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Offens A, Teeuwen L, Gucluler-Akpinar G, Steiner L, Kooijmans S, Mamand D, Weissinger H, Käll A, Eldh M, Wiklander OPB, Andaloussi SEL, Karlsson MCI, Vader P, Gabrielsson S. A fusion protein that targets antigen-loaded extracellular vesicles to B cells enhances antigen-specific T cell expansion. J Control Release 2025:113665. [PMID: 40147536 DOI: 10.1016/j.jconrel.2025.113665] [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: 02/14/2025] [Revised: 03/15/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Extracellular vesicles (EVs) have the potential to modulate immune responses via their cargo molecules and are being explored as vehicles in cancer immunotherapy. Dendritic cell-derived EVs can induce antigen-specific immune responses leading to reduced tumor burden. This response was shown to depend partially on B cells. EVs can be targeted to certain cells or tissues, and EVs from Epstein-Barr Virus (EBV) infected cells were shown to carry the EV glycoprotein GP350 on their surface and target human CD21 (hCD21) on B cells. We therefore investigated whether targeting EVs to B cells via this mechanism could improve antigen-specific immune responses. A soluble fusion protein containing the phosphatidylserine-binding domain (C1C2) of lactadherin and hCD21-binding domain (D123) of GP350 was used to decorate and target EVs to B cells. D123-decorated EVs increased in vitro B cell targeting 5-fold compared to EVs decorated with a non-targeting control protein or undecorated EVs. Furthermore, in vivo, D123-decoration did not alter the biodistribution of EVs across organs but specifically targeted them to B cells in the spleen, blood and lymph nodes of hCD21-transgenic mice. Immunization with hCD21-targeted, OVA-loaded EVs resulted in a higher percentage of antigen-specific CD8+ T cells compared to untargeted EVs. Our data show that D123-decorated EVs efficiently target B cells and improve antigen-specific T cell responses in vivo, which could be explored in future therapeutic applications.
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Affiliation(s)
- Annemarijn Offens
- Division of Immunology and Respiratory Medicine, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden(1); Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine (CMM), Stockholm, Sweden
| | - Loes Teeuwen
- Division of Immunology and Respiratory Medicine, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden(1); Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine (CMM), Stockholm, Sweden
| | - Gozde Gucluler-Akpinar
- Division of Immunology and Respiratory Medicine, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden(1); Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine (CMM), Stockholm, Sweden
| | - Loïc Steiner
- Division of Immunology and Respiratory Medicine, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden(1); Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine (CMM), Stockholm, Sweden
| | - Sander Kooijmans
- CDL Research, University Medical Center, Utrecht, the Netherlands(2); Metabolic Diseases, Wilhelmina's Children's Hospital, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Center, Utrecht, the Netherlands(3)
| | - Doste Mamand
- Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden(4); Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Stockholm, Sweden; Karolinska ATMP Center, Karolinska Institutet, Huddinge, Stockholm, Sweden; Breast Center, Karolinska Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden
| | - Hannah Weissinger
- Division of Immunology and Respiratory Medicine, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden(1); Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Alexander Käll
- Division of Immunology and Respiratory Medicine, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden(1); Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Maria Eldh
- Division of Immunology and Respiratory Medicine, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden(1); Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine (CMM), Stockholm, Sweden
| | - Oscar P B Wiklander
- Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden(4); Karolinska ATMP Center, Karolinska Institutet, Huddinge, Stockholm, Sweden; Breast Center, Karolinska Comprehensive Cancer Center, Karolinska University Hospital, Stockholm, Sweden
| | - Samir E L Andaloussi
- Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden(4); Department of Cellular Therapy and Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital, Stockholm, Sweden; Karolinska ATMP Center, Karolinska Institutet, Huddinge, Stockholm, Sweden
| | - Mikael C I Karlsson
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden(5)
| | - Pieter Vader
- CDL Research, University Medical Center, Utrecht, the Netherlands(2)
| | - Susanne Gabrielsson
- Division of Immunology and Respiratory Medicine, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden(1); Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden; Center for Molecular Medicine (CMM), Stockholm, Sweden.
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Sangani GS, Hosseini Farash BR, Khamesipour A, Bandehpour M, Sangani PS, Jajarmi V, Mohebali M. Production of exosomal nanoparticles containing antigenic peptides LACK, KMP11, TSA and LmSTI1 of L. major and evaluation of their immunoprophylactic effect against L. major infection in a murine infection model. Microb Pathog 2025; 200:107316. [PMID: 39848299 DOI: 10.1016/j.micpath.2025.107316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 12/18/2024] [Accepted: 01/18/2025] [Indexed: 01/25/2025]
Affiliation(s)
- Ghodratollah Salehi Sangani
- Department of Medical Parasitology and Mycology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Cutaneous Leishmania Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Razieh Hosseini Farash
- Department of Medical Parasitology and Mycology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Cutaneous Leishmania Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Khamesipour
- Centre for Research and Training in Skin Diseases and Leprosy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mojgan Bandehpour
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biotechnology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Pouria Salehi Sangani
- Department of Medical Parasitology and Mycology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vahid Jajarmi
- Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Department of Biotechnology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mehdi Mohebali
- Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Center for Research of Endemic Parasites of Iran (CREPI), Tehran University of Medical Sciences, Tehran, Iran.
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Meng Y, Yao Z, Ke X, Hu M, Ren H, Gao S, Zhang H. Extracellular vesicles-based vaccines: Emerging immunotherapies against cancer. J Control Release 2025; 378:438-459. [PMID: 39667569 DOI: 10.1016/j.jconrel.2024.12.010] [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: 08/01/2024] [Revised: 12/03/2024] [Accepted: 12/05/2024] [Indexed: 12/14/2024]
Abstract
Cancer vaccines are promising therapeutic approaches to enhance specific T-cell immunity against most solid tumors. By stimulating anti-tumor immunity, clearing minimal residual disease, and minimizing adverse effects, these vaccines target tumor cells and are effective when combined with immune checkpoint blockade or other immunotherapies. However, the development of tumor cell-based vaccines faces quality issues due to poor immunogenicity, tumor heterogeneity, a suppressive tumor immune microenvironment, and ineffective delivery methods. In contrast, extracellular vesicles (EVs), naturally released by cells, are considered the ideal drug carriers and vaccine platforms. EVs offer highly organ-specific targeting, induce broader and more effective immune responses, and demonstrate superior tissue delivery ability. The development of EV vaccines is crucial for advancing cancer immunotherapy. Compared to cell-based vaccines, EV vaccines produced under Good Manufacturing Practices (GMP) offer advantages such as high safety, ease of preservation and transport, and a wide range of sources. This review summarizes the latest research findings on EV vaccine and potential applications in this field. It also highlights novel neoantigens for the development of EV vaccines against cancer.
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Affiliation(s)
- Yuhua Meng
- Department of General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China; State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Zhimeng Yao
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, Guangdong, China; Department of Urology Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China
| | - Xiurong Ke
- Department of Surgery, Laboratory for Translational Surgical Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Mengyuan Hu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, Jinan University, Guangzhou, Guangdong, China
| | - Hongzheng Ren
- Gongli Hospital of Shanghai Pudong New Area, Department of Pathology, Shanghai, China
| | - Shegan Gao
- College of Clinical Medicine, The First Affiliated Hospital of Henan University of Science and Technology, Henan Key Laboratory of Cancer Epigenetics, Luoyang, Henan, China.
| | - Hao Zhang
- Gongli Hospital of Shanghai Pudong New Area, Department of Pathology, Shanghai, China; Department of Pathology, and Institute of Precision Cancer Medicine and Pathology, School of Medicine, State Key Laboratory of Bioactive Molecules and Druggability Assessment, MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, Guangdong, China; Department of Thoracic Surgery and General Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China.
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Dai Z, Cai R, Zeng H, Zhu H, Dou Y, Sun S. Exosome may be the next generation of promising cell-free vaccines. Hum Vaccin Immunother 2024; 20:2345940. [PMID: 38714324 PMCID: PMC11086043 DOI: 10.1080/21645515.2024.2345940] [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: 01/12/2024] [Accepted: 04/18/2024] [Indexed: 05/09/2024] Open
Abstract
Traditional vaccines have limits against some persistent infections and pathogens. The development of novel vaccine technologies is particularly critical for the future. Exosomes play an important role in physiological and pathological processes. Exosomes present many advantages, such as inherent capacity being biocompatible, non-toxic, which make them a more desirable candidate for vaccines. However, research on exosomes are in their infancy and the barriers of low yield, low purity, and weak targeting of exosomes limit their applications in vaccines. Accordingly, further exploration is necessary to improve these problems and subsequently facilitate the functional studies of exosomes. In this study, we reviewed the origin, classification, functions, modifications, separation and purification, and characterization methods of exosomes. Meanwhile, we focused on the role and mechanism of exosomes for cancer and COVID-19 vaccines.
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Affiliation(s)
- Zelan Dai
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Ruiru Cai
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Hong Zeng
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Hailian Zhu
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Youwei Dou
- Department VII of Biological Products, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming, People’s Republic of China
| | - Shibo Sun
- Department of Pulmonary and Critical Care Medicine, First Affiliated Hospital, Kunming Medical University, Kunming, People’s Republic of China
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Abida, Alhuthali HM, Alshehri JM, Alkathiri A, Almaghrabi ROM, Alsaeed SS, Albebi SAH, Almethn RM, Alfuraydi BA, Alharbi SB, Kamal M, Imran M. Exosomes in infectious diseases: insights into leishmaniasis pathogenesis, immune modulation, and therapeutic potential. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024:10.1007/s00210-024-03702-7. [PMID: 39702600 DOI: 10.1007/s00210-024-03702-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/02/2024] [Indexed: 12/21/2024]
Abstract
Leishmaniasis continues to be a critical international health issue due to the scarcity of efficient treatment and the development of drug tolerance. New developments in the research of extracellular vesicles (EVs), especially exosomes, have revealed novel disease management approaches. Exosomes are small vesicles that transport lipids, nucleic acids, and proteins in cell signalling. Its biogenesis depends on several cellular processes, and their functions in immune response, encompassing innate and adaptive immunity, underline their function in the pathogen-host interface. Exosomes play a significant role in the pathogenesis of some parasitic infections, especially Leishmaniasis, by helping parasites escape host immunity and promote disease progression. This article explains that in the framework of parasitic diseases, exosomes can act as master regulators that define the pathogenesis of the disease, as illustrated by the engagement of exosomes in the Leishmaniasis parasite and immune escape processes. Based on many published articles on Leishmaniasis, this review aims to summarize the biogenesis of exosomes, the properties of the cargo in exosomes, and the modulation of immune responses. We delve deeper into the prospect of using exosomes for the therapy of Leishmaniasis based on the possibility of using these extracellular vesicles for drug delivery and as diagnostic and prognostic biomarkers. Lastly, we focus on the recent research perspectives and future developments, underlining the necessity to continue the investigation of exosome-mediated approaches in Leishmaniasis treatment. Thus, this review intends to draw attention to exosomes as a bright new perspective in the battle against this disabling affliction.
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Affiliation(s)
- Abida
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia
| | - Hayaa M Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P.O. Box 11099, 21944, Taif, Saudi Arabia
| | - Jawaher Mohammad Alshehri
- Optometry Department, Faculty of Applied Medical Sciences, Albaha University, 65431, Albaha, Saudi Arabia
| | - Afnan Alkathiri
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Albaha University, 65431, Albaha, Saudi Arabia
| | - Ruba Omar M Almaghrabi
- Laboratory Medicine Department, Faculty of Applied Medical Sciences, Albaha University, 65431, Albaha, Saudi Arabia
| | | | | | | | | | | | - Mehnaz Kamal
- Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia
| | - Mohd Imran
- Department of Pharmaceutical Chemistry, College of Pharmacy, Northern Border University, 91911, Rafha, Saudi Arabia.
- Center for Health Research, Northern Border University, Arar, Saudi Arabia.
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Hua Y, Jiang P, Dai C, Li M. Extracellular vesicle autoantibodies. J Autoimmun 2024; 149:103322. [PMID: 39341173 DOI: 10.1016/j.jaut.2024.103322] [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: 07/16/2024] [Revised: 09/24/2024] [Accepted: 09/25/2024] [Indexed: 09/30/2024]
Abstract
Autoantibodies are immunoglobulin proteins produced by autoreactive B cells responding to self-antigens. Extracellular vesicles (EVs) are membranous structures released by almost all types of cells and extensively distributed in various biological fluids. Studies have indicated that EVs loaded with self-antigens not only play important roles in antigen presentation and autoantibody production but can also form functional immune complexes with autoantibodies (termed EV autoantibodies). While numerous papers have summarized the production and function of pathogenic autoantibodies in diseases, especially autoimmune diseases, reviews on EV autoantibodies are rare. In this review, we outline the existing knowledge about EVs, autoantibodies, and EV antigens, highlighting the formation of EV autoantibodies and their functions in autoimmune diseases and cancers. In conclusion, EV autoantibodies may be involved in the occurrence of disease(s) and also serve as potential non-invasive markers that could help in the diagnosis and/or prognosis of disease. Additional studies designed to define in more detail the molecular characteristics of EV autoantibodies and their contribution to disease are recommended.
