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Zheng X, Yu S, Zhou Y, Yu K, Gao Y, Chen M, Duan D, Li Y, Cui X, Mou J, Yang Y, Wang X, Chen M, Jiu Y, Zhao J, Meng G. Interleukin-1 prevents SARS-CoV-2-induced membrane fusion to restrict viral transmission via induction of actin bundles. eLife 2025; 13:RP98593. [PMID: 39937682 PMCID: PMC11820142 DOI: 10.7554/elife.98593] [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] [Academic Contribution Register] [Indexed: 02/14/2025] Open
Abstract
Innate immune responses triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection play pivotal roles in the pathogenesis of COVID-19, while host factors including proinflammatory cytokines are critical for viral containment. By utilizing quantitative and qualitative models, we discovered that soluble factors secreted by human monocytes potently inhibit SARS-CoV-2-induced cell-cell fusion in viral-infected cells. Through cytokine screening, we identified that interleukin-1β (IL-1β), a key mediator of inflammation, inhibits syncytia formation mediated by various SARS-CoV-2 strains. Mechanistically, IL-1β activates RhoA/ROCK signaling through a non-canonical IL-1 receptor-dependent pathway, which drives the enrichment of actin bundles at the cell-cell junctions, thus prevents syncytia formation. Notably, in vivo infection experiments in mice confirmed that IL-1β significantly restricted SARS-CoV-2 spread in the lung epithelium. Together, by revealing the function and underlying mechanism of IL-1β on SARS-CoV-2-induced cell-cell fusion, our study highlights an unprecedented antiviral function for cytokines during viral infection.
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Affiliation(s)
- Xu Zheng
- The Center for Microbes, Development and Health, National Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of SciencesShanghaiChina
| | - Shi Yu
- The Center for Microbes, Development and Health, National Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of SciencesShanghaiChina
| | - Yanqiu Zhou
- Shanghai Municipal Center for Disease Control and PreventionShanghaiChina
| | - Kuai Yu
- The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory HealthGuangzhouChina
| | - Yuhui Gao
- The Center for Microbes, Development and Health, National Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of SciencesShanghaiChina
| | - Mengdan Chen
- The Center for Microbes, Development and Health, National Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of SciencesShanghaiChina
| | - Dong Duan
- The Center for Microbes, Development and Health, National Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of SciencesShanghaiChina
- School of Life Sciences, Soochow UniversityJiangsuChina
| | - Yunyi Li
- Shanghai Municipal Center for Disease Control and PreventionShanghaiChina
| | - Xiaoxian Cui
- Shanghai Municipal Center for Disease Control and PreventionShanghaiChina
| | - Jiabin Mou
- Shanghai Municipal Center for Disease Control and PreventionShanghaiChina
| | - Yuying Yang
- Shanghai Municipal Center for Disease Control and PreventionShanghaiChina
| | - Xun Wang
- Shanghai Blood CenterShanghaiChina
| | - Min Chen
- Shanghai Municipal Center for Disease Control and PreventionShanghaiChina
| | - Yaming Jiu
- The Center for Microbes, Development and Health, National Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of SciencesShanghaiChina
| | - Jincun Zhao
- The First Affiliated Hospital of Guangzhou Medical University, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory HealthGuangzhouChina
| | - Guangxun Meng
- The Center for Microbes, Development and Health, National Key Laboratory of Immune Response and Immunotherapy, Shanghai Institute of Immunity and Infection, Chinese Academy of Sciences, University of Chinese Academy of SciencesShanghaiChina
- School of Life Sciences, Soochow UniversityJiangsuChina
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Touramanidou L, Gurung S, Cozmescu CA, Perocheau D, Moulding D, Finn PF, Frassetto A, Waddington SN, Gissen P, Baruteau J. Macrophage Inhibitor Clodronate Enhances Liver Transduction of Lentiviral but Not Adeno-Associated Viral Vectors or mRNA Lipid Nanoparticles in Neonatal and Juvenile Mice. Cells 2024; 13:1979. [PMID: 39682727 DOI: 10.3390/cells13231979] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/31/2024] [Revised: 11/25/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
