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Lee D, Jeon HJ, Jang D, Lee D, Kim S, Han M, Jung SJ, Lee J, Choi J, Kim DH, Ahn DJ, Kim K, Kim S, Lee HJ, Suh S. Engineering Bacterial Secretion Systems for Enhanced Tumor Imaging and Surgical Guidance. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2025:e2504389. [PMID: 40395153 DOI: 10.1002/adma.202504389] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 04/10/2025] [Indexed: 05/22/2025]
Abstract
Current imaging techniques suffer from a lack of specificity and resolution, leading to inaccurate tumor imaging and limited applicability of targeted contrast agents, as they require cancer-specific development. The need for enhanced contrast through improved tumor-to-background ratio (TBR) and the toxicity from repeated injections due to fading fluorescent signals further complicate the issue. Additionally, challenges in visualizing the entire 3D tumor with surface-stained contrast agents highlight the demand for advanced imaging solutions for more precise surgical guidance. A novel approach is proposed utilizing Streptavidin Associated Salmonella (SAS) as a contrast agent for image-guided surgeries. SAS selectively proliferates in cancerous tissues and secretes streptavidin upon induction, enabling the binding of subsequently injected biotin-conjugated fluorescent dyes. This approach enhances tumor visualization with a TBR of up to 15.3, far surpassing conventional agents (TBR ∼ 2), while enabling prolonged 3-day imaging, deep tumor penetration, and precise invasive margin delineation with a single contrast agent injection. Furthermore, biosafety evaluations confirmed efficient bacterial clearance, absence of systemic toxicity, and stable physiological responses, supporting its potential for safe clinical translation. This innovative method offers substantial improvements over existing fluorescent contrast agents and holds promise for both diagnostic and therapeutic applications in cancer surgery.
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Affiliation(s)
- Dohee Lee
- Bionics Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
- Department of Chemical and Biological Engineering, Korea University, Seoul, 02841, Republic of Korea
| | - Heung Jin Jeon
- Cancer Research Institute, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Dohyub Jang
- Chemical and Biological integrative Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
- Department of Biomicrosystem Technology, Korea University, Seoul, 02841, Republic of Korea
| | - Deukhee Lee
- Bionics Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Solbi Kim
- Cancer Research Institute, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Minju Han
- Department of Medical Science and Cancer Research Institute, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - Sharon Jiyoon Jung
- Technological Convergence Support Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Junghyun Lee
- Department of Chemical and Biological Engineering, Korea University, Seoul, 02841, Republic of Korea
| | - Jia Choi
- KU-KIST Graduate School of Conversing Science and Technology, Korea University, Seoul, 02841, Republic of Korea
| | - Dong Ha Kim
- Department of Chemistry and Nano Science, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Dong June Ahn
- Department of Chemical and Biological Engineering, Korea University, Seoul, 02841, Republic of Korea
- Department of Biomicrosystem Technology, Korea University, Seoul, 02841, Republic of Korea
| | - Keri Kim
- Bionics Research Center, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea
| | - Sehoon Kim
- KU-KIST Graduate School of Conversing Science and Technology, Korea University, Seoul, 02841, Republic of Korea
| | - Hyo-Jin Lee
- Cancer Research Institute, Chungnam National University, Daejeon, 35015, Republic of Korea
| | - SeungBeum Suh
- Division of Bio-Medical Science & Technology, University of Science & Technology, Seoul, 02792, Republic of Korea
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Yin J, Sun W, Xiong H, Yao W, Liu X, Jiang H, Wang X. Photoactivated in-situ engineered-bacteria as an efficient H 2S generator to enhance photodynamic immunotherapy via remodeling the tumor microenvironment. Biomaterials 2025; 322:123388. [PMID: 40344882 DOI: 10.1016/j.biomaterials.2025.123388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2025] [Revised: 04/28/2025] [Accepted: 05/02/2025] [Indexed: 05/11/2025]
Abstract
Based on the unique biological advantages of bacteria and their derivatives, biosynthetic nanomaterials have been widely used in the field of tumor therapy. Although conventional bacterial treatments demonstrate potential in activating tumor immunity, their efficacy in inhibiting tumor growth remains constrained. In this study, a photoactivated hydrogen sulfide (H2S) generator was successfully prepared by in-situ engineering of bacteria, after Pt/MoS2 nanocomposites were in-situ generated by Escherichia coli (E. coli) and loaded with photosensitizer Ce6. This engineered-bacteria has been proved to have good tumor targeting ability and can enhance the effect of photodynamic therapy in the hypoxic tumor microenvironment. While reactive oxygen species (ROS) is effectively released, the fragmentation of bacteria can accelerate the release of abundant H2S, and promote tumor-specific H2S gas therapy, which can effectively remodel the tumor microenvironment and promote the activation of anti-tumor immunotherapy. This engineered bacteria not only improves the tumor specificity and effectiveness of H2S treatment, but also provides a new idea for nanomaterials in bacterial-mediated synergistic cancer treatment.
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Affiliation(s)
- Jiajia Yin
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Wenyu Sun
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Hongjie Xiong
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Wenyan Yao
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China
| | - Xiaohui Liu
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China.
| | - Hui Jiang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China.
| | - Xuemei Wang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science and Medical Engineering, Southeast University, Nanjing, 210096, China.
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Kang MK, Bevington J, Tullman-Ercek D. Evaluation of the Salmonella type 3 secretion system (T3SS) as part of a protein production platform for space biology applications. Front Bioeng Biotechnol 2025; 13:1567596. [PMID: 40242353 PMCID: PMC12000002 DOI: 10.3389/fbioe.2025.1567596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Accepted: 03/18/2025] [Indexed: 04/18/2025] Open
Abstract
As interest in space exploration and in situ resource utilization grows, the potential to leverage synthetic biology and engineered microorganisms has garnered significant attention. Microorganisms provide a robust and efficient biological chassis to demonstrate the human blueprint for advancing space biology. However, progress toward these applications is hindered by the limited access to space-like environments and a lack of knowledge about how unique environmental factors affect relevant microbial systems. To address these issues, we evaluated the Salmonella Pathogenicity Island 1 (SPI-1) type Ⅲ secretion system (T3SS) as a protein production platform for space applications. Using a NASA-designed microgravity-simulating bioreactor system, we investigated the effects of simulated microgravity on cell growth, stress response, and protein secretion via SPI-1 T3SS. Our results demonstrated increased stress responses in cells grown under simulated microgravity. However, the SPI-1 T3SS maintained its ability to secrete proteins directly into the extracellular space in a single step under simulated microgravity, simplifying downstream purification processes. These findings suggest that the SPI-1 T3SS is a viable candidate for future space biology applications.
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Affiliation(s)
- Min-Kyoung Kang
- Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, United States
- Anti-aging Bio Cell factory Regional Leading Research Center (ABC-RLRC), Gyeongsang National University, Jinju, Republic of Korea
| | - James Bevington
- Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, United States
- Interplanetary Exploration Institute Ltd., Sydney, Australia
| | - Danielle Tullman-Ercek
- Department of Chemical and Biological Engineering, Northwestern University, Evanston, IL, United States
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Senevirathne A, Lloren KKS, Aganja RP, Kwon J, Lee JH. Transforming bacterial pathogens into wonder tools in cancer immunotherapy. Mol Ther 2025; 33:866-882. [PMID: 39825565 PMCID: PMC11897747 DOI: 10.1016/j.ymthe.2025.01.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/02/2024] [Accepted: 01/14/2025] [Indexed: 01/20/2025] Open
Abstract
Cancer immunotherapy has revolutionized cancer treatment due to its precise, target-specific approach compared with conventional therapies. However, treating solid tumors remains challenging as these tumors are inherently immunosuppressive, and their tumor microenvironment (TME) often limits therapeutic efficacy. Interestingly, certain bacterial species offer a promising alternative by exhibiting an innate ability to target and proliferate within tumor environments. Bacterial structural and functional components can activate innate and adaptive immune responses, creating tumor-suppressive conditions that reduce tumor mass. Additionally, bacteria can deliver effector molecules directly into tumor cells, inducing apoptotic and necrotic cell death. Despite their potential, the use of bacteria in cancer immunotherapy poses risks due to possible toxicities and unpredictable in vivo behavior. Advances in genetic engineering have addressed these concerns by enabling the development of attenuated bacterial strains with enhanced anticancer properties for safer medical applications. This review highlights the role of bacteria in TME modulation, recent strategies to bioengineer bacterial pathogens as therapeutic tools, and the synergistic effects of combining bacteria with other immunotherapies. It also discusses the challenges and prospects of translating this innovative approach into clinical practice, offering a comprehensive overview of bacteria-based cancer immunotherapy's potential to reshape the future of cancer treatment.
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Affiliation(s)
- Amal Senevirathne
- College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan City, Jeollabuk-do 54596, Republic of Korea
| | - Khristine Kaith S Lloren
- College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan City, Jeollabuk-do 54596, Republic of Korea
| | - Ram Prasad Aganja
- College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan City, Jeollabuk-do 54596, Republic of Korea
| | - Jun Kwon
- College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan City, Jeollabuk-do 54596, Republic of Korea
| | - John Hwa Lee
- College of Veterinary Medicine, Jeonbuk National University, 79 Gobong-ro, Iksan City, Jeollabuk-do 54596, Republic of Korea.