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Affiliation(s)
- Yan Hua
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, China; Department of Laboratory Medicine, Anhui Provincial Cancer Hospital, Hefei, Anhui, 230031, China; Core Unit of National Clinical Research Center for Laboratory Medicine of China, Hefei, Anhui, 230001, China
| | - Panpan Jiang
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, China; Department of Laboratory Medicine, Anhui Provincial Cancer Hospital, Hefei, Anhui, 230031, China
| | - Chunyang Dai
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, China; Department of Laboratory Medicine, Anhui Provincial Cancer Hospital, Hefei, Anhui, 230031, China; Core Unit of National Clinical Research Center for Laboratory Medicine of China, Hefei, Anhui, 230001, China
| | - Ming Li
- Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, China; Department of Laboratory Medicine, Anhui Provincial Cancer Hospital, Hefei, Anhui, 230031, China; Core Unit of National Clinical Research Center for Laboratory Medicine of China, Hefei, Anhui, 230001, China.
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Kalluri R. The biology and function of extracellular vesicles in immune response and immunity. Immunity 2024; 57:1752-1768. [PMID: 39142276 PMCID: PMC11401063 DOI: 10.1016/j.immuni.2024.07.009] [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: 04/13/2023] [Revised: 01/02/2024] [Accepted: 07/15/2024] [Indexed: 08/16/2024]
Abstract
Extracellular vesicles (EVs), such as ectosomes and exosomes, contain DNA, RNA, proteins and are encased in a phospholipid bilayer. EVs provide intralumenal cargo for delivery into the cytoplasm of recipient cells with an impact on the function of immune cells, in part because their biogenesis can also intersect with antigen processing and presentation. Motile EVs from activated immune cells may increase the frequency of immune synapses on recipient cells in a proximity-independent manner for local and long-distance modulation of systemic immunity in inflammation, autoimmunity, organ fibrosis, cancer, and infections. Natural and engineered EVs exhibit the ability to impact innate and adaptive immunity and are entering clinical trials. EVs are likely a component of an optimally functioning immune system, with the potential to serve as immunotherapeutics. Considering the evolving evidence, it is possible that EVs could be the original primordial organic units that preceded the creation of the first cell.
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Affiliation(s)
- Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Bioengineering, Rice University, Houston, TX, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
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Menay F, Cocozza F, Gravisaco MJ, Elisei A, Re JI, Ferella A, Waldner C, Mongini C. Extracellular vesicles derived from antigen-presenting cells pulsed with foot and mouth virus vaccine-antigens act as carriers of viral proteins and stimulate B cell response. Front Immunol 2024; 15:1440667. [PMID: 39176090 PMCID: PMC11338771 DOI: 10.3389/fimmu.2024.1440667] [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: 05/29/2024] [Accepted: 07/23/2024] [Indexed: 08/24/2024] Open
Abstract
Foot and mouth disease (FMD) is a highly contagious infection caused by FMD-virus (FMDV) that affects livestock worldwide with significant economic impact. The main strategy for the control is vaccination with FMDV chemically inactivated with binary ethylenimine (FMDVi). In FMDV infection and vaccination, B cell response plays a major role by providing neutralizing/protective antibodies in animal models and natural hosts. Extracellular vesicles (EVs) and small EVs (sEVs) such as exosomes are important in cellular communication. EVs secreted by antigen-presenting cells (APC) like dendritic cells (DCs) participate in the activation of B and T cells through the presentation of native antigen membrane-associated to B cells or by transferring MHC-peptide complexes to T cells and even complete antigens from DCs. In this study, we demonstrate for the first time that APC activated with the FMDVi O1 Campos vaccine-antigens secrete EVs expressing viral proteins/peptides that could stimulate FMDV-specific immune response. The secretion of EVs-FMDVi is a time-dependent process and can only be isolated within the first 24 h post-activation. These vesicles express classical EVs markers (CD9, CD81, and CD63), along with immunoregulatory molecules (MHC-II and CD86). With an average size of 155 nm, they belong to the category of EVs. Studies conducted in vitro have demonstrated that EVs-FMDVi express antigens that can stimulate a specific B cell response against FMDV, including both marginal zone B cells (MZB) and follicular B cells (FoB). These vesicles can also indirectly or directly affect T cells, indicating that they express both B and T epitopes. Additionally, lymphocyte expansion induced by EVs-FMDVi is greater in splenocytes that have previously encountered viral antigens in vivo. The present study sheds light on the role of EVs derived from APC in regulating the adaptive immunity against FMDV. This novel insight contributes to our current understanding of the immune mechanisms triggered by APC during the antiviral immune response. Furthermore, these findings may have practical implications for the development of new vaccine platforms, providing a rational basis for the design of more effective vaccines against FMDV and other viral diseases.
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Affiliation(s)
- Florencia Menay
- Laboratorio de Microvesículas, Exosomas y miRNA, Instituto de Virología y Innovaciones Tecnológicas (IVIT)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Instituto Nacional de Tecnología Agropecuaria (INTA), Hurlingham, Buenos Aires, Argentina
- Centro de Investigación en Ciencias Veterinarias y Agronómicas (CICVYA), Instituto Nacional de Tecnología Agropecuaria (INTA), Hurlingham, Buenos Aires, Argentina
| | - Federico Cocozza
- Institut National de la Santé et de la Recherche Médicale (INSERM-U932), Institut Curie, París, France
| | - Maria J. Gravisaco
- Centro de Investigación en Ciencias Veterinarias y Agronómicas (CICVYA), Instituto Nacional de Tecnología Agropecuaria (INTA), Hurlingham, Buenos Aires, Argentina
| | - Analia Elisei
- Centro de Investigación en Ciencias Veterinarias y Agronómicas (CICVYA), Instituto Nacional de Tecnología Agropecuaria (INTA), Hurlingham, Buenos Aires, Argentina
- Departamento de Patología, Servicio Nacional de Salud y Calidad Agroalimentaria (SENASA), Martinez, Buenos Aires, Argentina
| | - Javier Ignacio Re
- Centro de Investigación en Ciencias Veterinarias y Agronómicas (CICVYA), Instituto Nacional de Tecnología Agropecuaria (INTA), Hurlingham, Buenos Aires, Argentina
| | - Alejandra Ferella
- Laboratorio de Microvesículas, Exosomas y miRNA, Instituto de Virología y Innovaciones Tecnológicas (IVIT)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Instituto Nacional de Tecnología Agropecuaria (INTA), Hurlingham, Buenos Aires, Argentina
- Centro de Investigación en Ciencias Veterinarias y Agronómicas (CICVYA), Instituto Nacional de Tecnología Agropecuaria (INTA), Hurlingham, Buenos Aires, Argentina
| | - Claudia Waldner
- Laboratorio de Inmunología Celular y Molecular, Centro de Estudios Farmacologicos y Botanicos (CEFYBO) CONICET, Ciudad Autónoma de Buenos Aires, Argentina
| | - Claudia Mongini
- Laboratorio de Microvesículas, Exosomas y miRNA, Instituto de Virología y Innovaciones Tecnológicas (IVIT)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Instituto Nacional de Tecnología Agropecuaria (INTA), Hurlingham, Buenos Aires, Argentina
- Centro de Investigación en Ciencias Veterinarias y Agronómicas (CICVYA), Instituto Nacional de Tecnología Agropecuaria (INTA), Hurlingham, Buenos Aires, Argentina
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Wu X, Niu J, Shi Y. Exosomes target HBV-host interactions to remodel the hepatic immune microenvironment. J Nanobiotechnology 2024; 22:315. [PMID: 38840207 PMCID: PMC11151510 DOI: 10.1186/s12951-024-02544-y] [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: 11/21/2023] [Accepted: 05/09/2024] [Indexed: 06/07/2024] Open
Abstract
Chronic hepatitis B poses a significant global burden, modulating immune cells, leading to chronic inflammation and long-term damage. Due to its hepatotropism, the hepatitis B virus (HBV) cannot infect other cells. The mechanisms underlying the intercellular communication among different liver cells in HBV-infected individuals and the immune microenvironment imbalance remain elusive. Exosomes, as important intercellular communication and cargo transportation tools between HBV-infected hepatocytes and immune cells, have been shown to assist in HBV cargo transportation and regulate the immune microenvironment. However, the role of exosomes in hepatitis B has only gradually received attention in recent years. Minimal literature has systematically elaborated on the role of exosomes in reshaping the immune microenvironment of the liver. This review unfolds sequentially based on the biological processes of exosomes: exosomes' biogenesis, release, transport, uptake by recipient cells, and their impact on recipient cells. We delineate how HBV influences the biogenesis of exosomes, utilizing exosomal covert transmission, and reshapes the hepatic immune microenvironment. And based on the characteristics and functions of exosomes, potential applications of exosomes in hepatitis B are summarized and predicted.
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Affiliation(s)
- Xiaojing Wu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, 130021, People's Republic of China
| | - Junqi Niu
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, 130021, People's Republic of China.
| | - Ying Shi
- Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, The First Hospital of Jilin University, Changchun, Jilin, 130021, People's Republic of China.
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Tiwari P, Yadav K, Shukla RP, Bakshi AK, Panwar D, Das S, Mishra PR. Extracellular vesicles-powered immunotherapy: Unleashing the potential for safer and more effective cancer treatment. Arch Biochem Biophys 2024; 756:110022. [PMID: 38697343 DOI: 10.1016/j.abb.2024.110022] [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: 03/20/2024] [Revised: 04/29/2024] [Accepted: 04/29/2024] [Indexed: 05/04/2024]
Abstract
Cancer treatment has seen significant advancements with the introduction of Onco-immunotherapies (OIMTs). Although some of these therapies have received approval for use, others are either undergoing testing or are still in the early stages of development. Challenges persist in making immunotherapy widely applicable to cancer treatment. To maximize the benefits of immunotherapy and minimize potential side effects, it's essential to improve response rates across different immunotherapy methods. A promising development in this area is the use of extracellular vesicles (EVs) as novel delivery systems. These small vesicles can effectively deliver immunotherapies, enhancing their effectiveness and reducing harmful side effects. This article discusses the importance of integrating nanomedicines into OIMTs, highlighting the challenges with current anti-OIMT methods. It also explores key considerations for designing nanomedicines tailored for OIMTs, aiming to improve upon existing immunotherapy techniques. Additionally, the article looks into innovative approaches like biomimicry and the use of natural biomaterial-based nanocarriers (NCs). These advancements have the potential to transform the delivery of immunotherapy. Lastly, the article addresses the challenges of moving OIMTs from theory to clinical practice, providing insights into the future of using advanced nanotechnology in cancer treatment.
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Affiliation(s)
- Pratiksha Tiwari
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India; Jawaharlal Nehru University, New Delhi, India
| | - Krishna Yadav
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Ravi Prakash Shukla
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Avijit Kumar Bakshi
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Dilip Panwar
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Sweety Das
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India
| | - Prabhat Ranjan Mishra
- Division of Pharmaceutics and Pharmacokinetics, CSIR-Central Drug Research Institute Lucknow, India; Academy of Scientific and Innovation Research (AcSIR), Ghaziabad, 201002, U.P., India.
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11
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Pordanjani PM, Bolhassani A, Pouriayevali MH, Milani A, Rezaei F. Engineered dendritic cells-derived exosomes harboring HIV-1 Nef mut-Tat fusion protein and heat shock protein 70: A promising HIV-1 safe vaccine candidate. Int J Biol Macromol 2024; 270:132236. [PMID: 38768924 DOI: 10.1016/j.ijbiomac.2024.132236] [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: 03/23/2024] [Revised: 05/04/2024] [Accepted: 05/07/2024] [Indexed: 05/22/2024]
Abstract
Antigen presenting cells (APCs)-derived exosomes are nano-vesicles that can induce antigen-specific T cell responses, and possess therapeutic effects in clinical settings. Moreover, dendritic cells (DCs)-based vaccines have been developed to combat human immunodeficiency virus-1 (HIV-1) infection in preclinical and clinical trials. We investigated the immunostimulatory effects (B- and T-cells activities) of DCs- and exosomes-based vaccine constructs harboring HIV-1 Nefmut-Tat fusion protein as an antigen candidate and heat shock protein 70 (Hsp70) as an adjuvant in mice. The modified DCs and engineered exosomes harboring Nefmut-Tat protein or Hsp70 were prepared using lentiviral vectors compared to electroporation, characterized and evaluated by in vitro and in vivo immunological tests. Our data indicated that the engineered exosomes induced high levels of total IgG, IgG2a, IFN-γ, TNF-α and Granzyme B. Moreover, co-injection of exosomes harboring Hsp70 could significantly increase the secretion of antibodies, cytokines and Granzyme B. The highest levels of IFN-γ and TNF-α were observed in exosomes harboring Nefmut-Tat combined with exosomes harboring Hsp70 (Exo-Nefmut-Tat + Exo-Hsp70) regimen after single-cycle replicable (SCR) HIV-1 exposure. Generally, Exo-Nefmut-Tat + Exo-Hsp70 regimen can be considered as a promising safe vaccine candidate due to high T-cells (Th1 and CTL) activity and its maintenance against SCR HIV-1 exposure.