Recently approved adeno-associated viral (AAV) vectors for liver monogenic diseases haemophilia A and B are exemplifying the success of liver-directed viral gene therapy. In parallel, additional gene therapy strategies are rapidly emerging to overcome some inherent AAV limitations, such as the non-persistence of the episomal transgene in the rapidly growing liver and immune response. Viral integrating vectors such as in vivo lentiviral gene therapy and non-viral vectors such as lipid nanoparticles encapsulating mRNA (LNP-mRNA) are rapidly being developed, currently at the preclinical and clinical stages, respectively. Macrophages are the first effector cells of the innate immune response triggered by gene therapy vectors. Macrophage uptake and activation following administration of viral gene therapy and LNP have been reported. In this study, we assessed the biodistribution of AAV, lentiviral, and LNP-mRNA gene therapy following the depletion of tissue macrophages by clodronate pre-treatment in neonatal and juvenile mice. Both neonatal and adult clodronate-treated mice showed a significant increase in lentiviral-transduced hepatocytes. In contrast, clodronate pre-treatment did not modify hepatocyte transduction mediated by hepatotropic AAV8 but reduced LNP-mRNA transfection in neonatal and juvenile animals. These results highlight the importance of age-specific responses in the liver and will have translational applications for gene therapy programs.
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Affiliation(s)
- Loukia Touramanidou
- Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK
| | - Sonam Gurung
- Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK
| | - Claudiu A Cozmescu
- Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK
| | - Dany Perocheau
- Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK
| | - Dale Moulding
- Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK
| | | | | | - Simon N Waddington
- Institute for Women's Health, University College London, London WC1E 6HX, UK
- Wits/SAMRC Antiviral Gene Therapy Research Unit, Faculty of Health Sciences, University of Witswatersrand, Johannesburg 2193, South Africa
| | - Paul Gissen
- Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK
- Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK
| | - Julien Baruteau
- Great Ormond Street Institute of Child Health, University College London, London WC1E 1EH, UK
- Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK
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3
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He B, Wilson B, Chen SH, Sharma K, Scappini E, Cook M, Petrovich R, Martin NP. Molecular Engineering of Virus Tropism. Int J Mol Sci 2024; 25:11094. [PMID: 39456875 PMCID: PMC11508178 DOI: 10.3390/ijms252011094] [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] [Academic Contribution Register] [Received: 09/18/2024] [Revised: 10/03/2024] [Accepted: 10/07/2024] [Indexed: 10/28/2024] Open
Abstract
Engineered viral vectors designed to deliver genetic material to specific targets offer significant potential for disease treatment, safer vaccine development, and the creation of novel biochemical research tools. Viral tropism, the specificity of a virus for infecting a particular host, is often modified in recombinant viruses to achieve precise delivery, minimize off-target effects, enhance transduction efficiency, and improve safety. Key factors influencing tropism include surface protein interactions between the virus and host-cell, the availability of host-cell machinery for viral replication, and the host immune response. This review explores current strategies for modifying the tropism of recombinant viruses by altering their surface proteins. We provide an overview of recent advancements in targeting non-enveloped viruses (adenovirus and adeno-associated virus) and enveloped viruses (retro/lentivirus, Rabies, Vesicular Stomatitis Virus, and Herpesvirus) to specific cell types. Additionally, we discuss approaches, such as rational design, directed evolution, and in silico and machine learning-based methods, for generating novel AAV variants with the desired tropism and the use of chimeric envelope proteins for pseudotyping enveloped viruses. Finally, we highlight the applications of these advancements and discuss the challenges and future directions in engineering viral tropism.