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Zhang X, Zang Z, Liang Z, Xu X, Zheng J, Liang N, Shabiti S, Wang Z, Yu S, Wang Y, Liu C, Li W, Cai L. Nanobiohybrid Oncolytic Bacteria with Optimized Intratumoral Distribution for Combined Sono-Photodynamic/Immunotherapy. ACS NANO 2025; 19:6437-6453. [PMID: 39902865 DOI: 10.1021/acsnano.4c16740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2025]
Abstract
"Living therapeutic carriers" present a promising avenue for cancer research, but it is still challenging to achieve uniform and durable distribution of payloads throughout the solid tumor owing to the tumor microenvironment heterogeneity. Herein, a living drug sprinkle biohybrid (YB1-HCNs) was constructed by hitching acid/enzyme-triggered detachable nanoparticles (HCNs) backpack on the surface of metabolic oligosaccharide-engineered oncolytic bacteria YB1. Along with the process of tumor penetration by bacterial hypoxia navigation, YB1-HCNs responsively and continuously release HCNs, achieving a uniform distribution of loaded agents throughout the tumor. Upon successive irradiation of laser and ultrasound (US), the HCNs can separately generate type II and type I ROS for superior sono-photodynamic therapy (SPDT), which enables HCNs to synergize with YB1 for a satisfactory therapeutic effect in both superficial normoxic and deep hypoxic regions of the tumor. After a single dose, this efficient combination realized 98.3% primary tumor inhibition rate and prolonged survival of mice for 90 days with no recurrence, further inducing a powerful immunological memory effect to completely suppress tumor rechallenge in cured mice. Such a bacterial hybridization vector enables optimization of the spatial distribution of YB1 and HCNs, providing an innovative strategy to maximize therapeutic outcomes and evoke durable antitumor immunity.
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Affiliation(s)
- Xu Zhang
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Zhongsheng Zang
- Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Zhenguo Liang
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
| | - Xiaoyu Xu
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
| | - Jinling Zheng
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Na Liang
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
| | - Shayibai Shabiti
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Zixi Wang
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Shiwen Yu
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
| | - Yujue Wang
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
| | - Chenli Liu
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
- Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Wenjun Li
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
| | - Lintao Cai
- Guangdong Key Laboratory of Nanomedicine, CAS-HK Joint Lab of Biomaterials, CAS Key Laboratory of Biomedical Imaging Science and System, Institute of Biomedicine and Biotechnology, Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences, Shenzhen 518055, P. R. China
- University of Chinese Academy of Sciences, Beijing 100049, P. R. China
- Sino-Euro Center of Biomedicine and Health, Luohu, Shenzhen, 518024, P. R. China
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6
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Heggie A, Thurston TLM, Ellis T. Microbial messengers: nucleic acid delivery by bacteria. Trends Biotechnol 2025; 43:145-161. [PMID: 39117490 DOI: 10.1016/j.tibtech.2024.07.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/15/2024] [Accepted: 07/16/2024] [Indexed: 08/10/2024]
Abstract
The demand for diverse nucleic acid delivery vectors, driven by recent biotechnological breakthroughs, offers opportunities for continuous improvements in efficiency, safety, and delivery capacity. With their enhanced safety and substantial cargo capacity, bacterial vectors offer significant potential across a variety of applications. In this review, we explore methods to engineer bacteria for nucleic acid delivery, including strategies such as engineering attenuated strains, lysis circuits, and conjugation machinery. Moreover, we explore pioneering techniques, such as manipulating nanoparticle (NP) coatings and outer membrane vesicles (OMVs), representing the next frontier in bacterial vector engineering. We foresee these advancements in bacteria-mediated nucleic acid delivery, through combining bacterial pathogenesis with engineering biology techniques, as a pivotal step forward in the evolution of nucleic acid delivery technologies.
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Affiliation(s)
- Alison Heggie
- Centre for Bacterial Resistance Biology, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK; Imperial College Centre for Synthetic Biology, South Kensington Campus, London, SW7 2AZ, UK; Department of Bioengineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
| | - Teresa L M Thurston
- Centre for Bacterial Resistance Biology, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK
| | - Tom Ellis
- Imperial College Centre for Synthetic Biology, South Kensington Campus, London, SW7 2AZ, UK; Department of Bioengineering, Imperial College London, South Kensington Campus, London, SW7 2AZ, UK.
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7
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He X, Guo J, Bai Y, Sun H, Yang J. Salmonella-based therapeutic strategies: improving tumor microenvironment and bringing new hope for cancer immunotherapy. Med Oncol 2024; 42:27. [PMID: 39666238 DOI: 10.1007/s12032-024-02578-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 11/29/2024] [Indexed: 12/13/2024]
Abstract
Immunotherapy has revolutionized cancer treatment, yet its effectiveness is limited by immunosuppressive tumor microenvironment (TME). To overcome this challenge, innovative strategies to effectively modulate the TME are urgently needed. Over the past decades, bacteria-mediated cancer immunotherapy has recaptured increasing attention, driven by advances in synthetic biology, genetic engineering and our knowledge of host-pathogen interactions. Among various bacterial species, Salmonella has emerged as a leading candidate with significant therapeutic potential due to its broad-spectrum anti-tumor activity, tumor-targeting ability, immunomodulatory effects, oncolytic properties, genetic programmability, and engineering flexibility. These characteristics enable Salmonella to reshape the immunosuppressive TME, thereby enhancing anti-tumor efficacy. This review elaborates the regulatory effects of Salmonella on key components of the TME, the versatile engineering strategies for optimizing Salmonella's ability to modulate the TME, and recent advancements in combination cancer therapies. We also summarize current clinical applications and discuss challenges of developing safer and more effective Salmonella-based cancer immunotherapy.
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Affiliation(s)
- Xiaoe He
- Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Cuiying Gate 82, Lanzhou, 730030, Gansu, China
| | - Jiayin Guo
- Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Cuiying Gate 82, Lanzhou, 730030, Gansu, China
| | - Yanrui Bai
- Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Cuiying Gate 82, Lanzhou, 730030, Gansu, China
| | - Hui Sun
- Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Cuiying Gate 82, Lanzhou, 730030, Gansu, China
| | - Jing Yang
- Cuiying Biomedical Research Center, The Second Hospital & Clinical Medical School, Lanzhou University, Cuiying Gate 82, Lanzhou, 730030, Gansu, China.
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8
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Harmak Z, Kone AS, Ghouzlani A, Ghazi B, Badou A. Beyond Tumor Borders: Intratumoral Microbiome Effects on Tumor Behavior and Therapeutic Responses. Immune Netw 2024; 24:e40. [PMID: 39801738 PMCID: PMC11711125 DOI: 10.4110/in.2024.24.e40] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 11/11/2024] [Accepted: 11/12/2024] [Indexed: 01/16/2025] Open
Abstract
The human body contains a diverse array of microorganisms, which exert a significant impact on various physiological processes, including immunity, and can significantly influence susceptibility to various diseases such as cancer. Recent advancements in metagenomic sequencing have uncovered the role of intratumoral microbiome, which covertly altered the development of cancer, the growth of tumors, and the response to existing treatments through multiple mechanisms. These mechanisms involve mainly DNA damage induction, oncogenic signaling pathway activation, and the host's immune response modulation. To explore novel therapeutic options and effectively target and regulate the intratumoral microbiome, a comprehensive understanding of these processes is indispensable. Here, we will explore various potential actions of the intratumoral microbiome concerning the initiation and progression of tumors. We will examine its impact on responses to chemotherapy, radiotherapy, and immunotherapy. Additionally, we will discuss the current state of knowledge regarding the use of genetically modified bacteria as a promising treatment option for cancer.
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Affiliation(s)
- Zakia Harmak
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, University Hassan II, Casablanca 20000, Morocco
| | - Abdou-Samad Kone
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, University Hassan II, Casablanca 20000, Morocco
| | - Amina Ghouzlani
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, University Hassan II, Casablanca 20000, Morocco
| | - Bouchra Ghazi
- Immunopathology-Immunomonitoring-Immunotherapy Laboratory, Faculty of Medicine, Mohammed IV University of Sciences and Health, Casablanca 82403, Morocco
- IVF Laboratory, Department of Reproductive Medicine, Mohammed VI International University Hospital, Bouskoura 27182, Morocco
| | - Abdallah Badou
- Immuno-Genetics and Human Pathology Laboratory, Faculty of Medicine and Pharmacy, University Hassan II, Casablanca 20000, Morocco
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Yang S, Sheffer M, Kaplan IE, Wang Z, Tarannum M, Dinh K, Abdulhamid Y, Bobilev E, Shapiro R, Porter R, Soiffer R, Ritz J, Koreth J, Wei Y, Chen P, Zhang K, Márquez-Pellegrin V, Bonanno S, Joshi N, Guan M, Yang M, Li D, Bellini C, Liu F, Chen J, Wu CJ, Barbie D, Li J, Romee R. Non-pathogenic E. coli displaying decoy-resistant IL18 mutein boosts anti-tumor and CAR NK cell responses. Nat Biotechnol 2024:10.1038/s41587-024-02418-6. [PMID: 39367093 DOI: 10.1038/s41587-024-02418-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 08/29/2024] [Indexed: 10/06/2024]
Abstract
The tumor microenvironment can inhibit the efficacy of cancer therapies through mechanisms such as poor trafficking and exhaustion of immune cells. Here, to address this challenge, we exploited the safety, tumor tropism and ease of genetic manipulation of non-pathogenic Escherichia coli (E. coli) to deliver key immune-activating cytokines to tumors via surface display on the outer membrane of E. coli K-12 DH5α. Non-pathogenic E. coli expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8+ T and natural killer (NK) cell-dependent immune responses and suppressed tumor progression in immune-competent colorectal carcinoma and melanoma mouse models. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting chimeric antigen receptor (CAR) NK cells and enhance their trafficking into tumors, which extended survival in an NK cell treatment-resistant mesothelioma xenograft model by enhancing TNF signaling and upregulating NK activation markers. Our live bacteria-based immunotherapeutic system safely and effectively induces potent anti-tumor responses in treatment-resistant solid tumors, motivating further evaluation of this approach in the clinic.