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Affiliation(s)
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran.
| | - Mohammad Hassan Pouriayevali
- Department of Arboviruses and Viral Hemorrhagic Fevers (National Reference Laboratory), Pasteur Institute of Iran, Tehran, Iran
| | - Alireza Milani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran; Iranian Comprehensive Hemophilia Care Center, Tehran, Iran
| | - Fatemeh Rezaei
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
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12
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Gong T, Liu YT, Fan J. Exosomal mediators in sepsis and inflammatory organ injury: unraveling the role of exosomes in intercellular crosstalk and organ dysfunction. Mil Med Res 2024; 11:24. [PMID: 38644472 PMCID: PMC11034107 DOI: 10.1186/s40779-024-00527-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 04/02/2024] [Indexed: 04/23/2024] Open
Abstract
Sepsis, a severe systemic inflammatory response to infection, remains a leading cause of morbidity and mortality worldwide. Exosomes, as mediators of intercellular communication, play a pivotal role in the pathogenesis of sepsis through modulating immune responses, metabolic reprogramming, coagulopathy, and organ dysfunction. This review highlights the emerging significance of exosomes in these processes. Initially, it provides an in-depth insight into exosome biogenesis and characterization, laying the groundwork for understanding their diverse and intricate functions. Subsequently, it explores the regulatory roles of exosomes in various immune cells such as neutrophils, macrophages, dendritic cells, T cells, and B cells. This analysis elucidates how exosomes are pivotal in modulating immune responses, thus contributing to the complexity of sepsis pathophysiology. Additionally, this review delves into the role of exosomes in the regulation of metabolism and subsequent organ dysfunction in sepsis. It also establishes a connection between exosomes and the coagulation cascade, which affects endothelial integrity and promotes thrombogenesis in sepsis. Moreover, the review discusses the dual role of exosomes in the progression and resolution of sepsis, exploring their complex involvement in inflammation and healing processes. Furthermore, it underscores their potential as biomarkers and therapeutic targets. Understanding these mechanisms presents new opportunities for novel interventions to mitigate the severe outcomes of sepsis, emphasizing the therapeutic promise of exosome research in critical care settings.
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Affiliation(s)
- Ting Gong
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangzhou, 518110, China.
| | - You-Tan Liu
- Department of Anesthesiology, Shenzhen Hospital, Southern Medical University, Shenzhen, Guangzhou, 518110, China
| | - Jie Fan
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, PA, 15240, USA.
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA.
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA, 15219, USA.
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13
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Mobasher M, Ansari R, Castejon AM, Barar J, Omidi Y. Advanced nanoscale delivery systems for mRNA-based vaccines. Biochim Biophys Acta Gen Subj 2024; 1868:130558. [PMID: 38185238 DOI: 10.1016/j.bbagen.2024.130558] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 12/24/2023] [Accepted: 01/02/2024] [Indexed: 01/09/2024]
Abstract
The effectiveness of messenger RNA (mRNA) vaccines, especially those designed for COVID-19, relies heavily on sophisticated delivery systems that ensure efficient delivery of mRNA to target cells. A variety of nanoscale vaccine delivery systems (VDSs) have been explored for this purpose, including lipid nanoparticles (LNPs), liposomes, and polymeric nanoparticles made from biocompatible polymers such as poly(lactic-co-glycolic acid), as well as viral vectors and lipid-polymer hybrid complexes. Among these, LNPs are particularly notable for their efficiency in encapsulating and protecting mRNA. These nanoscale VDSs can be engineered to enhance stability and facilitate uptake by cells. The choice of delivery system depends on factors like the specific mRNA vaccine, target cell types, stability requirements, and desired immune response. In this review, we shed light on recent advances in delivery mechanisms for self-amplifying RNA (saRNA) vaccines, emphasizing groundbreaking studies on nanoscale delivery systems aimed at improving the efficacy and safety of mRNA/saRNA vaccines.
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Affiliation(s)
- Maha Mobasher
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Rais Ansari
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Ana M Castejon
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Jaleh Barar
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA
| | - Yadollah Omidi
- Department of Pharmaceutical Sciences, Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA.
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Abstract
Extracellular vesicles (EVs) are membrane-bound structures released by cells and have become significant players in immune system functioning, primarily by facilitating cell-to-cell communication. Immune cells like neutrophils and dendritic cells release EVs containing bioactive molecules that modulate chemotaxis, activate immune cells, and induce inflammation. EVs also contribute to antigen presentation, lymphocyte activation, and immune tolerance. Moreover, EVs play pivotal roles in antimicrobial host defense. They deliver microbial antigens to antigen-presenting cells (APCs), triggering immune responses, or act as decoys to neutralize virulence factors and toxins. This review discusses host and microbial EVs' multifaceted roles in innate and adaptive immunity, highlighting their involvement in immune cell development, antigen presentation, and antimicrobial responses.
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Affiliation(s)
- Puja Kumari
- Department of Immunology, University of Connecticut Health School of Medicine, 263 Farmington Ave, Farmington, CT 06030, USA
| | - Skylar S. Wright
- Department of Immunology, University of Connecticut Health School of Medicine, 263 Farmington Ave, Farmington, CT 06030, USA
| | - Vijay A. Rathinam
- Department of Immunology, University of Connecticut Health School of Medicine, 263 Farmington Ave, Farmington, CT 06030, USA
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15
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Zhang J, Wu J, Wang G, He L, Zheng Z, Wu M, Zhang Y. Extracellular Vesicles: Techniques and Biomedical Applications Related to Single Vesicle Analysis. ACS NANO 2023; 17:17668-17698. [PMID: 37695614 DOI: 10.1021/acsnano.3c03172] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/12/2023]
Abstract
Extracellular vesicles (EVs) are extensively dispersed lipid bilayer membrane vesicles involved in the delivery and transportation of molecular payloads to certain cell types to facilitate intercellular interactions. Their significant roles in physiological and pathological processes make EVs outstanding biomarkers for disease diagnosis and treatment monitoring as well as ideal candidates for drug delivery. Nevertheless, differences in the biogenesis processes among EV subpopulations have led to a diversity of biophysical characteristics and molecular cargos. Additionally, the prevalent heterogeneity of EVs has been found to substantially hamper the sensitivity and accuracy of disease diagnosis and therapeutic monitoring, thus impeding the advancement of clinical applications. In recent years, the evolution of single EV (SEV) analysis has enabled an in-depth comprehension of the physical properties, molecular composition, and biological roles of EVs at the individual vesicle level. This review examines the sample acquisition tactics prior to SEV analysis, i.e., EV isolation techniques, and outlines the current state-of-the-art label-free and label-based technologies for SEV identification. Furthermore, the challenges and prospects of biomedical applications based on SEV analysis are systematically discussed.
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Affiliation(s)
- Jie Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Jiacheng Wu
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Guanzhao Wang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Luxuan He
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Ziwei Zheng
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
| | - Minhao Wu
- Department of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, P. R. China
| | - Yuanqing Zhang
- Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, P. R. China
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16
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Tiberti N, Longoni SS, Combes V, Piubelli C. Host-Derived Extracellular Vesicles in Blood and Tissue Human Protozoan Infections. Microorganisms 2023; 11:2318. [PMID: 37764162 PMCID: PMC10536481 DOI: 10.3390/microorganisms11092318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/08/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
Blood and tissue protozoan infections are responsible for an enormous burden in tropical and subtropical regions, even though they can also affect people living in high-income countries, mainly as a consequence of migration and travel. These pathologies are responsible for heavy socio-economic issues in endemic countries, where the lack of proper therapeutic interventions and effective vaccine strategies is still hampering their control. Moreover, the pathophysiological mechanisms associated with the establishment, progression and outcome of these infectious diseases are yet to be fully described. Among all the players, extracellular vesicles (EVs) have raised significant interest during the last decades due to their capacity to modulate inter-parasite and host-parasite interactions. In the present manuscript, we will review the state of the art of circulating host-derived EVs in clinical samples or in experimental models of human blood and tissue protozoan diseases (i.e., malaria, leishmaniasis, Chagas disease, human African trypanosomiasis and toxoplasmosis) to gain novel insights into the mechanisms of pathology underlying these conditions and to identify novel potential diagnostic markers.
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Affiliation(s)
- Natalia Tiberti
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar di Valpolicella, Italy; (S.S.L.); (C.P.)
| | - Silvia Stefania Longoni
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar di Valpolicella, Italy; (S.S.L.); (C.P.)
| | - Valéry Combes
- Microvesicles and Malaria Research Group, School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia;
| | - Chiara Piubelli
- Department of Infectious, Tropical Diseases and Microbiology, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar di Valpolicella, Italy; (S.S.L.); (C.P.)
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17
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Wang X, Xia J, Yang L, Dai J, He L. Recent progress in exosome research: isolation, characterization and clinical applications. Cancer Gene Ther 2023; 30:1051-1065. [PMID: 37106070 DOI: 10.1038/s41417-023-00617-y] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 03/22/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023]
Abstract
Exosomes, a kind of nano-vesicles released by various cell types, carry a variety of "cargos" including proteins, RNAs, DNAs and lipids. There is substantial evidence that exosomes are involved in intercellular communication by exchanging "cargos" among cells and play important roles in cancer development. Because of the different expressions of "cargos" carried by exosomes in biological fluids under physiological and pathological conditions, exosomes have the potential as a minimally invasive method of liquid biopsy for cancer diagnosis and prognosis. In addition, due to their good biocompatibility, safety, biodistribution and low immunogenicity, exosomes also have potential applications in the development of promising cancer treatment methods. In this review, we summarize the recent progress in the isolation and characterization techniques of exosomes. Moreover, we review the biological functions of exosomes in regulating tumor metastasis, drug resistance and immune regulation during cancer development and outline the applications of exosomes in cancer therapy.
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Affiliation(s)
- Xi Wang
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Jingyi Xia
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China
| | - Lei Yang
- Department of Pharmacy, The people's hospital of jianyang city, Jianyang, 641400, China
| | - Jingying Dai
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
| | - Lin He
- Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, China.
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18
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Luo S, Chen J, Xu F, Chen H, Li Y, Li W. Dendritic Cell-Derived Exosomes in Cancer Immunotherapy. Pharmaceutics 2023; 15:2070. [PMID: 37631284 PMCID: PMC10457773 DOI: 10.3390/pharmaceutics15082070] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 07/21/2023] [Accepted: 07/25/2023] [Indexed: 08/27/2023] Open
Abstract
Exosomes are nanoscale vesicles released by diverse types of cells for complex intercellular communication. Numerous studies have shown that exosomes can regulate the body's immune response to tumor cells and interfere with the tumor microenvironment (TME). In clinical trials on dendritic cell (DC)-based antitumor vaccines, no satisfactory results have been achieved. However, recent studies suggested that DC-derived exosomes (DEXs) may be superior to DC-based antitumor vaccines in avoiding tumor cell-mediated immunosuppression. DEXs contain multiple DC-derived surface markers that capture tumor-associated antigens (TAAs) and promote immune cell-dependent tumor rejection. These findings indicate the necessity of the further development and improvement of DEX-based cell-free vaccines to complement chemotherapy, radiotherapy, and other immunotherapies. In this review, we highlighted the recent progress of DEXs in cancer immunotherapy, particularly by concentrating on landmark studies and the biological characterization of DEXs, and we summarized their important role in the tumor immune microenvironment (TIME) and clinical application in targeted cancer immunotherapy. This review could enhance comprehension of advances in cancer immunotherapy and contribute to the elucidation of how DEXs regulate the TIME, thereby providing a reference for utilizing DEX-based vaccines in clinical practice.
