolysin A (ClyA), a cytolytic anti-cancer agent, and Vibrio vulnificus flagellin B (FlaB), a potent inducer of anti-tumor innate immunity. Localized secretion of ClyA from SAM-FC induces immunogenic cancer cell death and promotes release of tumor-specific antigens and damage-associated molecular patterns, which establish long-term antitumor memory. Localized secretion of FlaB promotes phenotypic and functional remodeling of intratumoral macrophages that markedly inhibits tumor metastasis in mice bearing tumors of mouse and human origin. Both primary and metastatic tumors from bacteria-treated female mice are characterized by massive infiltration of anti-tumorigenic innate immune cells and activated tumor-specific effector/memory T cells; however, the percentage of immunosuppressive cells is low. Here, we show that SAM-FC induces functional reprogramming of the tumor immune microenvironment by activating both the innate and adaptive arms of the immune system and can be used for targeted delivery of multiple immunotherapeutic payloads for the establishment of potent and long-lasting antitumor immunity. |
| format | Article |
| id | doaj-art-b576ac3584e64476b87361f24f3c58bb |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b576ac3584e64476b87361f24f3c58bb2025-02-02T12:30:56ZengNature PortfolioNature Communications2041-17232024-08-0115111710.1038/s41467-024-50950-5Reprogramming the tumor immune microenvironment using engineered dual-drug loaded SalmonellaDinh-Huy Nguyen0Sung-Hwan You1Hien Thi-Thu Ngo2Khuynh Van Nguyen3Khang Vuong Tran4Tan-Huy Chu5So-young Kim6Sang-Jun Ha7Yeongjin Hong8Jung-Joon Min9Institute for Molecular Imaging and Theranostics, Chonnam National University Medical SchoolCNCure Co. LtdInstitute for Molecular Imaging and Theranostics, Chonnam National University Medical SchoolInstitute for Molecular Imaging and Theranostics, Chonnam National University Medical SchoolInstitute for Molecular Imaging and Theranostics, Chonnam National University Medical SchoolResearch Center for Cancer Immunotherapy, Chonnam National University Hwasun HospitalInstitute for Molecular Imaging and Theranostics, Chonnam National University Medical SchoolDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei UniversityInstitute for Molecular Imaging and Theranostics, Chonnam National University Medical SchoolInstitute for Molecular Imaging and Theranostics, Chonnam National University Medical SchoolAbstract Synergistic combinations of immunotherapeutic agents can improve the performance of anti-cancer therapies but may lead to immune-mediated adverse effects. These side-effects can be overcome by using a tumor-specific delivery system. Here, we report a method of targeted immunotherapy using an attenuated Salmonella typhimurium (SAM-FC) engineered to release dual payloads: cytolysin A (ClyA), a cytolytic anti-cancer agent, and Vibrio vulnificus flagellin B (FlaB), a potent inducer of anti-tumor innate immunity. Localized secretion of ClyA from SAM-FC induces immunogenic cancer cell death and promotes release of tumor-specific antigens and damage-associated molecular patterns, which establish long-term antitumor memory. Localized secretion of FlaB promotes phenotypic and functional remodeling of intratumoral macrophages that markedly inhibits tumor metastasis in mice bearing tumors of mouse and human origin. Both primary and metastatic tumors from bacteria-treated female mice are characterized by massive infiltration of anti-tumorigenic innate immune cells and activated tumor-specific effector/memory T cells; however, the percentage of immunosuppressive cells is low. Here, we show that SAM-FC induces functional reprogramming of the tumor immune microenvironment by activating both the innate and adaptive arms of the immune system and can be used for targeted delivery of multiple immunotherapeutic payloads for the establishment of potent and long-lasting antitumor immunity.https://doi.org/10.1038/s41467-024-50950-5 |
| spellingShingle | Dinh-Huy Nguyen Sung-Hwan You Hien Thi-Thu Ngo Khuynh Van Nguyen Khang Vuong Tran Tan-Huy Chu So-young Kim Sang-Jun Ha Yeongjin Hong Jung-Joon Min Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella Nature Communications |
| title | Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella |
| title_full | Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella |
| title_fullStr | Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella |
| title_full_unstemmed | Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella |
| title_short | Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella |
| title_sort | reprogramming the tumor immune microenvironment using engineered dual drug loaded salmonella |
| url | https://doi.org/10.1038/s41467-024-50950-5 |
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