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Affiliation(s)
- Shaobo Yang
- Department of Bioengineering, Northeastern University, Boston, MA, USA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Michal Sheffer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Isabel E Kaplan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Zongqi Wang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
| | - Mubin Tarannum
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Khanhlinh Dinh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Yasmin Abdulhamid
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Eden Bobilev
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Roman Shapiro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Rebecca Porter
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Robert Soiffer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jerome Ritz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - John Koreth
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Yun Wei
- Department of Chemistry and Chemical Engineering, Northeastern University, Boston, MA, USA
| | - Peiru Chen
- Department of Chemistry and Chemical Engineering, Northeastern University, Boston, MA, USA
| | - Ke Zhang
- Department of Bioengineering, Northeastern University, Boston, MA, USA
- Department of Chemistry and Chemical Engineering, Northeastern University, Boston, MA, USA
| | | | - Shanna Bonanno
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Neel Joshi
- Department of Chemistry and Chemical Engineering, Northeastern University, Boston, MA, USA
| | - Ming Guan
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Mengdi Yang
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Deng Li
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Chiara Bellini
- Department of Bioengineering, Northeastern University, Boston, MA, USA
| | - Fuguo Liu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jianzhu Chen
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - David Barbie
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jiahe Li
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.
| | - Rizwan Romee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
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10
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Xie D, Huang L, Li C, Wu R, Zheng Z, Liu F, Cheng H. Identification of PANoptosis-related genes as prognostic indicators of thyroid cancer. Heliyon 2024; 10:e31707. [PMID: 38845990 PMCID: PMC11153176 DOI: 10.1016/j.heliyon.2024.e31707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 04/24/2024] [Accepted: 05/21/2024] [Indexed: 06/09/2024] Open
Abstract
Background Thyroid cancer (THCA) has become a common malignancy in recent years, with the mortality rate steadily increasing. PANoptosis is a unique kind of programmed cell death (PCD), including pyroptosis, necroptosis, and apoptosis, and is involved in the proliferation and prognosis of numerous cancers. This paper demonstrated the connection between PANoptosis-related genes and THCA based on the analyses of Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, which have not been evaluated yet. Methods We identified PANoptosis-related differentially expressed genes (PRDEGs) by multi-analyzing the TCGA-THCA and GEO datasets. To identify the significant PRDEGs, a prognostic model was constructed using least absolute shrinkage and selection operator regression (LASSO). The predictive values of the significant PRDEGs for THCA outcomes were determined using Cox regression analysis and nomograms. Gene enrichment analyses were performed. Finally, immunohistochemistry was carried out using the human protein atlas. Results A LASSO regression model based on nine PRDEGs was constructed, and the prognostic value of key PRDEGs was explored via risk score. Univariate and multivariate Cox regression were implemented to identify further three significant PRDEGs closely related to distant metastasis, lymph node metastasis, and tumor stage. Then, a nomogram was constructed, which presented high predictive accuracy for 5 years survival of THCA patients. Gene enrichment analyses in THCA were strongly associated with PCD pathways. CASP6 presented significantly differential expression during clinical T stage, N stage, and PFI events (P < 0.05 for all) and demonstrated the highest degree of diagnostic efficacy in PRDEGs (HR: 2.060, 95 % CI: 1.170-3.628, P < 0.05). Immunohistochemistry showed CASP6 was more abundant in THCA tumor tissue. Conclusion A potential prognostic role for PRDEGs in THCA was identified, providing a new direction for treatment. CASP6 may be a potential therapeutic target and a novel prognostic biomarker for THCA.
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Affiliation(s)
- Diya Xie
- Department of General Surgery, First General Hospital of Fuzhou Affiliated of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Liyong Huang
- Department of General Surgery, First General Hospital of Fuzhou Affiliated of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Cheng Li
- Department of General Surgery, First General Hospital of Fuzhou Affiliated of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Ruozhen Wu
- Department of Gastrointestinal Surgery, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Zhigang Zheng
- Department of General Surgery, First General Hospital of Fuzhou Affiliated of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Fengmin Liu
- Department of Endocrinology, First General Hospital of Fuzhou Affiliated of Fujian Medical University, Fuzhou, Fujian Province, China
| | - Huayong Cheng
- Department of General Surgery, First General Hospital of Fuzhou Affiliated of Fujian Medical University, Fuzhou, Fujian Province, China
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11
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Profir M, Roşu OA, Creţoiu SM, Gaspar BS. Friend or Foe: Exploring the Relationship between the Gut Microbiota and the Pathogenesis and Treatment of Digestive Cancers. Microorganisms 2024; 12:955. [PMID: 38792785 PMCID: PMC11124004 DOI: 10.3390/microorganisms12050955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/25/2024] [Accepted: 05/06/2024] [Indexed: 05/26/2024] Open
Abstract
Digestive cancers are among the leading causes of cancer death in the world. However, the mechanisms of cancer development and progression are not fully understood. Accumulating evidence in recent years pointing to the bidirectional interactions between gut dysbiosis and the development of a specific type of gastrointestinal cancer is shedding light on the importance of this "unseen organ"-the microbiota. This review focuses on the local role of the gut microbiota imbalance in different digestive tract organs and annexes related to the carcinogenic mechanisms. Microbiota modulation, either by probiotic administration or by dietary changes, plays an important role in the future therapies of various digestive cancers.
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Affiliation(s)
- Monica Profir
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania; (M.P.); (O.A.R.)
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Oana Alexandra Roşu
- Department of Oncology, Elias University Emergency Hospital, 011461 Bucharest, Romania; (M.P.); (O.A.R.)
| | - Sanda Maria Creţoiu
- Department of Morphological Sciences, Cell and Molecular Biology and Histology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Bogdan Severus Gaspar
- Surgery Clinic, Emergency Clinical Hospital of Bucharest, 014461 Bucharest, Romania;
- Department of Surgery, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
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12
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Zhou Y, Li Q, Wu Y, Zhang W, Ding L, Ji C, Li P, Chen T, Feng L, Tang BZ, Huang X. Synergistic Brilliance: Engineered Bacteria and Nanomedicine Unite in Cancer Therapy. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2024; 36:e2313953. [PMID: 38400833 DOI: 10.1002/adma.202313953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Revised: 02/21/2024] [Indexed: 02/26/2024]
Abstract
Engineered bacteria are widely used in cancer treatment because live facultative/obligate anaerobes can selectively proliferate at tumor sites and reach hypoxic regions, thereby causing nutritional competition, enhancing immune responses, and producing anticancer microbial agents in situ to suppress tumor growth. Despite the unique advantages of bacteria-based cancer biotherapy, the insufficient treatment efficiency limits its application in the complete ablation of malignant tumors. The combination of nanomedicine and engineered bacteria has attracted increasing attention owing to their striking synergistic effects in cancer treatment. Engineered bacteria that function as natural vehicles can effectively deliver nanomedicines to tumor sites. Moreover, bacteria provide an opportunity to enhance nanomedicines by modulating the TME and producing substrates to support nanomedicine-mediated anticancer reactions. Nanomedicine exhibits excellent optical, magnetic, acoustic, and catalytic properties, and plays an important role in promoting bacteria-mediated biotherapies. The synergistic anticancer effects of engineered bacteria and nanomedicines in cancer therapy are comprehensively summarized in this review. Attention is paid not only to the fabrication of nanobiohybrid composites, but also to the interpromotion mechanism between engineered bacteria and nanomedicine in cancer therapy. Additionally, recent advances in engineered bacteria-synergized multimodal cancer therapies are highlighted.