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Affiliation(s)
- Shumin Luo
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
| | - Jing Chen
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
| | - Fang Xu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
| | - Huan Chen
- Integrated Chinese and Western Medicine Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China;
| | - Yiru Li
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
| | - Weihua Li
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China; (S.L.); (J.C.); (F.X.); (Y.L.)
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19
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Xiong J, Chi H, Yang G, Zhao S, Zhang J, Tran LJ, Xia Z, Yang F, Tian G. Revolutionizing anti-tumor therapy: unleashing the potential of B cell-derived exosomes. Front Immunol 2023; 14:1188760. [PMID: 37342327 PMCID: PMC10277631 DOI: 10.3389/fimmu.2023.1188760] [Citation(s) in RCA: 41] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/22/2023] [Indexed: 06/22/2023] Open
Abstract
B cells occupy a vital role in the functioning of the immune system, working in tandem with T cells to either suppress or promote tumor growth within the tumor microenvironment(TME). In addition to direct cell-to-cell communication, B cells and other cells release exosomes, small membrane vesicles ranging in size from 30-150 nm, that facilitate intercellular signaling. Exosome research is an important development in cancer research, as they have been shown to carry various molecules such as major histocompatibility complex(MHC) molecules and integrins, which regulate the TME. Given the close association between TME and cancer development, targeting substances within the TME has emerged as a promising strategy for cancer therapy. This review aims to present a comprehensive overview of the contributions made by B cells and exosomes to the tumor microenvironment (TME). Additionally, we delve into the potential role of B cell-derived exosomes in the progression of cancer.
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Affiliation(s)
- Jingwen Xiong
- Department of Sports Rehabilitation, Southwest Medical University, Luzhou, China
| | - Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH, United States
| | - Songyun Zhao
- Department of Neurosurgery, Wuxi People’s Hospital Affiliated to Nanjing Medical University, Wuxi, China
| | - Jing Zhang
- Division of Basic Biomedical Sciences, The University of South Dakota Sanford School of Medicine, Vermillion, SD, United States
| | - Lisa Jia Tran
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Zhijia Xia
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Fang Yang
- Department of Ophthalmology, Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Gang Tian
- Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, China
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20
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Sako Y, Sato-Kaneko F, Shukla NM, Yao S, Belsuzarri MM, Chan M, Saito T, Lao FS, Kong H, Puffer M, Messer K, Pu M, Cottam HB, Carson DA, Hayashi T. Identification of a Novel Small Molecule That Enhances the Release of Extracellular Vesicles with Immunostimulatory Potency via Induction of Calcium Influx. ACS Chem Biol 2023; 18:982-993. [PMID: 37039433 PMCID: PMC10127211 DOI: 10.1021/acschembio.3c00134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 03/30/2023] [Indexed: 04/12/2023]
Abstract
Extracellular vesicles (EVs) transfer antigens and immunomodulatory molecules in immunologic synapses as a part of intracellular communication, and EVs equipped with immunostimulatory functions have been utilized for vaccine formulation. Hence, we sought small-molecule compounds that increase immunostimulatory EVs released by antigen-presenting dendritic cells (DCs) for enhancement of vaccine immunogenicity. We previously performed high-throughput screening on a 28K compound library using three THP-1 reporter cell lines with CD63 Turbo-Luciferase, NF-κB, and interferon-sensitive response element (ISRE) reporter constructs, respectively. Because intracellular Ca2+ elevation enhances EV release, we screened 80 hit compounds and identified compound 634 as a Ca2+ influx inducer. 634 enhanced EV release in murine bone marrow-derived dendritic cells (mBMDCs) and increased costimulatory molecule expression on the surface of EVs and the parent cells. EVs isolated from 634-treated mBMDCs induced T cell proliferation in the presence of antigenic peptides. To assess the roles of intracellular Ca2+ elevation in immunostimulatory EV release, we performed structure-activity relationship (SAR) studies of 634. The analogues that retained the ability to induce Ca2+ influx induced more EVs with immunostimulatory properties from mBMDCs than did those that lacked the ability to induce Ca2+ influx. The levels of Ca2+ induction of synthesized analogues correlated with the numbers of EVs released and costimulatory molecule expression on the parent cells. Collectively, our study presents that a small molecule, 634, enhances the release of EVs with immunostimulatory potency via induction of Ca2+ influx. This agent is a novel tool for EV-based immune studies and vaccine development.
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Affiliation(s)
- Yukiya Sako
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Fumi Sato-Kaneko
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Nikunj M. Shukla
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Shiyin Yao
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Masiel M. Belsuzarri
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Michael Chan
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Tetsuya Saito
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
- Department
of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo 113-8519, Japan
| | - Fitzgerald S. Lao
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Helen Kong
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Marina Puffer
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Karen Messer
- The
Herbert Wertheim School of Public Health and Longevity, University of California San Diego, La Jolla, California 92093-0901, United States
| | - Minya Pu
- The
Herbert Wertheim School of Public Health and Longevity, University of California San Diego, La Jolla, California 92093-0901, United States
| | - Howard B. Cottam
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Dennis A. Carson
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
| | - Tomoko Hayashi
- Moores
Cancer Center, University of California
San Diego, 9500 Gilman Dr, La Jolla, California 92093-0809, United States
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Plattner K, Bachmann MF, Vogel M. On the complexity of IgE: The role of structural flexibility and glycosylation for binding its receptors. FRONTIERS IN ALLERGY 2023; 4:1117611. [PMID: 37056355 PMCID: PMC10089267 DOI: 10.3389/falgy.2023.1117611] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/13/2023] [Indexed: 03/30/2023] Open
Abstract
It is well established that immunoglobulin E (IgE) plays a crucial role in atopy by binding to two types of Fcε receptors (FcεRI and FcεRII, also known as CD23). The cross-linking of FcεRI-bound IgE on effector cells, such as basophils and mast cells, initiates the allergic response. Conversely, the binding of IgE to CD23 modulates IgE serum levels and antigen presentation. In addition to binding to FcεRs, IgE can also interact with other receptors, such as certain galectins and, in mice, some FcγRs. The binding strength of IgE to its receptors is affected by its valency and glycosylation. While FcεRI shows reduced binding to IgE immune complexes (IgE-ICs), the binding to CD23 is enhanced. There is no evidence that galectins bind IgE-ICs. On the other hand, IgE glycosylation plays a crucial role in the binding to FcεRI and galectins, whereas the binding to CD23 seems to be independent of glycosylation. In this review, we will focus on receptors that bind to IgE and examine how the glycosylation and complexation of IgE impact their binding.
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Affiliation(s)
- Kevin Plattner
- Department of Immunology, University Clinic for Rheumatology and Immunology, University of Bern, Bern, Switzerland
- Department of Biomedical Research Bern (DBMR), University of Bern, Bern, Switzerland
| | - Martin F. Bachmann
- Department of Immunology, University Clinic for Rheumatology and Immunology, University of Bern, Bern, Switzerland
- Department of Biomedical Research Bern (DBMR), University of Bern, Bern, Switzerland
- Nuffield Department of Medicine, The Jenner Institute, University of Oxford, Oxford, United Kingdom
| | - Monique Vogel
- Department of Immunology, University Clinic for Rheumatology and Immunology, University of Bern, Bern, Switzerland
- Department of Biomedical Research Bern (DBMR), University of Bern, Bern, Switzerland
- Correspondence: Monique Vogel
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22
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Veerman RE, Akpinar GG, Offens A, Steiner L, Larssen P, Lundqvist A, Karlsson MCI, Gabrielsson S. Antigen-Loaded Extracellular Vesicles Induce Responsiveness to Anti-PD-1 and Anti-PD-L1 Treatment in a Checkpoint Refractory Melanoma Model. Cancer Immunol Res 2023; 11:217-227. [PMID: 36546872 PMCID: PMC9896027 DOI: 10.1158/2326-6066.cir-22-0540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Revised: 09/23/2022] [Accepted: 11/30/2022] [Indexed: 12/24/2022]
Abstract
Extracellular vesicles (EV) are important mediators of intercellular communication and are potential candidates for cancer immunotherapy. Immune checkpoint blockade, specifically targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis, mitigates T-cell exhaustion, but is only effective in a subset of patients with cancer. Reasons for therapy resistance include low primary T-cell activation to cancer antigens, poor antigen presentation, and reduced T-cell infiltration into the tumor. Therefore, combination strategies have been extensively explored. Here, we investigated whether EV therapy could induce susceptibility to anti-PD-1 or anti-PD-L1 therapy in a checkpoint-refractory B16 melanoma model. Injection of dendritic cell-derived EVs, but not checkpoint blockade, induced a potent antigen-specific T-cell response and reduced tumor growth in tumor-bearing mice. Combination therapy of EVs and anti-PD-1 or anti-PD-L1 potentiated immune responses to ovalbumin- and α-galactosylceramide-loaded EVs in the therapeutic model. Moreover, combination therapy resulted in increased survival in a prophylactic tumor model. This demonstrates that EVs can induce potent antitumor immune responses in checkpoint refractory cancer and induce anti-PD-1 or anti-PD-L1 responses in a previously nonresponsive tumor model.
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Affiliation(s)
- Rosanne E Veerman
- Division of Immunology and Allergy, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Gözde Güclüler Akpinar
- Division of Immunology and Allergy, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Annemarijn Offens
- Division of Immunology and Allergy, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Loïc Steiner
- Division of Immunology and Allergy, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Pia Larssen
- Division of Immunology and Allergy, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Andreas Lundqvist
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Mikael C I Karlsson
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Susanne Gabrielsson
- Division of Immunology and Allergy, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden.,Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
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Wang S, Shi Y. Exosomes Derived from Immune Cells: The New Role of Tumor Immune Microenvironment and Tumor Therapy. Int J Nanomedicine 2022; 17:6527-6550. [PMID: 36575698 PMCID: PMC9790146 DOI: 10.2147/ijn.s388604] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Accepted: 12/09/2022] [Indexed: 12/29/2022] Open
Abstract
Exosomes are small vesicles secreted by living cells, with a typical lipid bilayer structure. They carry a variety of proteins, lipids, RNA and other important information, play an important role in the transmission of substances and information between cells, and gradually become a marker for early diagnosis of many diseases and an important tool in drug delivery system. Immune cells are an important part of tumor microenvironment, and they can affect tumor progression by secreting a variety of immunoreactive substances. This review focuses on the effects of various immune cell-derived exosomes on tumor cells, different immune cells and other stromal cells in tumor microenvironment. Exosomes derived from different immune cells can not only reshape a pro-inflammatory microenvironment to inhibit tumor progression, but also promote tumor progression by inhibiting the killing effect of NK cells, CD8+T cells and other cells or promoting tumor cells and immunosuppressive immune cells. In addition, we also discussed that some exosomes derived from immune cells (such as DC, M1 macrophages and neutrophils) play a tumor inhibitory role after being engineered.
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Affiliation(s)
- Shiyang Wang
- Department of Geriatric Surgery, The First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China
| | - Yue Shi
- Department of Geriatric Surgery, The First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China,Correspondence: Yue Shi, Department of Geriatric Surgery, The First Hospital of China Medical University, Shenyang, 110001, People’s Republic of China, Tel +86-13842073309, Email
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24
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Raghav A, Ashraf H, Jeong GB. Engineered Extracellular Vesicles in Treatment of Type 1 Diabetes Mellitus: A Prospective Review. Biomedicines 2022; 10:3042. [PMID: 36551798 PMCID: PMC9775549 DOI: 10.3390/biomedicines10123042] [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] [Revised: 11/08/2022] [Accepted: 11/14/2022] [Indexed: 11/26/2022] Open
Abstract
Insulin replacement is an available treatment for autoimmune type 1 diabetes mellitus (T1DM). There are multiple limitations in the treatment of autoimmune diseases such as T1DM by immunosuppression using drugs and chemicals. The advent of extracellular vesicle (EV)-based therapies for the treatment of various diseases has attracted much attention to the field of bio-nanomedicine. Tolerogenic nanoparticles can induce immune tolerance, especially in autoimmune diseases. EVs can deliver cargo to specific cells without restrictions. Accordingly, EVs can be used to deliver tolerogenic nanoparticles, including iron oxide-peptide-major histocompatibility complex, polyethylene glycol-silver-2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester, and carboxylated poly (lactic-co-glycolic acid) nanoparticles coupled with or encapsulating an antigen, to effectively treat autoimmune T1DM. The present work highlights the advances in exosome-based delivery of tolerogenic nanoparticles for the treatment of autoimmune T1DM.