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Affiliation(s)
- Bo He
- Viral Vector Core, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; (B.H.); (B.W.); (S.-H.C.)
| | - Belinda Wilson
- Viral Vector Core, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; (B.H.); (B.W.); (S.-H.C.)
| | - Shih-Heng Chen
- Viral Vector Core, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; (B.H.); (B.W.); (S.-H.C.)
| | - Kedar Sharma
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; (K.S.); (M.C.); (R.P.)
| | - Erica Scappini
- Fluorescent Microscopy and Imaging Center, Molecular and Cellular Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA;
| | - Molly Cook
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; (K.S.); (M.C.); (R.P.)
| | - Robert Petrovich
- Genome Integrity and Structural Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; (K.S.); (M.C.); (R.P.)
| | - Negin P. Martin
- Viral Vector Core, Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA; (B.H.); (B.W.); (S.-H.C.)
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Morales-Molina A, Rodriguez-Milla MA, Garcia-Rodriguez P, Hidalgo L, Alemany R, Garcia-Castro J. Deletion of the RGD motif from the penton base in oncolytic adenoviruses enhances antitumor efficacy of combined CAR T cell therapy. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200863. [PMID: 39290319 PMCID: PMC11406095 DOI: 10.1016/j.omton.2024.200863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 04/18/2024] [Revised: 07/17/2024] [Accepted: 08/20/2024] [Indexed: 09/19/2024]
Abstract
Oncolytic viruses often face challenges in achieving optimal antitumor immunity as standalone therapies. The penton base RGD-integrin interactions play a significant role in wild-type adenovirus-induced innate immune responses. To modify these responses, we present ISC301, a novel oncolytic adenovirus engineered by deleting the natural RGD motifs in the penton base while incorporating artificial RGD motifs in the fiber knobs. ISC301 demonstrated comparable in vitro infectivity, cytotoxic effects, and signaling profiles across various cell types to its parental ICOVIR-5, which retains the penton base RGD motif. In immunodeficient and immunocompetent mouse models, ISC301 exhibited similar in vivo antitumor efficacy to ICOVIR-5. However, ISC301 induced higher intratumoral inflammation through NF-κB activation, leading to increased levels of tumor-infiltrating leukocytes and higher proportion of cytotoxic CD8+ T cells. In addition, ISC301 elicits a heightened pro-inflammatory response in peripheral blood. Importantly, when combined with CAR T cell therapy, ISC301 exhibited superior antitumor efficacy, surpassing monotherapy outcomes. These findings emphasize the impact of adenoviral modifications on antitumor immune responses. The deletion of penton base RGD motifs enhances ISC301's pro-inflammatory profile and boosts CAR T cell therapy efficacy. This study enhances understanding of oncolytic virus engineering strategies, positioning ISC301 as a promising candidate for combined immunotherapeutic approaches in cancer treatment.
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Affiliation(s)
| | | | - Patricia Garcia-Rodriguez
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, Spain
- Universidad Nacional de Educación a Distancia, UNED, 28015 Madrid, Spain
| | - Laura Hidalgo
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, Spain
| | - Ramon Alemany
- Oncobell and ProCure Programs, IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, 08908 Barcelona, Spain
| | - Javier Garcia-Castro
- Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220 Madrid, Spain
- Instituto de Investigación de Enfermedades Raras (IIER) & Departamento de Desarrollo de Medicamentos de Terapias Avanzadas (DDMTA), Instituto de Salud Carlos III, 28220 Madrid, Spain
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5
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Song Y, Wang J, Yang Z, He Q, Bao C, Xie Y, Sun Y, Li S, Quan Y, Yang H, Li C. Heterologous booster vaccination enhances antibody responses to SARS-CoV-2 by improving Tfh function and increasing B-cell clonotype SHM frequency. Front Immunol 2024; 15:1406138. [PMID: 38975334 PMCID: PMC11224535 DOI: 10.3389/fimmu.2024.1406138] [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] [Academic Contribution Register] [Received: 03/24/2024] [Accepted: 06/06/2024] [Indexed: 07/09/2024] Open
Abstract
Heterologous prime-boost has broken the protective immune response bottleneck of the COVID-19 vaccines. however, the underlying mechanisms have not been fully elucidated. Here, we investigated antibody responses and explored the response of germinal center (GC) to priming with inactivated vaccines and boosting with heterologous adenoviral-vectored vaccines or homologous inactivated vaccines in mice. Antibody responses were dramatically enhanced by both boosting regimens. Heterologous immunization induced more robust GC activation, characterized by increased Tfh cell populations and enhanced helper function. Additionally, increased B-cell activation and antibody production were observed in a heterologous regimen. Libra-seq was used to compare the differences of S1-, S2- and NTD-specific B cells between homologous and heterologous vaccination, respectively. S2-specific CD19+ B cells presented increased somatic hypermutations (SHMs), which were mainly enriched in plasma cells. Moreover, a heterologous booster dose promoted the clonal expansion of B cells specific to S2 and NTD regions. In conclusion, the functional role of Tfh and B cells following SARS-CoV-2 heterologous vaccination may be important for modulating antibody responses. These findings provide new insights for the development of SARS-CoV-2 vaccines that induce more robust antibody response.