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Affiliation(s)
- Yaofeng Zhou
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Nanchang University, Nanchang, 330047, P. R. China
| | - Qianying Li
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Nanchang University, Nanchang, 330047, P. R. China
| | - Yuhao Wu
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Nanchang University, Nanchang, 330047, P. R. China
| | - Wan Zhang
- Department of Thoracic Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, P. R. China
| | - Lu Ding
- Department of Cardiology, Jiangxi Hypertension Research Institute, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, P. R. China
| | - Chenlin Ji
- School of Engineering, Westlake University, Hangzhou, 310030, P. R. China
| | - Ping Li
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Nanchang University, Nanchang, 330047, P. R. China
| | - Tingtao Chen
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, 330036, P. R. China
| | - Lili Feng
- Key Laboratory of Superlight Materials and Surface Technology Ministry of Education, College of Material Sciences and Chemical Engineering, Harbin Engineering University, Harbin, 150001, P. R. China
| | - Ben Zhong Tang
- School of Science and Engineering, The Chinese University of Hong Kong, Shenzhen (CUHK-Shenzhen), Guangdong, 518172, P. R. China
| | - Xiaolin Huang
- State Key Laboratory of Food Science and Resources, School of Food Science and Technology, Nanchang University, Nanchang, 330047, P. R. China
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13
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Chen YY, Xu XZ, Xu XJ. Low interleukin-10 level indicates a good prognosis in Salmonella enterica serovar typhimurium-induced pediatric hemophagocytic lymphohistiocytosis: A case report. World J Clin Cases 2024; 12:1660-1668. [PMID: 38576747 PMCID: PMC10989434 DOI: 10.12998/wjcc.v12.i9.1660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/10/2024] [Accepted: 03/05/2024] [Indexed: 03/25/2024] Open
Abstract
BACKGROUND Secondary hemophagocytic lymphohistiocytosis (sHLH) triggered by Salmonella enterica serovar Typhimurium is rare in pediatric patients. There is no consensus on how to treat S. typhimurium-triggered sHLH. CASE SUMMARY A 9-year-old boy with intermittent fever for 3 d presented to our hospital with positive results for S. typhimurium, human rhinovirus, and Mycoplasma pneumoniae infections. At the time of admission to our institution, the patient's T helper 1/T helper 2 cytokine levels were 326 pg/mL for interleukin 6 (IL-6), 9.1 pg/mL for IL-10, and 246.7 pg/mL for interferon-gamma (IFN-γ), for which the ratio of IL-10 to IFN-γ was 0.04. In this study, the patient received meropenem, linezolid, and cefoperazone/sulbactam in combination with high-dose methylprednisolone therapy (10 mg/kg/d for 3 d) and antishock supportive treatment twice. After careful evaluation, this patient did not receive HLH chemotherapy and recovered well. CONCLUSION S. Typhimurium infection-triggered sHLH patient had a ratio of IL-10 to IFN-γ ≤ 1.33, an IL-10 concentration ≤ 10.0 pg/mL, and/or an IFN-γ concentration ≤ 225 pg/mL at admission. Early antimicrobial and supportive treatment was sufficient, and the HLH-94/2004 protocol was not necessary under these conditions.
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Affiliation(s)
- Yuan-Yuan Chen
- Division/Center of Pediatric Hematology Oncology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xiang-Zhi Xu
- Pediatric Intensive Care Unit, Children’s Hospital of Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
| | - Xiao-Jun Xu
- Division/Center of Pediatric Hematology Oncology, Children’s Hospital, Zhejiang University School of Medicine, Hangzhou 310003, Zhejiang Province, China
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Yang S, Sheffer M, Kaplan IE, Wang Z, Tarannum M, Dinh K, Abdulhamid Y, Shapiro R, Porter R, Soiffer R, Ritz J, Koreth J, Wei Y, Chen P, Zhang K, Márquez-Pellegrin V, Bonanno S, Joshi N, Guan M, Yang M, Li D, Bellini C, Chen J, Wu CJ, Barbie D, Li J, Romee R. Nonpathogenic E. coli engineered to surface display cytokines as a new platform for immunotherapy. RESEARCH SQUARE 2024:rs.3.rs-4031911. [PMID: 38562821 PMCID: PMC10984091 DOI: 10.21203/rs.3.rs-4031911/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/04/2024]
Abstract
Given the safety, tumor tropism, and ease of genetic manipulation in non-pathogenic Escherichia coli (E. coli), we designed a novel approach to deliver biologics to overcome poor trafficking and exhaustion of immune cells in the tumor microenvironment, via the surface display of key immune-activating cytokines on the outer membrane of E. coli K-12 DH5α. Bacteria expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8+ T and NK cell-dependent immune responses leading to dramatic tumor control, extending survival, and curing a significant proportion of immune-competent mice with colorectal carcinoma and melanoma. The engineered bacteria demonstrated tumor tropism, while the abscopal and recall responses suggested epitope spreading and induction of immunologic memory. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting CAR NK cells and safely enhanced their trafficking into the tumors, leading to improved control and survival in xenograft mice bearing mesothelioma tumor cells, otherwise resistant to NK cells. Gene expression analysis of the bacteria-primed CAR NK cells showed enhanced TNFα signaling via NFkB and upregulation of multiple activation markers. Our novel live bacteria-based immunotherapeutic platform safely and effectively induces potent anti-tumor responses in otherwise hard-to-treat solid tumors, motivating further evaluation of this approach in the clinic.
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Affiliation(s)
- Shaobo Yang
- Department of Bioengineering, Northeastern University, Boston, MA
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Michal Sheffer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Isabel E Kaplan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Zongqi Wang
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI
| | - Mubin Tarannum
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Khanhlinh Dinh
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Yasmin Abdulhamid
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Roman Shapiro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Rebecca Porter
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Robert Soiffer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Jerome Ritz
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - John Koreth
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Yun Wei
- Department of Chemistry and Chemical Engineering, Northeastern University, Boston, MA
| | - Peiru Chen
- Department of Chemistry and Chemical Engineering, Northeastern University, Boston, MA
| | - Ke Zhang
- Department of Bioengineering, Northeastern University, Boston, MA
- Department of Chemistry and Chemical Engineering, Northeastern University, Boston, MA
| | | | - Shanna Bonanno
- Department of Bioengineering, Northeastern University, Boston, MA
| | - Neel Joshi
- Department of Chemistry and Chemical Engineering, Northeastern University, Boston, MA
| | - Ming Guan
- Department of Bioengineering, Northeastern University, Boston, MA
| | - Mengdi Yang
- Department of Bioengineering, Northeastern University, Boston, MA
| | - Deng Li
- Department of Bioengineering, Northeastern University, Boston, MA
| | - Chiara Bellini
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Jianzhu Chen
- Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA
| | - Catherine J. Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - David Barbie
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Jiahe Li
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI
| | - Rizwan Romee
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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15
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Wang Q, Tang Y, Dai A, Li T, Pei Y, Zhang Z, Hu X, Chen T, Chen Q. VNP20009-Abvec-Igκ-MIIP suppresses ovarian cancer progression by modulating Ras/MEK/ERK signaling pathway. Appl Microbiol Biotechnol 2024; 108:218. [PMID: 38372808 PMCID: PMC10876780 DOI: 10.1007/s00253-024-13047-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Revised: 01/15/2024] [Accepted: 01/30/2024] [Indexed: 02/20/2024]
Abstract
Ovarian cancer poses a significant threat to women's health, with conventional treatment methods encountering numerous limitations, and the emerging engineered bacterial anti-tumor strategies offer newfound hope for ovarian cancer treatment. In this study, we constructed the VNP20009-Abvec-Igκ-MIIP (VM) engineered strain and conducted initial assessments of its in vitro growth performance and the expression capability of migration/invasion inhibitory protein (MIIP). Subsequently, ID8 ovarian cancer cells and mouse cancer models were conducted to investigate the impact of VM on ovarian cancer. Our results revealed that the VM strain demonstrated superior growth performance, successfully invaded ID8 ovarian cancer cells, and expressed MIIP, consequently suppressing cell proliferation and migration. Moreover, VM specifically targeted tumor sites and expressed MIIP which further reduced the tumor volume of ovarian cancer mice (p < 0.01), via the downregulation of epidermal growth factor receptor (EGFR), Ras, p-MEK, and p-ERK. The downregulation of the PI3K/AKT signaling pathway and the decrease in Bcl-2/Bax levels also indicated VM's apoptotic potency on ovarian cancer cells. In summary, our research demonstrated that VM exhibits promising anti-tumor effects both in vitro and in vivo, underscoring its potential for clinical treatment of ovarian cancer. KEY POINTS: • This study has constructed an engineered strain of Salmonella typhimurium capable of expressing anticancer proteins • The engineered bacteria can target and colonize tumor sites in vivo • VM can inhibit the proliferation, migration, and invasion of ovarian cancer cells.
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Affiliation(s)
- Qian Wang
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Donghu District, Nanchang City, 330000, Jiangxi Province, China
| | - Yuwen Tang
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Donghu District, Nanchang City, 330000, Jiangxi Province, China
| | - Ang Dai
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Donghu District, Nanchang City, 330000, Jiangxi Province, China
| | - Tiange Li
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Donghu District, Nanchang City, 330000, Jiangxi Province, China
| | - Yulin Pei
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Donghu District, Nanchang City, 330000, Jiangxi Province, China
| | - Zuo Zhang
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Donghu District, Nanchang City, 330000, Jiangxi Province, China
| | - Xinyue Hu
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Donghu District, Nanchang City, 330000, Jiangxi Province, China
| | - Tingtao Chen
- National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Jiangxi Medical College, Nanchang University, No. 1299, Xuefu Avenue, Honggutan District, Nanchang City, Jiangxi Province, China.
| | - Qi Chen
- Department of Obstetrics and Gynecology, The 2nd Affiliated Hospital, Jiangxi Medical College, Nanchang University, 1 Minde Road, Donghu District, Nanchang City, 330000, Jiangxi Province, China.