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Affiliation(s)
- Alok Raghav
- Multidisciplinary Research Unit, Sponsored by Department of Health Research, Ministry of Health and Family Welfare, GSVM Medical College, Kanpur 208002, India
| | - Hamid Ashraf
- Rajiv Gandhi Centre for Diabetes and Endocrinology, J.N. Medical College, Aligarh Muslim University, Aligarh 202002, India
| | - Goo-Bo Jeong
- Department of Anatomy and Cell Biology, College of Medicine, Gachon University, 155 Getbeol-ro Yeonsu-gu, Incheon 21999, Republic of Korea
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25
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de Almeida Fuzeta M, Gonçalves PP, Fernandes-Platzgummer A, Cabral JMS, Bernardes N, da Silva CL. From Promise to Reality: Bioengineering Strategies to Enhance the Therapeutic Potential of Extracellular Vesicles. Bioengineering (Basel) 2022; 9:675. [PMID: 36354586 PMCID: PMC9687169 DOI: 10.3390/bioengineering9110675] [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: 10/08/2022] [Revised: 10/31/2022] [Accepted: 11/03/2022] [Indexed: 11/13/2022] Open
Abstract
Extracellular vesicles (EVs) have been the focus of great attention over the last decade, considering their promising application as next-generation therapeutics. EVs have emerged as relevant mediators of intercellular communication, being associated with multiple physiological processes, but also in the pathogenesis of several diseases. Given their natural ability to shuttle messages between cells, EVs have been explored both as inherent therapeutics in regenerative medicine and as drug delivery vehicles targeting multiple diseases. However, bioengineering strategies are required to harness the full potential of EVs for therapeutic use. For that purpose, a good understanding of EV biology, from their biogenesis to the way they are able to shuttle messages and establish interactions with recipient cells, is needed. Here, we review the current state-of-the-art on EV biology, complemented by representative examples of EVs roles in several pathophysiological processes, as well as the intrinsic therapeutic properties of EVs and paradigmatic strategies to produce and develop engineered EVs as next-generation drug delivery systems.
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Affiliation(s)
- Miguel de Almeida Fuzeta
- iBB–Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB–Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Pedro P. Gonçalves
- iBB–Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB–Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Ana Fernandes-Platzgummer
- iBB–Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB–Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Joaquim M. S. Cabral
- iBB–Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB–Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Nuno Bernardes
- iBB–Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB–Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
| | - Cláudia L. da Silva
- iBB–Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
- Associate Laboratory i4HB–Institute for Health and Bioeconomy at Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal
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Qian K, Fu W, Li T, Zhao J, Lei C, Hu S. The roles of small extracellular vesicles in cancer and immune regulation and translational potential in cancer therapy. J Exp Clin Cancer Res 2022; 41:286. [PMID: 36167539 PMCID: PMC9513874 DOI: 10.1186/s13046-022-02492-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 09/08/2022] [Indexed: 11/23/2022] Open
Abstract
Extracellular vesicles (EVs) facilitate the extracellular transfer of proteins, lipids, and nucleic acids and mediate intercellular communication among multiple cells in the tumour environment. Small extracellular vesicles (sEVs) are defined as EVs range in diameter from approximately 50 to 150 nm. Tumour-derived sEVs (TDsEVs) and immune cell-derived sEVs have significant immunological activities and participate in cancer progression and immune responses. Cancer-specific molecules have been identified on TDsEVs and can function as biomarkers for cancer diagnosis and prognosis, as well as allergens for TDsEVs-based vaccination. Various monocytes, including but not limited to dendritic cells (DCs), B cells, T cells, natural killer (NK) cells, macrophages, and myeloid-derived suppressor cells (MDSCs), secrete sEVs that regulate immune responses in the complex immune network with either protumour or antitumour effects. After engineered modification, sEVs from immune cells and other donor cells can provide improved targeting and biological effects. Combined with their naïve characteristics, these engineered sEVs hold great potential as drug carriers. When used in a variety of cancer therapies, they can adjunctly enhance the safety and antitumor efficacy of multiple therapeutics. In summary, both naïve sEVs in the tumour environment and engineered sEVs with effector cargoes are regarded as showing promising potential for use in cancer diagnostics and therapeutics.
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27
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Exosomes and cancer - Diagnostic and prognostic biomarkers and therapeutic vehicle. Oncogenesis 2022; 11:54. [PMID: 36109501 PMCID: PMC9477829 DOI: 10.1038/s41389-022-00431-5] [Citation(s) in RCA: 112] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 08/24/2022] [Accepted: 08/26/2022] [Indexed: 11/08/2022] Open
Abstract
AbstractExosomes belong to a subpopulation of extracellular vesicles secreted by the dynamic multistep endocytosis process and carry diverse functional molecular cargoes, including proteins, lipids, nucleic acids (DNA, messenger and noncoding RNA), and metabolites to promote intercellular communication. Proteins and noncoding RNA are among the most abundant contents in exosomes; they have biological functions and are selectively packaged into exosomes. Exosomes derived from tumor, stromal and immune cells contribute to the multiple stages of cancer progression as well as resistance to therapy. In this review, we will discuss the biogenesis of exosomes and their roles in cancer development. Since specific contents within exosomes originate from their cells of origin, this property allows exosomes to function as valuable biomarkers. We will also discuss the potential use of exosomes as diagnostic and prognostic biomarkers or predictors for different therapeutic strategies for multiple cancers. Furthermore, the applications of exosomes as direct therapeutic targets or engineered vehicles for drugs are an important field of exosome study. Better understanding of exosome biology may pave the way to promising exosome-based clinical applications.
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Abstract
The twenty-first century has witnessed major developments in the field of extracellular vesicle (EV) research, including significant steps towards defining standard criteria for the separation and detection of EVs. The recent recognition that EVs have the potential to function as biomarkers or as therapeutic tools has attracted even greater attention to their study. With this progress in mind, an updated comprehensive overview of the roles of EVs in the immune system is timely. This Review summarizes the roles of EVs in basic processes of innate and adaptive immunity, including inflammation, antigen presentation, and the development and activation of B cells and T cells. It also highlights key progress related to deciphering the roles of EVs in antimicrobial defence and in allergic, autoimmune and antitumour immune responses. It ends with a focus on the relevance of EVs to immunotherapy and vaccination, drawing attention to ongoing or recently completed clinical trials that aim to harness the therapeutic potential of EVs.
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29
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Xia J, Miao Y, Wang X, Huang X, Dai J. Recent progress of dendritic cell-derived exosomes (Dex) as an anti-cancer nanovaccine. Biomed Pharmacother 2022; 152:113250. [PMID: 35700679 DOI: 10.1016/j.biopha.2022.113250] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 05/27/2022] [Accepted: 06/02/2022] [Indexed: 11/02/2022] Open
Abstract
Although cancer vaccines such as dendritic cell (DC) vaccines and peptide vaccines have become appealing and attractive anticancer immunotherapy options in recent decades, some obstacles have hindered their successful application in the clinical setting. The difficulties associated with the high cost of DC preparation, storage of DC vaccines, tumor-mediated immunosuppressive environment, identification of specific tumor antigens, and high degradation of antigen peptides in vivo limit the clinical application and affect the outcomes of these cancer vaccines. Recently, nanocarriers have been considered as a new approach for vaccine delivery. As biogenic nanocarriers, exosomes are small membrane vesicles secreted by cells that carry various proteins, RNAs, and lipids. More importantly, DC-derived exosomes (Dex) express tumor antigens, MHC molecules, and co-stimulatory molecules on their surface, which trigger the release of antigen-specific CD4+ and CD8+ T cells. With their membrane structure, Dex can avoid high degradation while ensuring favorable biocompatibility and biosafety in vivo. In addition, Dex can be stored in vitro for a longer period, which facilitates a significant reduction in production costs. Furthermore, they have shown better antitumor efficacy in preclinical studies compared with DC vaccines owing to their higher immunogenicity and stronger resistance to immunosuppressive effects. However, the clinical efficacy of Dex vaccines remains limited. In this review, we aimed to evaluate the efficacy of Dex as an anticancer nanovaccine.
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Affiliation(s)
- Jingyi Xia
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
| | - Yangbao Miao
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
| | - Xi Wang
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
| | - Xiaobing Huang
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
| | - Jingying Dai
- Department of Hematology, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine of University of Electronic Science and Technology of China, No. 32, West Section 2, First Ring Road, Qingyang District, Chengdu 610000, China.
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30
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Du Z, Huang Z, Chen X, Jiang G, Peng Y, Feng W, Huang N. Modified dendritic cell-derived exosomes activate both NK cells and T cells through the NKG2D/NKG2D-L pathway to kill CML cells with or without T315I mutation. Exp Hematol Oncol 2022; 11:36. [PMID: 35672796 PMCID: PMC9172178 DOI: 10.1186/s40164-022-00289-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 05/22/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Tyrosine kinase inhibitors have achieved quite spectacular advances in the treatment of chronic myeloid leukemia (CML), but disease progression and drug resistance that related to the T315I mutation, remain major obstacles. Dendritic cell-derived exosomes (Dex) induce NK cell immunity, but have yet to achieve satisfactory clinical efficacy. An approach to potentiate antitumor immunity by inducing both NK- and T-cell activation is urgently needed. Retinoic acid early inducible-1γ (RAE-1γ), a major ligand of natural killer group 2 member D (NKG2D), plays an important role in NK-cell and T-lymphocyte responses. We generated RAE-1γ enriched CML-specific Dex (CML-RAE-1γ-Dex) from dendritic cells (DCs) pulsed with lysates of RAE-1γ-expressing CML cells or T315I-mutant CML cells, aiming to simultaneously activate NK cells and T lymphocytes. METHODS We generated novel CML-RAE-1γ-Dex vaccines, which expressed RAE-1γ, and were loaded with CML tumor cell lysates. NK cells or T lymphocytes were coincubated with CML-RAE-1γ-Dex vaccines. Flow cytometry was performed to evaluate the activation and proliferation of these immune cells. Cytokine production and cytotoxicity toward CML cells with or without the T315I mutation were detected by ELISPOT, ELISA and LDH assays. CML models induced by BCR-ABL or BCR-ABLT315I were used to determine the immunological function of Dex in vivo. RESULTS Herein, CML-RAE-1γ-Dex were prepared. CML-RAE-1γ-Dex effectively enhanced the proliferation and effector functions of NK cells, CD4+ T cells and CD8+ T cells, which in turn produced strong anti-CML efficacy in vitro. Moreover, CML-RAE-1γ-Dex-based immunotherapy inhibited leukemogenesis and generated durable immunological memory in CML mouse models. Similar immune responses were also observed with imatinib-resistant CML cells carrying the T315I mutation. CONCLUSIONS This approach based on CML-RAE-1γ-Dex vaccines may be a promising strategy for CML treatment, especially for cases with the T315I mutation.
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Affiliation(s)
- Zhuanyun Du
- Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated By Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Zhenglan Huang
- Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated By Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Xi Chen
- Center for Clinical Molecular Medicine, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Guoyun Jiang
- Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated By Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Yuhang Peng
- Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated By Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, China
| | - Wenli Feng
- Department of Clinical Hematology, Key Laboratory of Laboratory Medical Diagnostics Designated By Ministry of Education, School of Laboratory Medicine, Chongqing Medical University, No.1, Yixueyuan Road, Yuzhong District, Chongqing, 400016, China.
| | - Ningshu Huang
- Department of Clinical Laboratory, Chongqing Key Laboratory of Pediatrics, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
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Lu J, Wei N, Zhu S, Chen X, Gong H, Mi R, Huang Y, Chen Z, Li G. Exosomes Derived From Dendritic Cells Infected With Toxoplasma gondii Show Antitumoral Activity in a Mouse Model of Colorectal Cancer. Front Oncol 2022; 12:899737. [PMID: 35600363 PMCID: PMC9114749 DOI: 10.3389/fonc.2022.899737] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Accepted: 04/11/2022] [Indexed: 11/17/2022] Open
Abstract
Pathogen-based cancer therapies have been widely studied. Parasites, such as Toxoplasma gondii have elicited great interest in cancer therapy. Considering safety in clinical applications, we tried to develop an exosome-based immunomodulator instead of a live parasite for tumor treatment. The exosomes, called DC-Me49-exo were isolated from culture supernatants of dendritic cells (DCs) infected with the Me49 strain of T. gondii and identified. We assessed the antitumoral effect of these exosomes in a mouse model of colorectal cancer (CRC). Results showed that the tumor growth was significantly inhibited after treatment with DC-Me49-exo. Proportion of polymorphonuclear granulocytic bone marrow-derived suppressor cells (G-MDSCs, CD11b+Ly6G+) and monocytic myeloid-derived suppressor cells (M-MDSCs, CD11b+Ly6C+) were decreased in the DC-Me49-exo group compared with the control groups in vitro and in vivo. The proportion of DCs (CD45+CD11c+) increased significantly in the DC-Me49-exo group. Levels of interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly decreased after treatment with DC-Me49-exo. Furthermore, we found that DC-Me49-exo regulated the lever of MDSC mainly by inhibiting the signal transducer and activator of transcription (STAT3) signaling pathway. These results indicated that exosomes derived from DCs infected with T. gondii could be used as part of a novel cancer therapeutic strategy by reducing the proportion of MDSCs.