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Affiliation(s)
- Yanli Song
- Division of the Second Vaccines, Wuhan Institute of Biological Products Co. Ltd., Wuhan, China
| | - Jiaolei Wang
- Divsion of Respiratory Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Zhihui Yang
- Division of the Second Vaccines, Wuhan Institute of Biological Products Co. Ltd., Wuhan, China
| | - Qian He
- Divsion of Respiratory Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Chunting Bao
- Divsion of Respiratory Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Ying Xie
- Divsion of Respiratory Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Yufang Sun
- Divsion of Respiratory Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Shuyan Li
- Divsion of Respiratory Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Yaru Quan
- Divsion of Respiratory Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Huijie Yang
- Divsion of Respiratory Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
| | - Changgui Li
- Divsion of Respiratory Virus Vaccines, National Institutes for Food and Drug Control, Beijing, China
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6
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Wallace R, Bliss CM, Parker AL. The Immune System-A Double-Edged Sword for Adenovirus-Based Therapies. Viruses 2024; 16:973. [PMID: 38932265 PMCID: PMC11209478 DOI: 10.3390/v16060973] [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] [Academic Contribution Register] [Received: 05/25/2024] [Revised: 06/12/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Pathogenic adenovirus (Ad) infections are widespread but typically mild and transient, except in the immunocompromised. As vectors for gene therapy, vaccine, and oncology applications, Ad-based platforms offer advantages, including ease of genetic manipulation, scale of production, and well-established safety profiles, making them attractive tools for therapeutic development. However, the immune system often poses a significant challenge that must be overcome for adenovirus-based therapies to be truly efficacious. Both pre-existing anti-Ad immunity in the population as well as the rapid development of an immune response against engineered adenoviral vectors can have detrimental effects on the downstream impact of an adenovirus-based therapeutic. This review focuses on the different challenges posed, including pre-existing natural immunity and anti-vector immunity induced by a therapeutic, in the context of innate and adaptive immune responses. We summarise different approaches developed with the aim of tackling these problems, as well as their outcomes and potential future applications.
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Affiliation(s)
- Rebecca Wallace
- Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; (R.W.); (C.M.B.)
| | - Carly M. Bliss
- Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; (R.W.); (C.M.B.)
- Systems Immunity University Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
| | - Alan L. Parker
- Division of Cancer and Genetics, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK; (R.W.); (C.M.B.)