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16
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Horiuchi Y, Nakamura A, Imai T, Murakami T. Infection of tumor cells with Salmonella typhimurium mimics immunogenic cell death and elicits tumor-specific immune responses. PNAS NEXUS 2024; 3:pgad484. [PMID: 38213616 PMCID: PMC10783808 DOI: 10.1093/pnasnexus/pgad484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 12/21/2023] [Indexed: 01/13/2024]
Abstract
Some properties of Salmonella-infected cells overlap with immunogenic cell death. In this study, we demonstrated that intracellular infection of melanoma with Salmonella typhimurium induced high immunogenicity in melanoma cells, leading to antitumor effects with melanoma-antigen-specific T-cell responses. Murine B16F10 melanoma cells were infected with tdTomato-expressing attenuated S. typhimurium (VNP20009; VNP-tdT), triggering massive cell vacuolization. VNP-tdT-infected B16F10 cells were phagocytosed efficiently, which induced the activation of antigen-presenting cells with CD86 expression in vitro. Subcutaneous coimplantation of uninfected and VNP-tdT-infected B16F10 cells into C57BL/6 mice significantly suppressed tumor growth compared with the implantation of uninfected B16F10 cells alone. Inoculation of mice with VNP-tdT-infected B16F10 cells elicited the proliferation of melanoma-antigen (gp100)-specific T cells, and it protected the mice from the second tumor challenge of uninfected B16F10 cells. These results suggest that Salmonella-infected tumor cells acquire effective adjuvanticity, leading to ideal antitumor immune responses.
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Affiliation(s)
- Yutaka Horiuchi
- Department of Microbiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan
| | - Akihiro Nakamura
- Department of Microbiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan
| | - Takashi Imai
- Department of Microbiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan
| | - Takashi Murakami
- Department of Microbiology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan
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17
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Sivasankar C, Hewawaduge C, Muthuramalingam P, Lee JH. Tumor-targeted delivery of lnc antisense RNA against RCAS1 by live-attenuated tryptophan-auxotrophic Salmonella inhibited 4T1 breast tumors and metastasis in mice. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 34:102053. [PMID: 37941832 PMCID: PMC10628790 DOI: 10.1016/j.omtn.2023.102053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 10/11/2023] [Indexed: 11/10/2023]
Abstract
Emerging chemo- and radiotherapy resistance exacerbated the cancer risk and necessitated novel treatment strategies. Although RNA therapeutics against pro-oncogenic genes are highly effective, tumor-specific delivery remains a barrier to the implementation of this valuable tool. In this study, we report a tryptophan-auxotrophic Salmonella typhimurium strain as an onco-therapeutic delivery system with tumor-targeting ability using 4T1 mice breast-cancer model. The receptor-binding cancer antigen expressed on SiSo cell (RCAS1) is a cancer-specific protein that induces the apoptosis of peripheral lymphocytes and confers tumor immune evasion. We designed a long non-coding antisense-RNA against RCAS1 (asRCAS1) and delivered by Salmonella using a non-antibiotic, auxotrophic-selective, eukaryotic expression plasmid, pJHL204. After in vivo tumor-to-tumor passaging, the JOL2888 (ΔtrpA, ΔtrpE, Δasd + asRCAS1) strain exhibited high sustainability in tumors, but did not last in healthy organs, thereby demonstrating tumor specificity and safety. RCAS1 inhibition in the tumor was confirmed by western blotting and qPCR. In mice, JOL2888 treatment reduced tumor-associated macrophages, improved the T cell population, elicited cell-mediated immunity, and suppressed cancer-promoting genes. Consequently, the JOL2888 treatment significantly decreased the tumor volume by 80%, decreased splenomegaly by 30%, and completely arrested lung metastasis. These findings highlight the intrinsic tumor-targeting ability of tryptophan-auxotrophic Salmonella for delivering onco-therapeutic macromolecules.
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Affiliation(s)
- Chandran Sivasankar
- College of Veterinary Medicine, Jeonbuk National University, Iksan Campus 54596, Republic of Korea
| | - Chamith Hewawaduge
- College of Veterinary Medicine, Jeonbuk National University, Iksan Campus 54596, Republic of Korea
| | | | - John Hwa Lee
- College of Veterinary Medicine, Jeonbuk National University, Iksan Campus 54596, Republic of Korea
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18
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Sharma S, Sharma H, Gogoi H. Bacterial immunotherapy: is it a weapon in our arsenal in the fight against cancer? Front Immunol 2023; 14:1277677. [PMID: 38090593 PMCID: PMC10711065 DOI: 10.3389/fimmu.2023.1277677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 11/03/2023] [Indexed: 12/18/2023] Open
Abstract
Advances in understanding the genetic basis of cancer have driven alternative treatment approaches. Recent findings have demonstrated the potential of bacteria and it's components to serve as robust theranostic agents for cancer eradication. Compared to traditional cancer therapies like surgery, chemotherapy, radiotherapy, bacteria mediated tumor therapy has exhibited superior cancer suppressing property which is attributed a lot to it's tumor proliferating and accumulating characteristics. Genetically modified bacteria has reduced inherent toxicity and enhanced specificity towards tumor microenvironment. This anti- tumor activity of bacteria is attributed to its toxins and other active components from the cell membrane, cell wall and spores. Furthermore, bacterial genes can be regulated to express and deliver cytokines, antibodies and cancer therapeutics. Although there is less clinical data available, the pre- clinical research clearly indicates the feasibility and potential of bacteria- mediated cancer therapy.
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Affiliation(s)
- Shubhra Sharma
- Amity Institute of Microbial Technology, Amity University Rajasthan, Jaipur, India
| | - Himani Sharma
- Amity Institute of Microbial Technology, Amity University Rajasthan, Jaipur, India
| | - Himanshu Gogoi
- Amity Institute of Microbial Technology, Amity University Rajasthan, Jaipur, India
- Translational Health Science and Technology Institute, National Capital Region (NCR) Biotech Science Cluster, Faridabad, India
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19
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Zong R, Ruan H, Liu C, Fan S, Li J. Bacteria and Bacterial Components as Natural Bio-Nanocarriers for Drug and Gene Delivery Systems in Cancer Therapy. Pharmaceutics 2023; 15:2490. [PMID: 37896250 PMCID: PMC10610331 DOI: 10.3390/pharmaceutics15102490] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Revised: 10/06/2023] [Accepted: 10/16/2023] [Indexed: 10/29/2023] Open
Abstract
Bacteria and bacterial components possess multifunctional properties, making them attractive natural bio-nanocarriers for cancer diagnosis and targeted treatment. The inherent tropic and motile nature of bacteria allows them to grow and colonize in hypoxic tumor microenvironments more readily than conventional therapeutic agents and other nanomedicines. However, concerns over biosafety, limited antitumor efficiency, and unclear tumor-targeting mechanisms have restricted the clinical translation and application of natural bio-nanocarriers based on bacteria and bacterial components. Fortunately, bacterial therapies combined with engineering strategies and nanotechnology may be able to reverse a number of challenges for bacterial/bacterial component-based cancer biotherapies. Meanwhile, the combined strategies tend to enhance the versatility of bionanoplasmic nanoplatforms to improve biosafety and inhibit tumorigenesis and metastasis. This review summarizes the advantages and challenges of bacteria and bacterial components in cancer therapy, outlines combinatorial strategies for nanocarriers and bacterial/bacterial components, and discusses their clinical applications.
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Affiliation(s)
| | | | | | - Shaohua Fan
- School of Life Science, Jiangsu Normal University, Xuzhou 221116, China
| | - Jun Li
- School of Life Science, Jiangsu Normal University, Xuzhou 221116, China
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20
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Zhou M, Tang Y, Xu W, Hao X, Li Y, Huang S, Xiang D, Wu J. Bacteria-based immunotherapy for cancer: a systematic review of preclinical studies. Front Immunol 2023; 14:1140463. [PMID: 37600773 PMCID: PMC10436994 DOI: 10.3389/fimmu.2023.1140463] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/30/2023] [Indexed: 08/22/2023] Open
Abstract
Immunotherapy has been emerging as a powerful strategy for cancer management. Recently, accumulating evidence has demonstrated that bacteria-based immunotherapy including naive bacteria, bacterial components, and bacterial derivatives, can modulate immune response via various cellular and molecular pathways. The key mechanisms of bacterial antitumor immunity include inducing immune cells to kill tumor cells directly or reverse the immunosuppressive microenvironment. Currently, bacterial antigens synthesized as vaccine candidates by bioengineering technology are novel antitumor immunotherapy. Especially the combination therapy of bacterial vaccine with conventional therapies may further achieve enhanced therapeutic benefits against cancers. However, the clinical translation of bacteria-based immunotherapy is limited for biosafety concerns and non-uniform production standards. In this review, we aim to summarize immunotherapy strategies based on advanced bacterial therapeutics and discuss their potential for cancer management, we will also propose approaches for optimizing bacteria-based immunotherapy for facilitating clinical translation.