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Affiliation(s)
- Jinmiao Lu
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.,Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Nana Wei
- Key Laboratory of Adolescent Health Assessment and Exercise Intervention of Ministry of Education, East China Normal University, Shanghai, China
| | - Shilan Zhu
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.,Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Xiaoyu Chen
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China.,Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Haiyan Gong
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Rongsheng Mi
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Yan Huang
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Zhaoguo Chen
- Key Laboratory of Animal Parasitology of Ministry of Agriculture, Laboratory of Quality and Safety Risk Assessment for Animal Products on Biohazards (Shanghai) of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China
| | - Guoqing Li
- Guangdong Provincial Key Laboratory of Zoonosis Prevention and Control, College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
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Ngai HW, Kim DH, Hammad M, Gutova M, Aboody K, Cox CD. Stem Cell-based therapies for COVID-19-related acute respiratory distress syndrome. J Cell Mol Med 2022; 26:2483-2504. [PMID: 35426198 PMCID: PMC9077311 DOI: 10.1111/jcmm.17265] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 02/24/2022] [Accepted: 02/28/2022] [Indexed: 11/30/2022] Open
Abstract
As the number of confirmed cases and resulting death toll of the COVID-19 pandemic continue to increase around the globe - especially with the emergence of new mutations of the SARS-CoV-2 virus in addition to the known alpha, beta, gamma, delta and omicron variants - tremendous efforts continue to be dedicated to the development of interventive therapeutics to mitigate infective symptoms or post-viral sequelae in individuals for which vaccines are not accessible, viable or effective in the prevention of illness. Many of these investigations aim to target the associated acute respiratory distress syndrome, or ARDS, which induces damage to lung epithelia and other physiologic systems and is associated with progression in severe cases. Recently, stem cell-based therapies have demonstrated preliminary efficacy against ARDS based on a number of preclinical and preliminary human safety studies, and based on promising outcomes are now being evaluated in phase II clinical trials for ARDS. A number of candidate stem cell therapies have been found to exhibit low immunogenicity, coupled with inherent tropism to injury sites. In recent studies, these have demonstrated the ability to modulate suppression of pro-inflammatory cytokine signals such as those characterizing COVID-19-associated ARDS. Present translational studies are aiming to optimize the safety, efficacy and delivery to fully validate stem cell-based strategies targeting COVID-19 associated ARDS for viable clinical application.
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Affiliation(s)
- Hoi Wa Ngai
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
| | - Dae Hong Kim
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
| | - Mohamed Hammad
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
| | - Margarita Gutova
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
| | - Karen Aboody
- Department of Stem Cell Biology and Regenerative MedicineCity of Hope Beckman Research InstituteDuarteCaliforniaUSA
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Abstract
Small extracellular vesicles (sEVs) secreted by most cells carry bioactive macromolecules including proteins, lipids, and nucleic acids for intercellular communication. Given that some immune cell-derived sEVs exhibit anti-cancer properties, these sEVs have received scientific attention for the development of novel anti-cancer immunotherapeutic agents. In this paper, we reviewed the latest advances concerning the biological roles of immune cell-derived sEVs for cancer therapy. sEVs derived from immune cells including dendritic cells (DCs), T cells, natural-killer (NK) cells, and macrophages are good candidates for sEV-based cancer therapy. Besides their role of cancer vaccines, DC-shed sEVs activated cytotoxic lymphocytes and killed tumor cells. sEVs isolated from NK cells and chimeric antigen receptor (CAR) T cells exhibited cytotoxicity against cancer cells. sEVs derived from CD8+ T and CD4+ T cells inhibited cancer-associated cells in tumor microenvironment (TME) and activated B cells, respectively. M1-macrophage-derived sEVs induced M2 to M1 repolarization and also created a pro-inflammatory environment. Hence, these sEVs, via mono or combination therapy, could be considered in the treatment of cancer patients in the future. In addition, sEVs derived from cytokine-stimulated immune cells or sEV engineering could improve their anti-tumor potency.
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Affiliation(s)
- Sung-Jin Choi
- Department of New Biology, DGIST, Daegu 42988, Republic of Korea
| | - Hanchae Cho
- Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
| | - Kyungmoo Yea
- Department of New Biology, DGIST, Daegu 42988, Republic of Korea
| | - Moon-Chang Baek
- Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea
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34
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Engeroff P, Vogel M. The Potential of Exosomes in Allergy Immunotherapy. Vaccines (Basel) 2022; 10:vaccines10010133. [PMID: 35062793 PMCID: PMC8780385 DOI: 10.3390/vaccines10010133] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/12/2022] [Accepted: 01/14/2022] [Indexed: 02/01/2023] Open
Abstract
Allergic diseases represent a global health and economic burden of increasing significance. The lack of disease-modifying therapies besides specific allergen immunotherapy (AIT) which is not available for all types of allergies, necessitates the study of novel therapeutic approaches. Exosomes are small endosome-derived vesicles delivering cargo between cells and thus allowing inter-cellular communication. Since immune cells make use of exosomes to boost, deviate, or suppress immune responses, exosomes are intriguing candidates for immunotherapy. Here, we review the role of exosomes in allergic sensitization and inflammation, and we discuss the mechanisms by which exosomes could potentially be used in immunotherapeutic approaches for the treatment of allergic diseases. We propose the following approaches: (a) Mast cell-derived exosomes expressing IgE receptor FcεRI could absorb IgE and down-regulate systemic IgE levels. (b) Tolerogenic exosomes could suppress allergic immune responses via induction of regulatory T cells. (c) Exosomes could promote TH1-like responses towards an allergen. (d) Exosomes could modulate IgE-facilitated antigen presentation.
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Affiliation(s)
- Paul Engeroff
- Sorbonne Université, INSERM, Immunology-Immunopathology-Immunotherapy (i3), F-75005 Paris, France;
| | - Monique Vogel
- Department of Immunology, University Hospital for Rheumatology, Immunology, and Allergology, 3010 Bern, Switzerland
- Department of BioMedical Research, University of Bern, 3008 Bern, Switzerland
- Correspondence:
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An efficient and safe MUC1-dendritic cell-derived exosome conjugate vaccine elicits potent cellular and humoral immunity and tumor inhibition in vivo. Acta Biomater 2022; 138:491-504. [PMID: 34757230 DOI: 10.1016/j.actbio.2021.10.041] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 10/20/2021] [Accepted: 10/24/2021] [Indexed: 12/15/2022]
Abstract
Antitumor vaccines are a promising strategy for preventing or treating cancers by eliciting antitumor immune responses and inducing protective immunity against specific antigens expressed on tumor cells. Vaccine formulations that enhance the humoral and cellular immune responses of vaccine candidates would be highly beneficial but are still limited. Here we developed an antitumor vaccine candidate by conjugating a MUC1 glycopeptide antigen to dendritic cell-derived exosomes (Dex). In vivo, the MUC1-Dex construct induced high MUC1-specific IgG antibody titers with strong binding affinities for MUC1-positive tumor cells and promoted cytokine secretion. Moreover, CD8+ T cells from immunized mice exhibited strong cytotoxicity against MUC1-positive tumor cells. Importantly, in both preventative and therapeutic tumor-bearing mouse models, the construct inhibited tumor growth and prolonged survival. Collectively, these results demonstrate that Dex is a promising vaccine carrier that can be used as adjuvant to enhance the immunological efficacy of tumor vaccines. STATEMENT OF SIGNIFICANCE.
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36
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Alghamdi M, Alamry SA, Bahlas SM, Uversky VN, Redwan EM. Circulating extracellular vesicles and rheumatoid arthritis: a proteomic analysis. Cell Mol Life Sci 2021; 79:25. [PMID: 34971426 PMCID: PMC11072894 DOI: 10.1007/s00018-021-04020-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 10/28/2021] [Accepted: 10/29/2021] [Indexed: 12/14/2022]
Abstract
Circulating extracellular vesicles (EVs) are membrane-bound nanoparticles secreted by most cells for intracellular communication and transportation of biomolecules. EVs carry proteins, lipids, nucleic acids, and receptors that are involved in human physiology and pathology. EV cargo is variable and highly related to the type and state of the cellular origin. Three subtypes of EVs have been identified: exosomes, microvesicles, and apoptotic bodies. Exosomes are the smallest and the most well-studied class of EVs that regulate different biological processes and participate in several diseases, such as cancers and autoimmune diseases. Proteomic analysis of exosomes succeeded in profiling numerous types of proteins involved in disease development and prognosis. In rheumatoid arthritis (RA), exosomes revealed a potential function in joint inflammation. These EVs possess a unique function, as they can transfer specific autoantigens and mediators between distant cells. Current proteomic data demonstrated that exosomes could provide beneficial effects against autoimmunity and exert an immunosuppressive action, particularly in RA. Based on these observations, effective therapeutic strategies have been developed for arthritis and other inflammatory disorders.
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Affiliation(s)
- Mohammed Alghamdi
- Biological Sciences Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah, 21589, Saudi Arabia
- Laboratory Department, University Medical Services Center, King Abdulaziz University, P.O. Box 80200, Jeddah, 21589, Saudi Arabia
| | - Sultan Abdulmughni Alamry
- Immunology Diagnostic Laboratory Department, King Abdulaziz University Hospital, P.O Box 80215, Jeddah, 21589, Saudi Arabia
| | - Sami M Bahlas
- Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, P.O. Box 80215, Jeddah, 21589, Saudi Arabia
| | - Vladimir N Uversky
- Biological Sciences Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah, 21589, Saudi Arabia
- Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Elrashdy M Redwan
- Biological Sciences Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah, 21589, Saudi Arabia.
- Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, 21934, Alexandria, Egypt.
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Elashiry M, Elsayed R, Cutler CW. Exogenous and Endogenous Dendritic Cell-Derived Exosomes: Lessons Learned for Immunotherapy and Disease Pathogenesis. Cells 2021; 11:cells11010115. [PMID: 35011677 PMCID: PMC8750541 DOI: 10.3390/cells11010115] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/22/2021] [Accepted: 12/23/2021] [Indexed: 12/12/2022] Open
Abstract
Immune therapeutic exosomes, derived exogenously from dendritic cells (DCs), the 'directors' of the immune response, are receiving favorable safety and tolerance profiles in phase I and II clinical trials for a growing number of inflammatory and neoplastic diseases. DC-derived exosomes (EXO), the focus of this review, can be custom tailored with immunoregulatory or immunostimulatory molecules for specific immune cell targeting. Moreover, the relative stability, small size and rapid uptake of EXO by recipient immune cells offer intriguing options for therapeutic purposes. This necessitates an in-depth understanding of mechanisms of EXO biogenesis, uptake and routing by recipient immune cells, as well as their in vivo biodistribution. Against this backdrop is recognition of endogenous exosomes, secreted by all cells, the molecular content of which is reflective of the metabolic state of these cells. In this regard, exosome biogenesis and secretion is regulated by cell stressors of chronic inflammation and tumorigenesis, including dysbiotic microbes, reactive oxygen species and DNA damage. Such cell stressors can promote premature senescence in young cells through the senescence associated secretory phenotype (SASP). Pathological exosomes of the SASP amplify inflammatory signaling in stressed cells in an autocrine fashion or promote inflammatory signaling to normal neighboring cells in paracrine, without the requirement of cell-to-cell contact. In summary, we review relevant lessons learned from the use of exogenous DC exosomes for immune therapy, as well as the pathogenic potential of endogenous DC exosomes.
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Kawashima M, Higuchi H, Kotani A. Significance of trogocytosis and exosome-mediated transport in establishing and maintaining the tumor microenvironment in lymphoid malignancies. J Clin Exp Hematop 2021; 61:192-201. [PMID: 34193756 PMCID: PMC8808107 DOI: 10.3960/jslrt.21005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/05/2021] [Accepted: 04/04/2021] [Indexed: 11/25/2022] Open
Abstract
It is widely accepted that the tumor microenvironment plays an important role in the progression of lymphoid malignancies. Interaction between the tumor and its surrounding immune cells is considered a potential therapeutic target. For example, anti-programmed cell death 1 (PD-1) antibody stimulates the surrounding exhausted immune cells to release PD-1/PD-L1, thereby leading to the regression of PD-L1-positive tumors. Recently, biological phenomena, such as trogocytosis and exosome-mediated transport were demonstrated to be involved in establishing and maintaining the tumor microenvironment. We found that trogocytosis-mediated PD-L1/L2 transfer from tumor cells to monocytes/macrophages is involved in immune dysfunction in classic Hodgkin lymphoma. Exosomes derived from Epstein-Barr virus (EBV)-associated lymphoma cells induce lymphoma tumorigenesis by transferring the EBV-coding microRNAs from the infected cells to macrophages. In this review, we summarized these biological phenomena based on our findings.