- Systems Immunity University Research Institute, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK
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Peng J, Zou WW, Wang XL, Zhang ZG, Huo R, Yang L. Viral-mediated gene therapy in pediatric neurological disorders. World J Pediatr 2024; 20:533-555. [PMID: 36607547 DOI: 10.1007/s12519-022-00669-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 05/13/2022] [Accepted: 11/27/2022] [Indexed: 01/07/2023]
Abstract
BACKGROUND Due to the broad application of next-generation sequencing, the molecular diagnosis of genetic disorders in pediatric neurology is no longer an unachievable goal. However, treatments for neurological genetic disorders in children remain primarily symptomatic. On the other hand, with the continuous evolution of therapeutic viral vectors, gene therapy is becoming a clinical reality. From this perspective, we wrote this review to illustrate the current state regarding viral-mediated gene therapy in childhood neurological disorders. DATA SOURCES We searched databases, including PubMed and Google Scholar, using the keywords "adenovirus vector," "lentivirus vector," and "AAV" for gene therapy, and "immunoreaction induced by gene therapy vectors," "administration routes of gene therapy vectors," and "gene therapy" with "NCL," "SMA," "DMD," "congenital myopathy," "MPS" "leukodystrophy," or "pediatric metabolic disorders". We also screened the database of ClinicalTrials.gov using the keywords "gene therapy for children" and then filtered the results with the ones aimed at neurological disorders. The time range of the search procedure was from the inception of the databases to the present. RESULTS We presented the characteristics of commonly used viral vectors for gene therapy for pediatric neurological disorders and summarized their merits and drawbacks, the administration routes of each vector, the research progress, and the clinical application status of viral-mediated gene therapy on pediatric neurological disorders. CONCLUSIONS Viral-mediated gene therapy is on the brink of broad clinical application. Viral-mediated gene therapy will dramatically change the treatment pattern of childhood neurological disorders, and many children with incurable diseases will meet the dawn of a cure. Nevertheless, the vectors must be optimized for better safety and efficacy.
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Affiliation(s)
- Jing Peng
- Department of Pediatrics, Clinical Research Center for Chidren Neurodevelopmental disablities of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wei-Wei Zou
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Xiao-Lei Wang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Zhi-Guo Zhang
- Reproductive Medicine Center, Department of Obstetrics and Gynecology, the First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ran Huo
- State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China
| | - Li Yang
- Department of Pediatrics, Clinical Research Center for Chidren Neurodevelopmental disablities of Hunan Province, Xiangya Hospital, Central South University, Changsha, 410008, China.
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8
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Iyer M, Ravichandran N, Karuppusamy PA, Gnanarajan R, Yadav MK, Narayanasamy A, Vellingiri B. Molecular insights and promise of oncolytic virus based immunotherapy. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 140:419-492. [PMID: 38762277 DOI: 10.1016/bs.apcsb.2023.12.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 05/20/2024]
Abstract
Discovering a therapeutic that can counteract the aggressiveness of this disease's mechanism is crucial for improving survival rates for cancer patients and for better understanding the most different types of cancer. In recent years, using these viruses as an anticancer therapy has been thought to be successful. They mostly work by directly destroying cancer cells, activating the immune system to fight cancer, and expressing exogenous effector genes. For the treatment of tumors, oncolytic viruses (OVs), which can be modified to reproduce only in tumor tissues and lyse them while preserving the healthy non-neoplastic host cells and reinstating antitumor immunity which present a novel immunotherapeutic strategy. OVs can exist naturally or be created in a lab by altering existing viruses. These changes heralded the beginning of a new era of less harmful virus-based cancer therapy. We discuss three different types of oncolytic viruses that have already received regulatory approval to treat cancer as well as clinical research using oncolytic adenoviruses. The primary therapeutic applications, mechanism of action of oncolytic virus updates, future views of this therapy will be covered in this chapter.
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Affiliation(s)
- Mahalaxmi Iyer
- Department of Microbiology, Central University of Punjab, Bathinda, India
| | - Nandita Ravichandran
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, Tamil Nadu, India
| | | | - Roselin Gnanarajan
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, Tamil Nadu, India
| | - Mukesh Kumar Yadav
- Department of Microbiology, Central University of Punjab, Bathinda, India
| | - Arul Narayanasamy
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, Tamil Nadu, India.
| | - Balachandar Vellingiri
- Human Cytogenetics and Stem Cell Laboratory, Department of Zoology, School of Basic Sciences, Central University of Punjab, Bathinda, Punjab, India.