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Affiliation(s)
- Min Zhou
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Yucheng Tang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wenjie Xu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Xinyan Hao
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Yongjiang Li
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Si Huang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Daxiong Xiang
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Junyong Wu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Changsha, China
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21
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Roe JM, Seely K, Bussard CJ, Eischen Martin E, Mouw EG, Bayles KW, Hollingsworth MA, Brooks AE, Dailey KM. Hacking the Immune Response to Solid Tumors: Harnessing the Anti-Cancer Capacities of Oncolytic Bacteria. Pharmaceutics 2023; 15:2004. [PMID: 37514190 PMCID: PMC10384176 DOI: 10.3390/pharmaceutics15072004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/13/2023] [Accepted: 07/18/2023] [Indexed: 07/30/2023] Open
Abstract
Oncolytic bacteria are a classification of bacteria with a natural ability to specifically target solid tumors and, in the process, stimulate a potent immune response. Currently, these include species of Klebsiella, Listeria, Mycobacteria, Streptococcus/Serratia (Coley's Toxin), Proteus, Salmonella, and Clostridium. Advancements in techniques and methodology, including genetic engineering, create opportunities to "hijack" typical host-pathogen interactions and subsequently harness oncolytic capacities. Engineering, sometimes termed "domestication", of oncolytic bacterial species is especially beneficial when solid tumors are inaccessible or metastasize early in development. This review examines reported oncolytic bacteria-host immune interactions and details the known mechanisms of these interactions to the protein level. A synopsis of the presented membrane surface molecules that elicit particularly promising oncolytic capacities is paired with the stimulated localized and systemic immunogenic effects. In addition, oncolytic bacterial progression toward clinical translation through engineering efforts are discussed, with thorough attention given to strains that have accomplished Phase III clinical trial initiation. In addition to therapeutic mitigation after the tumor has formed, some bacterial species, referred to as "prophylactic", may even be able to prevent or "derail" tumor formation through anti-inflammatory capabilities. These promising species and their particularly favorable characteristics are summarized as well. A complete understanding of the bacteria-host interaction will likely be necessary to assess anti-cancer capacities and unlock the full cancer therapeutic potential of oncolytic bacteria.
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Affiliation(s)
- Jason M Roe
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA
| | - Kevin Seely
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA
| | - Caleb J Bussard
- College of Osteopathic Medicine, Rocky Vista University, Parker, CO 80130, USA
| | | | - Elizabeth G Mouw
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA
| | - Kenneth W Bayles
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Michael A Hollingsworth
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - Amanda E Brooks
- College of Osteopathic Medicine, Rocky Vista University, Ivins, UT 84738, USA
- College of Osteopathic Medicine, Rocky Vista University, Parker, CO 80130, USA
- Office of Research & Scholarly Activity, Rocky Vista University, Ivins, UT 84738, USA
| | - Kaitlin M Dailey
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA
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22
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Koehle AP, Brumwell SL, Seto EP, Lynch AM, Urbaniak C. Microbial applications for sustainable space exploration beyond low Earth orbit. NPJ Microgravity 2023; 9:47. [PMID: 37344487 DOI: 10.1038/s41526-023-00285-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 05/25/2023] [Indexed: 06/23/2023] Open
Abstract
With the construction of the International Space Station, humans have been continuously living and working in space for 22 years. Microbial studies in space and other extreme environments on Earth have shown the ability for bacteria and fungi to adapt and change compared to "normal" conditions. Some of these changes, like biofilm formation, can impact astronaut health and spacecraft integrity in a negative way, while others, such as a propensity for plastic degradation, can promote self-sufficiency and sustainability in space. With the next era of space exploration upon us, which will see crewed missions to the Moon and Mars in the next 10 years, incorporating microbiology research into planning, decision-making, and mission design will be paramount to ensuring success of these long-duration missions. These can include astronaut microbiome studies to protect against infections, immune system dysfunction and bone deterioration, or biological in situ resource utilization (bISRU) studies that incorporate microbes to act as radiation shields, create electricity and establish robust plant habitats for fresh food and recycling of waste. In this review, information will be presented on the beneficial use of microbes in bioregenerative life support systems, their applicability to bISRU, and their capability to be genetically engineered for biotechnological space applications. In addition, we discuss the negative effect microbes and microbial communities may have on long-duration space travel and provide mitigation strategies to reduce their impact. Utilizing the benefits of microbes, while understanding their limitations, will help us explore deeper into space and develop sustainable human habitats on the Moon, Mars and beyond.
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Affiliation(s)
- Allison P Koehle
- Department of Plant Science, Pennsylvania State University, University Park, PA, USA
| | - Stephanie L Brumwell
- Department of Biochemistry, Schulich School of Medicine and Dentistry, The University of Western Ontario, London, ON, Canada
| | | | - Anne M Lynch
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Graduate Program in Developmental Biology, Baylor College of Medicine, Houston, TX, USA
| | - Camilla Urbaniak
- ZIN Technologies Inc, Middleburg Heights, OH, USA.
- NASA Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA, USA.
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23
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Zhou S, Lin Y, Zhao Z, Lai Y, Lu M, Shao Z, Mo X, Mu Y, Liang Z, Wang X, Qu J, Shen H, Li F, Zhao AZ. Targeted deprivation of methionine with engineered Salmonella leads to oncolysis and suppression of metastasis in broad types of animal tumor models. Cell Rep Med 2023:101070. [PMID: 37269826 DOI: 10.1016/j.xcrm.2023.101070] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/01/2022] [Accepted: 05/10/2023] [Indexed: 06/05/2023]
Abstract
The strong dependency of almost all malignant tumors on methionine potentially offers a pathway for cancer treatment. We engineer an attenuated strain of Salmonella typhimurium to overexpress an L-methioninase with the aim of specifically depriving tumor tissues of methionine. The engineered microbes target solid tumors and induce a sharp regression in several very divergent animal models of human carcinomas, cause a significant decrease in tumor cell invasion, and essentially eliminate the growth and metastasis of these tumors. RNA sequencing analyses reveal that the engineered Salmonella reduce the expression of a series of genes promoting cell growth, cell migration, and invasion. These findings point to a potential treatment modality for many metastatic solid tumors, which warrants further tests in clinical trials.
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Affiliation(s)
- Sujin Zhou
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong Province, China
| | - Yan Lin
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong Province, China; The Laboratory Center for Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Zhenggang Zhao
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong Province, China
| | - Yunhao Lai
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong Province, China
| | - Mengmeng Lu
- Guangzhou Sinogen Pharmaceutical Co., Ltd., Guangzhou, Guangdong Province, China
| | - Zishen Shao
- Guangzhou Sinogen Pharmaceutical Co., Ltd., Guangzhou, Guangdong Province, China
| | - Xinyu Mo
- Guangzhou Sinogen Pharmaceutical Co., Ltd., Guangzhou, Guangdong Province, China
| | - Yunping Mu
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong Province, China
| | - Zhipeng Liang
- Department of Radiology, Sir Ruan-Ruan Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Xinxing Wang
- Department of Oncology, Sir Ruan-Ruan Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Jingming Qu
- Department of Thoracic and Heart Surgery, Xuzhou Cancer Hospital, Jiangsu University, Xuzhou, Jiangsu Province, China
| | - Hua Shen
- Department of Oncology, Sir Ruan-Ruan Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China
| | - Fanghong Li
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong Province, China.
| | - Allan Z Zhao
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, Guangdong Province, China.
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24
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Feola S, Chiaro J, Cerullo V. Integrating immunopeptidome analysis for the design and development of cancer vaccines. Semin Immunol 2023; 67:101750. [PMID: 37003057 DOI: 10.1016/j.smim.2023.101750] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 03/17/2023] [Accepted: 03/17/2023] [Indexed: 04/03/2023]
Abstract
The repertoire of naturally presented peptides within the MHC (major histocompatibility complex) or HLA (human leukocyte antigens) system on the cellular surface of every mammalian cell is referred to as ligandome or immunopeptidome. This later gained momentum upon the discovery of CD8 + T cells able to recognize and kill cancer cells in an MHC-I antigen-restricted manner. Indeed, cancer immune surveillance relies on T cell recognition of MHC-I-restricted peptides, making the identification of those peptides the core for designing T cell-based cancer vaccines. Moreover, the breakthrough of antibodies targeting immune checkpoint molecules has led to a new and strong interest in discovering suitable targets for CD8 +T cells. Therapeutic cancer vaccines are designed for the artificial generation and/or stimulation of CD8 +T cells; thus, their combination with ICIs to unleash the breaks of the immune system comes as a natural consequence to enhance anti-tumor efficacy. In this context, the identification and knowledge of peptide candidates take advantage of the fast technology updates in immunopeptidome and mass spectrometric methodologies, paying the way to the rational design of vaccines for immunotherapeutic approaches. In this review, we discuss mainly the role of immunopeptidome analysis and its application for the generation of therapeutic cancer vaccines with main focus on HLA-I peptides. Here, we review cancer vaccine platforms based on two different preparation methods: pathogens (viruses and bacteria) and not (VLPs, nanoparticles, subunits vaccines) that exploit discoveries in the ligandome field to generate and/or enhance anti-tumor specific response. Finally, we discuss possible drawbacks and future challenges in the field that remain still to be addressed.
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Affiliation(s)
- Sara Feola
- Drug Research Program (DRP) ImmunoViroTherapy Lab (IVT), Faculty of Pharmacy Helsinki University, Viikinkaari 5E, Finland; Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Fabianinkatu 33, Finland; Translational Immunology Program (TRIMM), Faculty of Medicine Helsinki University, Haartmaninkatu 8, Finland
| | - Jacopo Chiaro
- Drug Research Program (DRP) ImmunoViroTherapy Lab (IVT), Faculty of Pharmacy Helsinki University, Viikinkaari 5E, Finland; Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Fabianinkatu 33, Finland; Translational Immunology Program (TRIMM), Faculty of Medicine Helsinki University, Haartmaninkatu 8, Finland
| | - Vincenzo Cerullo
- Drug Research Program (DRP) ImmunoViroTherapy Lab (IVT), Faculty of Pharmacy Helsinki University, Viikinkaari 5E, Finland; Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Fabianinkatu 33, Finland; Translational Immunology Program (TRIMM), Faculty of Medicine Helsinki University, Haartmaninkatu 8, Finland; Department of Molecular Medicine and Medical Biotechnology, Naples University "Federico II", S. Pansini 5, Italy.