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Borowiec BM, Angelova Volponi A, Mozdziak P, Kempisty B, Dyszkiewicz-Konwińska M. Small Extracellular Vesicles and COVID19-Using the "Trojan Horse" to Tackle the Giant. Cells 2021; 10:3383. [PMID: 34943891 PMCID: PMC8699232 DOI: 10.3390/cells10123383] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/21/2021] [Accepted: 11/25/2021] [Indexed: 12/12/2022] Open
Abstract
The COVID-19 pandemic is a global challenge, demanding researchers address different approaches in relation to prevention, diagnostics and therapeutics. Amongst the many tactics of tackling these therapeutic challenges, small extracellular vesicles (sEVs) or exosomes are emerging as a new frontier in the field of ameliorating viral infections. Exosomes are part of extracellular vesicles (EVs)-spherical biological structures with a lipid bilayer of a diameter of up to 5000 nm, which are released into the intercellular space by most types of eukaryotic cells, both in physiological and pathological states. EVs share structural similarities to viruses, such as small size, common mechanisms of biogenesis and mechanisms for cell entry. The role of EVs in promoting the viral spread by evading the immune response of the host, which is exhibited by retroviruses, indicates the potential for further investigation and possible manipulation of these processes when tackling the spread and treatment of COVID-19. The following paper introduces the topic of the use of exosomes in the treatment of viral infections, and presents the future prospects for the use of these EVs.
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Affiliation(s)
- Blanka Maria Borowiec
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (B.M.B.); (B.K.)
| | - Ana Angelova Volponi
- Centre for Craniofacial and Regenerative Biology, Faculty for Dentistry, Oral and Craniofacial Sciences, King’s College University of London, London SE1 9RT, UK;
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA;
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA
| | - Bartosz Kempisty
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (B.M.B.); (B.K.)
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Department of Diagnostics and Clinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Torun, Poland
| | - Marta Dyszkiewicz-Konwińska
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland
- Department of Biomaterials and Experimental Dentistry, Poznan University of Medical Sciences, Bukowska 70, 60-812 Poznan, Poland
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40
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Kumar S, Kumar P, Kodidela S, Duhart B, Cernasev A, Nookala A, Kumar A, Singh UP, Bissler J. Racial Health Disparity and COVID-19. J Neuroimmune Pharmacol 2021; 16:729-742. [PMID: 34499313 PMCID: PMC8426163 DOI: 10.1007/s11481-021-10014-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023]
Abstract
The infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and resultant coronavirus diseases-19 (COVID-19) disproportionally affects minorities, especially African Americans (AA) compared to the Caucasian population. The AA population is disproportionally affected by COVID-19, in part, because they have high prevalence of underlying conditions such as obesity, diabetes, and hypertension, which are known to exacerbate not only kidney diseases, but also COVID-19. Further, a decreased adherence to COVID-19 guidelines among tobacco smokers could result in increased infection, inflammation, reduced immune response, and lungs damage, leading to more severe form of COVID-19. As a result of high prevalence of underlying conditions that cause kidney diseases in the AA population coupled with tobacco smoking make the AA population vulnerable to severe form of both COVID-19 and kidney diseases. In this review, we describe how tobacco smoking interact with SARS-CoV-2 and exacerbates SARS-CoV-2-induced kidney diseases including renal failure, especially in the AA population. We also explore the role of extracellular vesicles (EVs) in COVID-19 patients who smoke tobacco. EVs, which play important role in tobacco-mediated pathogenesis in infectious diseases, have also shown to be important in COVID-19 pathogenesis and organ injuries including kidney. Further, we explore the potential role of EVs in biomarker discovery and therapeutics, which may help to develop early diagnosis and treatment of tobacco-induced renal injury in COVID-19 patients, respectively.
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Affiliation(s)
- Santosh Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Prashant Kumar
- Department of Pediatrics, University of Tennessee Health Science Center and Le Bonheur Children's Hospital, Memphis, TN, USA
| | - Sunitha Kodidela
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Benjamin Duhart
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Sciences Center, Memphis, TN, USA
| | - Alina Cernasev
- Department of Clinical Pharmacy and Translational Science, University of Tennessee Health Sciences Center, Nashville, TN, USA
| | | | - Asit Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - Udai P Singh
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN, USA
| | - John Bissler
- Department of Pediatrics, University of Tennessee Health Science Center and Le Bonheur Children's Hospital, Memphis, TN, USA.
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41
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Ravindranath MH, El Hilali F, Filippone EJ. The Impact of Inflammation on the Immune Responses to Transplantation: Tolerance or Rejection? Front Immunol 2021; 12:667834. [PMID: 34880853 PMCID: PMC8647190 DOI: 10.3389/fimmu.2021.667834] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 10/11/2021] [Indexed: 12/21/2022] Open
Abstract
Transplantation (Tx) remains the optimal therapy for end-stage disease (ESD) of various solid organs. Although alloimmune events remain the leading cause of long-term allograft loss, many patients develop innate and adaptive immune responses leading to graft tolerance. The focus of this review is to provide an overview of selected aspects of the effects of inflammation on this delicate balance following solid organ transplantation. Initially, we discuss the inflammatory mediators detectable in an ESD patient. Then, the specific inflammatory mediators found post-Tx are elucidated. We examine the reciprocal relationship between donor-derived passenger leukocytes (PLs) and those of the recipient, with additional emphasis on extracellular vesicles, specifically exosomes, and we examine their role in determining the balance between tolerance and rejection. The concept of recipient antigen-presenting cell "cross-dressing" by donor exosomes is detailed. Immunological consequences of the changes undergone by cell surface antigens, including HLA molecules in donor and host immune cells activated by proinflammatory cytokines, are examined. Inflammation-mediated donor endothelial cell (EC) activation is discussed along with the effect of donor-recipient EC chimerism. Finally, as an example of a specific inflammatory mediator, a detailed analysis is provided on the dynamic role of Interleukin-6 (IL-6) and its receptor post-Tx, especially given the potential for therapeutic interdiction of this axis with monoclonal antibodies. We aim to provide a holistic as well as a reductionist perspective of the inflammation-impacted immune events that precede and follow Tx. The objective is to differentiate tolerogenic inflammation from that enhancing rejection, for potential therapeutic modifications. (Words 247).
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Affiliation(s)
- Mepur H. Ravindranath
- Department of Hematology and Oncology, Children’s Hospital, Los Angeles, CA, United States
- Terasaki Foundation Laboratory, Santa Monica, CA, United States
| | | | - Edward J. Filippone
- Division of Nephrology, Department of Medicine, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, United States
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42
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Hodge AL, Baxter AA, Poon IKH. Gift bags from the sentinel cells of the immune system: The diverse role of dendritic cell-derived extracellular vesicles. J Leukoc Biol 2021; 111:903-920. [PMID: 34699107 DOI: 10.1002/jlb.3ru1220-801r] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Dendritic cells (DCs) are professional APCs of the immune system that continuously sample their environment and function to stimulate an adaptive immune response by initiating Ag-specific immunity or tolerance. Extracellular vesicles (EVs), small membrane-bound structures, are released from DCs and have been discovered to harbor functional peptide-MHC complexes, T cell costimulatory molecules, and other molecules essential for Ag presentation, immune cell regulation, and stimulating immune responses. As such, DC-derived EVs are being explored as potential immunotherapeutic agents. DC-derived EVs have also been implicated to function as a trafficking mechanism of infectious particles aiding viral propagation. This review will explore the unique features that enable DC-derived EVs to regulate immune responses and interact with recipient cells, their roles within Ag-presentation and disease settings, as well as speculating on a potential immunological role of apoptotic DC-derived EVs.
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Affiliation(s)
- Amy L Hodge
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - Amy A Baxter
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
| | - Ivan K H Poon
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia
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43
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Ma F, Vayalil J, Lee G, Wang Y, Peng G. Emerging role of tumor-derived extracellular vesicles in T cell suppression and dysfunction in the tumor microenvironment. J Immunother Cancer 2021; 9:jitc-2021-003217. [PMID: 34642246 PMCID: PMC8513270 DOI: 10.1136/jitc-2021-003217] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/19/2021] [Indexed: 02/07/2023] Open
Abstract
Immunotherapeutic drugs including immune checkpoint blockade antibodies have been approved to treat patients in many types of cancers. However, some patients have little or no reaction to the immunotherapy drugs. The mechanisms underlying resistance to tumor immunotherapy are complicated and involve multiple aspects, including tumor-intrinsic factors, formation of immunosuppressive microenvironment, and alteration of tumor and stromal cell metabolism in the tumor microenvironment. T cell is critical and participates in every aspect of antitumor response, and T cell dysfunction is a severe barrier for effective immunotherapy for cancer. Emerging evidence indicates that extracellular vesicles (EVs) secreted by tumor is one of the major factors that can induce T cell dysfunction. Tumor-derived EVs are widely distributed in serum, tissues, and the tumor microenvironment of patients with cancer, which serve as important communication vehicles for cancer cells. In addition, tumor-derived EVs can carry a variety of immune suppressive signals driving T cell dysfunction for tumor immunity. In this review, we explore the potential mechanisms employed by tumor-derived EVs to control T cell development and effector function within the tumor microenvironment. Especially, we focus on current understanding of how tumor-derived EVs molecularly and metabolically reprogram T cell fates and functions for tumor immunity. In addition, we discuss potential translations of targeting tumor-derived EVs to reconstitute suppressive tumor microenvironment or to develop antigen-based vaccines and drug delivery systems for cancer immunotherapy.
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Affiliation(s)
- Feiya Ma
- Biology, Saint Louis University, Saint Louis, Missouri, USA
| | - Jensen Vayalil
- Biology, Saint Louis University, Saint Louis, Missouri, USA
| | - Grace Lee
- Biology, Saint Louis University, Saint Louis, Missouri, USA
| | - Yuqi Wang
- Biology, Saint Louis University, Saint Louis, Missouri, USA
| | - Guangyong Peng
- Internal Medicine, Saint Louis University, Saint Louis, Missouri, USA
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44
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de Mol J, Kuiper J, Tsiantoulas D, Foks AC. The Dynamics of B Cell Aging in Health and Disease. Front Immunol 2021; 12:733566. [PMID: 34675924 PMCID: PMC8524000 DOI: 10.3389/fimmu.2021.733566] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 09/16/2021] [Indexed: 12/30/2022] Open
Abstract
Aging is considered to be an important risk factor for several inflammatory diseases. B cells play a major role in chronic inflammatory diseases by antibody secretion, antigen presentation and T cell regulation. Different B cell subsets have been implicated in infections and multiple autoimmune diseases. Since aging decreases B cell numbers, affects B cell subsets and impairs antibody responses, the aged B cell is expected to have major impacts on the development and progression of these diseases. In this review, we summarize the role of B cells in health and disease settings, such as atherosclerotic disease. Furthermore, we provide an overview of age-related changes in B cell development and function with respect to their impact in chronic inflammatory diseases.
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Affiliation(s)
- Jill de Mol
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | - Johan Kuiper
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
| | | | - Amanda C. Foks
- Division of BioTherapeutics, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands
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45
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Nazimek K, Bustos-Morán E, Blas-Rus N, Nowak B, Totoń-Żurańska J, Seweryn MT, Wołkow P, Woźnicka O, Szatanek R, Siedlar M, Askenase PW, Sánchez-Madrid F, Bryniarski K. Antibodies Enhance the Suppressive Activity of Extracellular Vesicles in Mouse Delayed-Type Hypersensitivity. Pharmaceuticals (Basel) 2021; 14:ph14080734. [PMID: 34451831 PMCID: PMC8398949 DOI: 10.3390/ph14080734] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 07/15/2021] [Accepted: 07/26/2021] [Indexed: 12/16/2022] Open
Abstract
Previously, we showed that mouse delayed-type hypersensitivity (DTH) can be antigen-specifically downregulated by suppressor T cell-derived miRNA-150 carried by extracellular vesicles (EVs) that target antigen-presenting macrophages. However, the exact mechanism of the suppressive action of miRNA-150-targeted macrophages on effector T cells remained unclear, and our current studies aimed to investigate it. By employing the DTH mouse model, we showed that effector T cells were inhibited by macrophage-released EVs in a miRNA-150-dependent manner. This effect was enhanced by the pre-incubation of EVs with antigen-specific antibodies. Their specific binding to MHC class II-expressing EVs was proved in flow cytometry and ELISA-based experiments. Furthermore, by the use of nanoparticle tracking analysis and transmission electron microscopy, we found that the incubation of macrophage-released EVs with antigen-specific antibodies resulted in EVs’ aggregation, which significantly enhanced their suppressive activity in vivo. Nowadays, it is increasingly evident that EVs play an exceptional role in intercellular communication and selective cargo transfer, and thus are considered promising candidates for therapeutic usage. However, EVs appear to be less effective than their parental cells. In this context, our current studies provide evidence that antigen-specific antibodies can be easily used for increasing EVs’ biological activity, which has great therapeutic potential.