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Maler MD, Zwick S, Kallfass C, Engelhard P, Shi H, Hellig L, Zhengyang P, Hardt A, Zissel G, Ruzsics Z, Jahnen-Dechent W, Martin SF, Nielsen PJ, Stolz D, Lopatecka J, Bastyans S, Beutler B, Schamel WW, Fejer G, Freudenberg MA. Type I Interferon, Induced by Adenovirus or Adenoviral Vector Infection, Regulates the Cytokine Response to Lipopolysaccharide in a Macrophage Type-Specific Manner. J Innate Immun 2024; 16:226-247. [PMID: 38527452 PMCID: PMC11023693 DOI: 10.1159/000538282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/17/2023] [Accepted: 03/06/2024] [Indexed: 03/27/2024] Open
Abstract
INTRODUCTION While TLR ligands derived from microbial flora and pathogens are important activators of the innate immune system, a variety of factors such as intracellular bacteria, viruses, and parasites can induce a state of hyperreactivity, causing a dysregulated and potentially life-threatening cytokine over-response upon TLR ligand exposure. Type I interferon (IFN-αβ) is a central mediator in the induction of hypersensitivity and is strongly expressed in splenic conventional dendritic cells (cDC) and marginal zone macrophages (MZM) when mice are infected with adenovirus. This study investigates the ability of adenoviral infection to influence the activation state of the immune system and underlines the importance of considering this state when planning the treatment of patients. METHODS Infection with adenovirus-based vectors (Ad) or pretreatment with recombinant IFN-β was used as a model to study hypersensitivity to lipopolysaccharide (LPS) in mice, murine macrophages, and human blood samples. The TNF-α, IL-6, IFN-αβ, and IL-10 responses induced by LPS after pretreatment were measured. Mouse knockout models for MARCO, IFN-αβR, CD14, IRF3, and IRF7 were used to probe the mechanisms of the hypersensitive reaction. RESULTS We show that, similar to TNF-α and IL-6 but not IL-10, the induction of IFN-αβ by LPS increases strongly after Ad infection. This is true both in mice and in human blood samples ex vivo, suggesting that the regulatory mechanisms seen in the mouse are also present in humans. In mice, the scavenger receptor MARCO on IFN-αβ-producing cDC and splenic marginal zone macrophages is important for Ad uptake and subsequent cytokine overproduction by LPS. Interestingly, not all IFN-αβ-pretreated macrophage types exposed to LPS exhibit an enhanced TNF-α and IL-6 response. Pretreated alveolar macrophages and alveolar macrophage-like murine cell lines (MPI cells) show enhanced responses, while bone marrow-derived and peritoneal macrophages show a weaker response. This correlates with the respective absence or presence of the anti-inflammatory IL-10 response in these different macrophage types. In contrast, Ad or IFN-β pretreatment enhances the subsequent induction of IFN-αβ in all macrophage types. IRF3 is dispensable for the LPS-induced IFN-αβ overproduction in infected MPI cells and partly dispensable in infected mice, while IRF7 is required. The expression of the LPS co-receptor CD14 is important but not absolutely required for the elicitation of a TNF-α over-response to LPS in Ad-infected mice. CONCLUSION Viral infections or application of virus-based vaccines induces type I interferon and can tip the balance of the innate immune system in the direction of hyperreactivity to a subsequent exposure to TLR ligands. The adenoviral model presented here is one example of how multiple factors, both environmental and genetic, affect the physiological responses to pathogens. Being able to measure the current reactivity state of the immune system would have important benefits for infection-specific therapies and for the prevention of vaccination-elicited adverse effects.