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25
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ECM-targeting bacteria enhance chemotherapeutic drug efficacy by lowering IFP in tumor mouse models. J Control Release 2023; 355:199-210. [PMID: 36750146 DOI: 10.1016/j.jconrel.2023.02.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 01/31/2023] [Accepted: 02/01/2023] [Indexed: 02/09/2023]
Abstract
Bacterial cancer therapies aim to manipulate bacteria to effectively deploy therapeutic payloads to tumors. Attenuated bacteria alone often cannot eradicate solid tumors. Attenuated Salmonella can be engineered to deliver cytotoxic drugs to either trigger an immune response or increase antitumor efficacy when combined with chemotherapeutic drugs. However, the extracellular matrix (ECM) surrounding cancer cells forms a barrier that often limits the ability of chemotherapeutic and cytotoxic drugs to penetrate and eliminate tumors. To overcome this limitation, we developed a strategy to combine chemotherapy with an attenuated Salmonella typhimurium strain engineered to secrete HysA protein (from Staphylococcus aureus; Hyaluronidase, HAase) in tumors. The engineered Salmonella effectively degraded hyaluronan (HA), which is a major ECM constituent in tumors, and suppressed tumor growth in mouse models of pancreatic adenocarcinoma (ASPC-1) and breast cancer (4T1). Furthermore, it prolonged survival when combined with chemotherapeutic drugs (doxorubicin or gemcitabine). Upon bacterial colonization, the HAase-mediated ECM degradation decreased interstitial fluid pressure (IFP) in the tumor microenvironment. Additionally, HA degradation using HAase-expressing bacteria in vivo led to decreased binding to the receptor, CD44, expressed in tumors. This may modulate proliferation- and apoptosis-related signal pathways. Therefore, ECM-targeting bacteria can be used as a synergistic anticancer therapeutic agent to maximize chemotherapeutic drug delivery into highly invasive tumors.
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26
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<italic>Salmonella typhimurium</italic> may support cancer treatment: a review. Acta Biochim Biophys Sin (Shanghai) 2023; 55:331-342. [PMID: 36786073 PMCID: PMC10160236 DOI: 10.3724/abbs.2023007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
<p indent="0mm">Antitumour treatments are evolving, including bacteria-mediated cancer therapy which is concurrently an ancient and cutting-edge approach. <italic>Salmonella typhimurium</italic> is a widely studied bacterial species that colonizes tumor tissues, showing oncolytic and immune system-regulating properties. It can be used as a delivery vector for genes and drugs, supporting conventional treatments that lack tumor-targeting abilities. This article summarizes recent evidence on the anticancer mechanisms of <italic>S</italic>. <italic>typhimurium</italic> alone and in combination with other anticancer treatments, suggesting that it may be a suitable approach to disease management. </p>.
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27
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Rybkin I, Pinyaev S, Sindeeva O, German S, Koblar M, Pyataev N, Čeh M, Gorin D, Sukhorukov G, Lapanje A. Modification of bacterial cells for in vivo remotely guided systems. Front Bioeng Biotechnol 2023; 10:1070851. [PMID: 36686260 PMCID: PMC9845715 DOI: 10.3389/fbioe.2022.1070851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 12/09/2022] [Indexed: 01/06/2023] Open
Abstract
It was shown recently that bacterial strains, which can act specifically against malignant cells, can be used efficiently in cancer therapy. Many appropriate bacterial strains are either pathogenic or invasive and there is a substantial shortage of methods with which to monitor in vivo the distribution of bacteria used in this way. Here, it is proposed to use a Layer-by-Layer (LbL) approach that can encapsulate individual bacterial cells with fluorescently labeled polyelectrolytes (PE)s and magnetite nanoparticles (NP)s. The NP enable remote direction in vivo to the site in question and the labeled shells in the far-red emission spectra allow non-invasive monitoring of the distribution of bacteria in the body. The magnetic entrapment of the modified bacteria causes the local concentration of the bacteria to increase by a factor of at least 5. The PEs create a strong barrier, and it has been shown in vitro experiments that the division time of bacterial cells coated in this way can be regulated, resulting in control of their invasion into tissues. That animals used in the study survived and did not suffer septic shock, which can be attributed to PE capsules that prevent release of endotoxins from bacterial cells.
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Affiliation(s)
- Iaroslav Rybkin
- Helmholtz-Zentrum Dresden-Rossendorf, Leipzig, Germany,Jožef Stefan Institute, Ljubljana, Slovenia,State University, Saratov, Russia,Jožef Stefan International Postgraduate School, Ljubljana, Slovenia
| | - Sergey Pinyaev
- National Research Ogerev Mordovia State University, Saransk, Russia
| | - Olga Sindeeva
- State University, Saratov, Russia,A.V. Zelman Center for Neurobiology and Brain Rehabilitation, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Sergey German
- Center of Photonic Science and Engineering, Skolkovo Institute of Science and Technology, Moscow, Russia,Institute of Spectroscopy of the Russian Academy of Sciences, Moscow, Russia
| | - Maja Koblar
- Jožef Stefan Institute, Ljubljana, Slovenia,Jožef Stefan International Postgraduate School, Ljubljana, Slovenia
| | - Nikolay Pyataev
- National Research Ogerev Mordovia State University, Saransk, Russia
| | - Miran Čeh
- Jožef Stefan Institute, Ljubljana, Slovenia
| | - Dmitry Gorin
- Center of Photonic Science and Engineering, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Gleb Sukhorukov
- A.V. Zelman Center for Neurobiology and Brain Rehabilitation, Skolkovo Institute of Science and Technology, Moscow, Russia,Queen Mary University of London, London, United Kingdom
| | - Aleš Lapanje
- Jožef Stefan Institute, Ljubljana, Slovenia,*Correspondence: Aleš Lapanje,
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28
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Liu Y, Feng J, Pan H, Zhang X, Zhang Y. Genetically engineered bacterium: Principles, practices, and prospects. Front Microbiol 2022; 13:997587. [PMID: 36312915 PMCID: PMC9606703 DOI: 10.3389/fmicb.2022.997587] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Accepted: 09/23/2022] [Indexed: 12/24/2022] Open
Abstract
Advances in synthetic biology and the clinical application of bacteriotherapy enable the use of genetically engineered bacteria (GEB) to combat various diseases. GEB act as a small 'machine factory' in the intestine or other tissues to continuously produce heterologous proteins or molecular compounds and, thus, diagnose or cure disease or work as an adjuvant reagent for disease treatment by regulating the immune system. Although the achievements of GEBs in the treatment or adjuvant therapy of diseases are promising, the practical implementation of this new therapeutic modality remains a grand challenge, especially at the initial stage. In this review, we introduce the development of GEBs and their advantages in disease management, summarize the latest research advances in microbial genetic techniques, and discuss their administration routes, performance indicators and the limitations of GEBs used as platforms for disease management. We also present several examples of GEB applications in the treatment of cancers and metabolic diseases and further highlight their great potential for clinical application in the near future.
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Affiliation(s)
- Yiting Liu
- Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
- Department of Biomedical Engineering, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
| | - Jing Feng
- Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
- Department of Biomedical Engineering, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
| | - Hangcheng Pan
- Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Xiuwei Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Yunlei Zhang
- Department of Respiratory and Critical Care Medicine, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
- Department of Biomedical Engineering, School of Biomedical Engineering and Informatics, Nanjing Medical University, Nanjing, China
- Central Laboratory, Translational Medicine Research Center, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
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29
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Molecular Characterization of CF33 Canine Cell Line and Evaluation of Its Ability to Respond against Infective Stressors in Sight of Anticancer Approaches. Vet Sci 2022; 9:vetsci9100543. [PMID: 36288156 PMCID: PMC9610178 DOI: 10.3390/vetsci9100543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 09/27/2022] [Accepted: 09/27/2022] [Indexed: 11/05/2022] Open
Abstract
Simple Summary Canine mammary cancer is very common and has many similarities with human breast cancer. Risk factors, physiological and pathological behaviors, and the clinical course in dogs are very similar to humans. Several molecular similarities have also been reported, such as overexpression of EGF, proliferation markers, metalloproteinase and cyclooxygenase, TP53 mutations, and CXCR4/SDF1 axis activation. These common characteristics make these breast tumors resistant to conventional therapies. It is therefore necessary to study therapeutic alternatives. Cell lines could be helpful to test in vitro immunomodulant anti-cancer therapies, allowing a reduction of laboratory animals’ involvement in the preliminary tests and achieving results in a shorter time. Although the canine mammary carcinoma cell line CF33 has been widely used in many studies on dog mammary cancer, characterization of its gene expression profile and of the influence of infective stressors of this cell line is poor. Our study shows the interaction of CF33 and Salmonella Typhimurium (ST) as an infective stressor, indicating that these cells may represent an in vitro model for assessing novel therapeutic approaches using bacteria. Abstract Spontaneous mammary tumors are the most frequent neoplasms in bitches and show similarities with human breast cancer in risk factors, clinical course, and histopathology. The poor prognosis of some cancer subtypes, both in human and dog, demands more effective therapeutic approaches. A possible strategy is the new anticancer therapy based on immune response modulation through bacteria or their derivatives on canine mammary carcinoma cell lines. The aim of the present study was to analyze the CF33 cell line in terms of basal expression of immune innate genes, CXCR4 expression, and interaction with infectious stressors. Our results highlight that CF33 maintains gene expression parameters typical of mammary cancer, and provides the basal gene expression of CF33, which is characterized by overexpression of CXCR4, CD44, RAD51, LY96, and a non-continuous expression of TP53 and PTEN. No mutations appeared in the CXCR4 gene until the 58th passage; this may represent important information for studying the CXCR4 pathway as a therapeutic target. Moreover, the CF33 cell line was shown to be able to interact with Salmonella Typhimurium (ST) (an infective stressor), indicating that these cells could be used as an in vitro model for developing innovative therapeutic approaches involving bacteria.