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Affiliation(s)
- Katarzyna Nazimek
- Department of Immunology, Jagiellonian University Medical College, 18 Czysta St., 31-121 Krakow, Poland; (K.N.); (B.N.)
- Department of Immunology, Hospital de la Princesa, Health Research Institute of Princesa Hospital (ISS-IP), Autonomous University of Madrid, 28006 Madrid, Spain; (E.B.-M.); (N.B.-R.); (F.S.-M.)
- Section of Rheumatology, Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 208011, USA;
| | - Eugenio Bustos-Morán
- Department of Immunology, Hospital de la Princesa, Health Research Institute of Princesa Hospital (ISS-IP), Autonomous University of Madrid, 28006 Madrid, Spain; (E.B.-M.); (N.B.-R.); (F.S.-M.)
| | - Noelia Blas-Rus
- Department of Immunology, Hospital de la Princesa, Health Research Institute of Princesa Hospital (ISS-IP), Autonomous University of Madrid, 28006 Madrid, Spain; (E.B.-M.); (N.B.-R.); (F.S.-M.)
| | - Bernadeta Nowak
- Department of Immunology, Jagiellonian University Medical College, 18 Czysta St., 31-121 Krakow, Poland; (K.N.); (B.N.)
| | - Justyna Totoń-Żurańska
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, 31-034 Krakow, Poland; (J.T.-Ż.); (M.T.S.); (P.W.)
| | - Michał T. Seweryn
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, 31-034 Krakow, Poland; (J.T.-Ż.); (M.T.S.); (P.W.)
| | - Paweł Wołkow
- Center for Medical Genomics OMICRON, Jagiellonian University Medical College, 31-034 Krakow, Poland; (J.T.-Ż.); (M.T.S.); (P.W.)
| | - Olga Woźnicka
- Department of Cell Biology and Imaging, Institute of Zoology and Biomedical Research, Jagiellonian University, 30-387 Krakow, Poland;
| | - Rafał Szatanek
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland; (R.S.); (M.S.)
| | - Maciej Siedlar
- Department of Clinical Immunology, Institute of Paediatrics, Jagiellonian University Medical College, 30-663 Krakow, Poland; (R.S.); (M.S.)
| | - Philip W. Askenase
- Section of Rheumatology, Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 208011, USA;
| | - Francisco Sánchez-Madrid
- Department of Immunology, Hospital de la Princesa, Health Research Institute of Princesa Hospital (ISS-IP), Autonomous University of Madrid, 28006 Madrid, Spain; (E.B.-M.); (N.B.-R.); (F.S.-M.)
| | - Krzysztof Bryniarski
- Department of Immunology, Jagiellonian University Medical College, 18 Czysta St., 31-121 Krakow, Poland; (K.N.); (B.N.)
- Section of Rheumatology, Allergy and Clinical Immunology, Yale University School of Medicine, New Haven, CT 208011, USA;
- Correspondence: ; Tel.: +48-12-632-58-65
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Yao Y, Fu C, Zhou L, Mi QS, Jiang A. DC-Derived Exosomes for Cancer Immunotherapy. Cancers (Basel) 2021; 13:cancers13153667. [PMID: 34359569 PMCID: PMC8345209 DOI: 10.3390/cancers13153667] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/16/2021] [Accepted: 07/18/2021] [Indexed: 12/18/2022] Open
Abstract
As the initiators of adaptive immune responses, DCs play a central role in regulating the balance between CD8 T cell immunity versus tolerance to tumor antigens. Exploiting their function to potentiate host anti-tumor immunity, DC-based vaccines have been one of most promising and widely used cancer immunotherapies. However, DC-based cancer vaccines have not achieved the promised success in clinical trials, with one of the major obstacles being tumor-mediated immunosuppression. A recent discovery on the critical role of type 1 conventional DCs (cDC1s) play in cross-priming tumor-specific CD8 T cells and determining the anti-tumor efficacy of cancer immunotherapies, however, has highlighted the need to further develop and refine DC-based vaccines either as monotherapies or in combination with other therapies. DC-derived exosomes (DCexos) have been heralded as a promising alternative to DC-based vaccines, as DCexos are more resistance to tumor-mediated suppression and DCexo vaccines have exhibited better anti-tumor efficacy in pre-clinical animal models. However, DCexo vaccines have only achieved limited clinical efficacy and failed to induce tumor-specific T cell responses in clinical trials. The lack of clinical efficacy might be partly due to the fact that all current clinical trials used peptide-loaded DCexos from monocyte-derived DCs. In this review, we will focus on the perspective of expanding current DCexo research to move DCexo cancer vaccines forward clinically to realize their potential in cancer immunotherapy.
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Affiliation(s)
- Yi Yao
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
- Immunology Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Chunmei Fu
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
| | - Li Zhou
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
- Immunology Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
| | - Qing-Sheng Mi
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
- Immunology Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
- Correspondence: (Q.-S.M.); (A.J.); Tel.: +313-876-1017 (Q.-S.M.); +313-876-7292 (A.J.)
| | - Aimin Jiang
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health System, Detroit, MI 48202, USA; (Y.Y.); (C.F.); (L.Z.)
- Immunology Program, Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI 48202, USA
- Correspondence: (Q.-S.M.); (A.J.); Tel.: +313-876-1017 (Q.-S.M.); +313-876-7292 (A.J.)
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Santos P, Almeida F. Exosome-Based Vaccines: History, Current State, and Clinical Trials. Front Immunol 2021; 12:711565. [PMID: 34335627 PMCID: PMC8317489 DOI: 10.3389/fimmu.2021.711565] [Citation(s) in RCA: 122] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 06/30/2021] [Indexed: 12/23/2022] Open
Abstract
Extracellular vesicles (EVs) are released by most cell types as part of an intracellular communication system in crucial processes such as inflammation, cell proliferation, and immune response. However, EVs have also been implicated in the pathogenesis of several diseases, such as cancer and numerous infectious diseases. An important feature of EVs is their ability to deliver a wide range of molecules to nearby targets or over long distances, which allows the mediation of different biological functions. This delivery mechanism can be utilized for the development of therapeutic strategies, such as vaccination. Here, we have highlighted several studies from a historical perspective, with respect to current investigations on EV-based vaccines. For example, vaccines based on exosomes derived from dendritic cells proved to be simpler in terms of management and cost-effectiveness than dendritic cell vaccines. Recent evidence suggests that EVs derived from cancer cells can be leveraged for therapeutics to induce strong anti-tumor immune responses. Moreover, EV-based vaccines have shown exciting and promising results against different types of infectious diseases. We have also summarized the results obtained from completed clinical trials conducted on the usage of exosome-based vaccines in the treatment of cancer, and more recently, coronavirus disease.
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Affiliation(s)
- Patrick Santos
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
| | - Fausto Almeida
- Department of Biochemistry and Immunology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, Brazil
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Haque S, Swami P, Khan A. S. Typhi derived vaccines and a proposal for outer membrane vesicles (OMVs) as potential vaccine for typhoid fever. Microb Pathog 2021; 158:105082. [PMID: 34265371 DOI: 10.1016/j.micpath.2021.105082] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 07/02/2021] [Accepted: 07/02/2021] [Indexed: 12/22/2022]
Abstract
Typhoid fever is a serious systemic infection caused by Salmonella Typhi (S. Typhi), spread by the feco-oral route and closely associated with poor food hygiene and inadequate sanitation. Nearly 93% of S. Typhi strains have acquired antibiotic resistance against most antibiotics. Vaccination is the only promising way to prevent typhoid fever. This review covers the nature and composition of S. Typhi, pathogenecity and mode of infection, epidemiology, and nature of drug resistance. Several components (Vi-polysaccharides, O-antigens, flagellar antigens, full length OMPs, and short peptides from OMPs) of S. Typhi have been utilized for vaccine design for protection against typhoid fever. Vaccine delivery systems also contribute to efficacy of the vaccines. In this study, we propose to develop S. Typhi derived OMVs as vaccine for protection against typhoid fevers.
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Affiliation(s)
- Shabirul Haque
- Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY, 11030, USA.
| | - Pooja Swami
- Feinstein Institute for Medical Research, Northwell Health, 350 Community Drive, Manhasset, NY, 11030, USA.
| | - Azhar Khan
- Faculty of Applied Sciences and Biotechnology, Shoolini University, Solan, Himachal, Pradesh, India.
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Prunevieille A, Babiker-Mohamed MH, Aslami C, Gonzalez-Nolasco B, Mooney N, Benichou G. T cell antigenicity and immunogenicity of allogeneic exosomes. Am J Transplant 2021; 21:2583-2589. [PMID: 33794063 PMCID: PMC10601455 DOI: 10.1111/ajt.16591] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 03/02/2021] [Accepted: 03/22/2021] [Indexed: 01/25/2023]
Abstract
Extracellular vesicles, including exosomes, are regularly released by allogeneic cells after transplantation. Recipient antigen-presenting cells (APCs) capture these vesicles and subsequently display donor MHC molecules on their surface. Recent evidence suggests that activation of alloreactive T cells by the so-called cross-dressed APCs plays an important role in initiating the alloresponse associated with allograft rejection. On the other hand, whether allogeneic exosomes can bind to T cells on their own and activate them remains unclear. In this study, we showed that allogeneic exosomes can bind to T cells but do not stimulate them in vitro unless they are cultured with APCs. On the other hand, allogeneic exosomes activate T cells in vivo and sensitize mice to alloantigens but only when delivered in an inflammatory environment.
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Affiliation(s)
- Aurore Prunevieille
- Transplant Research Center, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA
- Université de Paris, AP-HP, Hôpital Saint-Louis, Human Immunology, Pathophysiology and Immuntherapies, UMR976, INSERM, Paris, France
| | - Mohamed H. Babiker-Mohamed
- Transplant Research Center, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Colleen Aslami
- Transplant Research Center, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Bruno Gonzalez-Nolasco
- Transplant Research Center, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Nuala Mooney
- Université de Paris, AP-HP, Hôpital Saint-Louis, Human Immunology, Pathophysiology and Immuntherapies, UMR976, INSERM, Paris, France
| | - Gilles Benichou
- Transplant Research Center, Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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Engeroff P, Vogel M. The role of CD23 in the regulation of allergic responses. Allergy 2021; 76:1981-1989. [PMID: 33378583 PMCID: PMC8359454 DOI: 10.1111/all.14724] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 12/14/2020] [Accepted: 12/22/2020] [Indexed: 02/06/2023]
Abstract
IgE, the key molecule in atopy has been shown to bind two receptors, FcεRI, the high‐affinity receptor, and FcεRII (CD23), binding IgE with lower affinity. Whereas cross‐linking of IgE on FcεRI expressed by mast cells and basophils triggers the allergic reaction, binding of IgE to CD23 on B cells plays an important role in both IgE regulation and presentation. Furthermore, IgE‐immune complexes (IgE‐ICs) bound by B cells enhance antibody and T cell responses in mice and humans. However, the mechanisms that regulate the targeting of the two receptors and the respective function of the two pathways in inflammation or homeostasis are still a matter of debate. Here, we focus on CD23 and discuss several mechanisms related to IgE binding, as well as the impact of the IgE/antigen‐binding on different immune cells expressing CD23. One recent paper has shown that free IgE preferentially binds to FcεRI whereas IgE‐ICs are preferentially captured by CD23. Binding of IgE‐ICs to CD23 on B cells can, on one hand, regulate serum IgE and prevent effector cell activation and on the other hand facilitate antigen presentation by delivering the antigen to dendritic cells. These data argue for a multifunctional role of CD23 for modulating IgE serum levels and immune responses.
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Affiliation(s)
- Paul Engeroff
- INSERM UMR_S 959 Immunology‐Immunopathology‐Immunotherapy (i3) Sorbonne Université Paris France
| | - Monique Vogel
- Center for Clinical Research Region Västmanland/Uppsala University, Västmanland hospital Västerås Sweden
- Department of BioMedical Research University of Bern Bern Switzerland
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