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Affiliation(s)
- Mareike D. Maler
- Max-Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- Allergy Research Group, Department of Dermatology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Sophie Zwick
- Department of Pneumology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Carsten Kallfass
- Institute of Virology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Peggy Engelhard
- Department of Pneumology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Hexin Shi
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Laura Hellig
- Department of Pneumology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Pang Zhengyang
- Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Annika Hardt
- Department of Pneumology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Gernot Zissel
- Department of Pneumology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Zsolt Ruzsics
- Institute of Virology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Willi Jahnen-Dechent
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Stefan F. Martin
- Allergy Research Group, Department of Dermatology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Peter Jess Nielsen
- Max-Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
| | - Daiana Stolz
- Department of Pneumology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
| | - Justyna Lopatecka
- Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Faculty of Medicine, Aachen, Germany
| | - Sarah Bastyans
- Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Faculty of Medicine, Aachen, Germany
| | - Bruce Beutler
- Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Wolfgang W. Schamel
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany
- School of Biomedical Sciences, Faculty of Health, University of Plymouth, Plymouth, UK
| | - György Fejer
- Max-Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- Helmholtz-Institute for Biomedical Engineering, RWTH Aachen University, Faculty of Medicine, Aachen, Germany
| | - Marina Alexandra Freudenberg
- Max-Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
- Department of Pneumology, Medical Center – University of Freiburg, Faculty of Medicine, Freiburg, Germany
- Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany
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10
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Del Veliz S, Coughlan L. Viral platform engineering for targeted gene delivery to human hematopoietic stem cells. Mol Ther 2024; 32:6-8. [PMID: 38086382 PMCID: PMC10787161 DOI: 10.1016/j.ymthe.2023.11.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/28/2023] [Revised: 11/30/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Affiliation(s)
- Samanta Del Veliz
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Lynda Coughlan
- Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Center for Vaccine Development and Global Health (CVD), University of Maryland School of Medicine, Baltimore, MD 21201, USA.
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11
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Yao J, Atasheva S, Wagner N, Di Paolo NC, Stewart PL, Shayakhmetov DM. Targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells in vivo using the engineered AVID adenovirus vector platform. Mol Ther 2024; 32:103-123. [PMID: 37919899 PMCID: PMC10787117 DOI: 10.1016/j.ymthe.2023.10.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/14/2023] [Revised: 10/10/2023] [Accepted: 10/31/2023] [Indexed: 11/04/2023] Open
Abstract
Targeted delivery and cell-type-specific expression of gene-editing proteins in various cell types in vivo represent major challenges for all viral and non-viral delivery platforms developed to date. Here, we describe the development and analysis of artificial vectors for intravascular delivery (AVIDs), an engineered adenovirus-based gene delivery platform that allows for highly targeted, safe, and efficient gene delivery to human hematopoietic stem and progenitor cells (HSPCs) in vivo after intravenous vector administration. Due to a set of refined structural modifications, intravenous administration of AVIDs did not trigger cytokine storm, hepatotoxicity, or thrombocytopenia. Single intravenous administration of AVIDs to humanized mice, grafted with human CD34+ cells, led to up to 20% transduction of CD34+CD38-CD45RA- HSPC subsets in the bone marrow. Importantly, targeted in vivo transduction of CD34+CD38-CD45RA-CD90-CD49f+ subsets, highly enriched for human hematopoietic stem cells (HSCs), reached up to 19%, which represented a 1,900-fold selectivity in gene delivery to HSC-enriched over lineage-committed CD34-negative cell populations. Because the AVID platform allows for regulated, cell-type-specific expression of gene-editing technologies as well as expression of immunomodulatory proteins to ensure persistence of corrected HSCs in vivo, the HSC-targeted AVID platform may enable development of curative therapies through in vivo gene correction in human HSCs after a single intravenous administration.
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Affiliation(s)
- Jia Yao
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Svetlana Atasheva
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Nicole Wagner
- Cleveland Center for Membrane and Structural Biology, Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Nelson C Di Paolo
- AdCure Bio, LLC, Century Spring West, 6000 Lake Forrest Drive, Atlanta, GA 30328, USA
| | - Phoebe L Stewart
- Cleveland Center for Membrane and Structural Biology, Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Dmitry M Shayakhmetov
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA; Discovery and Developmental Therapeutics Program, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA.