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30
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Pandey M, Choudhury H, Vijayagomaran PA, Lian PNP, Ning TJ, Wai NZ, Xian-Zhuang N, Le Er C, Rahmah NSN, Kamaruzzaman NDB, Mayuren J, Candasamy M, Gorain B, Chawla PA, Amin MCIM. Recent Update on Bacteria as a Delivery Carrier in Cancer Therapy: From Evil to Allies. Pharm Res 2022; 39:1115-1134. [PMID: 35386012 PMCID: PMC8985562 DOI: 10.1007/s11095-022-03240-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 03/18/2022] [Indexed: 01/19/2023]
Abstract
Cancer is associated with a comprehensive burden that significantly affects patient’s quality of life. Even though patients’ disease condition is improving following conventional therapies, researchers are studying alternative tools that can penetrate solid tumours to deliver the therapeutics due to issues of developing resistance by the cancer cells. Treating cancer is not the only the goal in cancer therapy; it also includes protecting non-cancerous cells from the toxic effects of anti-cancer agents. Thus, various advanced techniques, such as cell-based drug delivery, bacteria-mediated therapy, and nanoparticles, are devised for site-specific delivery of drugs. One of the novel methods that can be targeted to deliver anti-cancer agents is by utilising genetically modified non-pathogenic bacterial species. This is due to the ability of bacterial species to multiply selectively or non-selectively on tumour cells, resulting in biofilms that leads to disruption of metastasis process. In preclinical studies, this technology has shown significant results in terms of efficacy, and some are currently under investigation. Therefore, researchers have conducted studies on bacteria transporting the anti-cancer drug to targeted tumours. Alternatively, bacterial ghosts and bacterial spores are utilised to deliver anti-cancer drugs. Although in vivo studies of bacteria-mediated cancer therapy have shown successful outcome, further research on bacteria, specifically their targeting mechanism, is required to establish a complete clinical approach in cancer treatment. This review has focused on the up-to-date understanding of bacteria as a therapeutic carrier in the treatment of cancer as an emerging field.
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Affiliation(s)
- Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, 57000 Bukit Jalil, Kuala Lumpur, Malaysia.
| | - Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
| | | | - Pauline Ng Poh Lian
- School of Pharmacy, International Medical University, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
| | - Tan Jing Ning
- School of Pharmacy, International Medical University, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
| | - Ng Zing Wai
- School of Pharmacy, International Medical University, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
| | - Ng Xian-Zhuang
- School of Pharmacy, International Medical University, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
| | - Chong Le Er
- School of Pharmacy, International Medical University, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
| | | | | | - Jayashree Mayuren
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
| | - Mayuren Candasamy
- Department of Life Sciences, School of Pharmacy, International Medical University, 57000 Bukit Jalil, Kuala Lumpur, Malaysia
| | - Bapi Gorain
- Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, 835215, India
| | - Pooja A Chawla
- Department of Pharmaceutical Chemistry and Analysis, ISF College of Pharmacy Moga, Ghall Kalan, Punjab, India
| | - Mohd Cairul Iqbal Mohd Amin
- Centre for Drug Delivery Technology, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300, Kuala Lumpur, Malaysia
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The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors. NANOMATERIALS 2021; 11:nano11113018. [PMID: 34835785 PMCID: PMC8623458 DOI: 10.3390/nano11113018] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 10/28/2021] [Accepted: 11/01/2021] [Indexed: 02/07/2023]
Abstract
While many classes of chemotherapeutic agents exist to treat solid tumors, few can generate a lasting response without substantial off-target toxicity despite significant scientific advancements and investments. In this review, the paths of development for nanoparticles, oncolytic viruses, and oncolytic bacteria over the last 20 years of research towards clinical translation and acceptance as novel cancer therapeutics are compared. Novel nanoparticle, oncolytic virus, and oncolytic bacteria therapies all start with a common goal of accomplishing therapeutic drug activity or delivery to a specific site while avoiding off-target effects, with overlapping methodology between all three modalities. Indeed, the degree of overlap is substantial enough that breakthroughs in one therapeutic could have considerable implications on the progression of the other two. Each oncotherapeutic modality has accomplished clinical translation, successfully overcoming the potential pitfalls promising therapeutics face. However, once studies enter clinical trials, the data all but disappears, leaving pre-clinical researchers largely in the dark. Overall, the creativity, flexibility, and innovation of these modalities for solid tumor treatments are greatly encouraging, and usher in a new age of pharmaceutical development.
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Highlights of Immunomodulation in Salmonella-Based Cancer Therapy. Biomedicines 2021; 9:biomedicines9111566. [PMID: 34829795 PMCID: PMC8615479 DOI: 10.3390/biomedicines9111566] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/22/2021] [Accepted: 10/27/2021] [Indexed: 12/24/2022] Open
Abstract
Bacteria-mediated cancer therapy (BMCT) is an emerging tool that may advance potential approaches in cancer immunotherapy, whereby tumors are eradicated by the hosts’ immune system upon recruitment and activation by bacteria such as Salmonella. This paper provides an emphasis on the immunomodulatory effects that encompasses both the innate and adaptive immune responses inherently triggered by Salmonella. Furthermore, modifications of Salmonella-based treatment in the attempt to improve tumor-specific immune responses including cytokine therapy, gene therapy, and DNA vaccine delivery are likewise discussed. The majority of the findings described herein incorporate cell-based experiments and murine model studies, and only a few accounts describe clinical trials. Salmonella-based cancer therapy is still under development; nonetheless, the pre-clinical research and early-phase clinical trials that have been completed so far have shown promising and convincing results. Certainly, the continuous development of, and innovation on, Salmonella-based therapy could pave the way for its eventual emergence as one of the mainstream therapeutic interventions addressing various types of cancer.
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Lu S, Gao J, Jia H, Li Y, Duan Y, Song F, Liu Z, Ma S, Wang M, Zhao T, Zhong J. PD-1-siRNA Delivered by Attenuated Salmonella Enhances the Antitumor Effect of Chloroquine in Colon Cancer. Front Immunol 2021; 12:707991. [PMID: 34295341 PMCID: PMC8290856 DOI: 10.3389/fimmu.2021.707991] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 06/21/2021] [Indexed: 01/11/2023] Open
Abstract
The widespread appearance of drug tolerance and the low efficiency of single treatment have severely affected the survival time of the patients with colorectal cancer. Exploring new treatment options and combined treatment strategies have become the key to improving the prognosis. The combination of immunotherapy and chemotherapy have shown good clinical expectations. Here, we studied the cooperative effects of chloroquine, an anti-malarial drug that is now widely used in anti-tumor research, and RNA interference (RNAi) targeting the immune checkpoint molecule Programmed Death-1 (PD-1) delivered with attenuated Salmonella. Our results show that chloroquine can not only significantly inhibit the survival of colon cancer cells and induce apoptosis, but also effectively inhibit cell invasion and migration. The results of in vivo experiments show that chloroquine can increase the expression of PD-1 in tumor tissues. Combining chloroquine and PD-1 siRNA can further inhibit the growth and metastases of colon cancer and induce apoptosis. The mechanism underlying this phenomenon is the occurrence of chloroquine-induced apoptosis and the effective immune response caused by the attenuated Salmonella carrying PD-1 siRNA. This study suggests that the combined application of PD-1-based immunotherapy and anti-cancer drugs has become a new expectation for clinical treatment of colorectal cancer.
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Affiliation(s)
- Shuya Lu
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Jianhui Gao
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
- College of Forensic Medicine, Xi’an Jiaotong University Health Science Center, Xi’an, China
| | - Huijie Jia
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Yang Li
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, China
| | - Yongbin Duan
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Fuyang Song
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Zhiang Liu
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, China
| | - Shuai Ma
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
| | - Mingyong Wang
- Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Tiesuo Zhao
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, China
| | - Jiateng Zhong
- Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
- Department of Pathology, Xinxiang Medical University, Xinxiang, China
- Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
- Xinxiang Key Laboratory of Tumor Vaccine and Immunotherapy, Xinxiang Medical University, Xinxiang, China
- Laboratory of Molecular Biology of Tumor Reversal, Xinxiang Medical University, Xinxiang, China
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