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12
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Wang X, Hetzel M, Zhang W, Ehrhardt A, Bayer W. Comparative analysis of the impact of 40 adenovirus types on dendritic cell activation and CD8 + T cell proliferation capacity for the identification of favorable immunization vector candidates. Front Immunol 2023; 14:1286622. [PMID: 37915567 PMCID: PMC10616870 DOI: 10.3389/fimmu.2023.1286622] [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] [Academic Contribution Register] [Received: 08/31/2023] [Accepted: 10/04/2023] [Indexed: 11/03/2023] Open
Abstract
For the development of new adenovirus (AdV)-based vectors, it is important to understand differences in immunogenicity. In a side-by-side in vitro analysis, we evaluated the effect of 40 AdV types covering human AdV (HAdV) species A through G on the expression of 11 activation markers and the secretion of 12 cytokines by AdV-transduced dendritic cells, and the effect on CD8+ T cell proliferation capacity. We found that the expression of activation markers and cytokines differed widely between the different HAdV types, and many types were able to significantly impair the proliferation capacity of CD8+ T cells. Univariate and multivariate regression analyses suggested an important role of type I interferons in mediating this suppression of CD8+ T cells, which we confirmed experimentally in a proliferation assay using a type I interferon receptor blocking antibody. Using Bayesian statistics, we calculated a prediction model that suggests HAdV types HAdV-C1, -D8, -B7, -F41, -D33, -C2, -A31, -B3 and -D65 as the most favorable candidates for vaccine vector development.
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Affiliation(s)
- Xiaoyan Wang
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Mario Hetzel
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Wenli Zhang
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Anja Ehrhardt
- Virology and Microbiology, Center for Biomedical Education and Research (ZBAF), Faculty of Health, Witten/Herdecke University, Witten, Germany
| | - Wibke Bayer
- Institute for Virology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
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13
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Rice-Boucher PJ, Mendonça SA, Alvarez AB, Sturtz AJ, Lorincz R, Dmitriev IP, Kashentseva EA, Lu ZH, Romano R, Selby M, Pingale K, Curiel DT. Adenoviral vectors infect B lymphocytes in vivo. Mol Ther 2023; 31:2600-2611. [PMID: 37452494 PMCID: PMC10492023 DOI: 10.1016/j.ymthe.2023.07.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/07/2023] [Revised: 05/14/2023] [Accepted: 07/10/2023] [Indexed: 07/18/2023] Open
Abstract
B cells are the antibody-producing arm of the adaptive immune system and play a critical role in controlling pathogens. Several groups have now demonstrated the feasibility of using engineered B cells as a therapy, including infectious disease control and gene therapy of serum deficiencies. These studies have largely utilized ex vivo modification of the cells. Direct in vivo engineering would be of utility to the field, particularly in infectious disease control where the infrastructure needs of ex vivo cell modification would make a broad vaccination campaign highly challenging. In this study we demonstrate that engineered adenoviral vectors are capable of efficiently transducing murine and human primary B cells both ex vivo and in vivo. We found that unmodified human adenovirus C5 was capable of infecting B cells in vivo, likely due to interactions between the virus penton base protein and integrins. We further describe vector modification with B cell-specific gene promoters and successfully restrict transgene expression to B cells, resulting in a strong reduction in gene expression from the liver, the main site of human adenovirus C5 infection in vivo.
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Affiliation(s)
- Paul J Rice-Boucher
- Department of Radiation Oncology, Biologic Therapeutics Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in Saint Louis, St. Louis, MO, USA
| | - Samir Andrade Mendonça
- Department of Radiation Oncology, Biologic Therapeutics Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Aluet Borrego Alvarez
- Department of Radiation Oncology, Biologic Therapeutics Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Alexandria J Sturtz
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
| | - Reka Lorincz
- Department of Radiation Oncology, Biologic Therapeutics Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Igor P Dmitriev
- Department of Radiation Oncology, Biologic Therapeutics Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Elena A Kashentseva
- Department of Radiation Oncology, Biologic Therapeutics Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Zhi Hong Lu
- Department of Radiation Oncology, Biologic Therapeutics Center, Washington University School of Medicine, St. Louis, MO, USA
| | - Rosa Romano
- Walking Fish Therapeutics, Inc., South San Francisco, CA, USA
| | - Mark Selby
- Walking Fish Therapeutics, Inc., South San Francisco, CA, USA
| | - Kunal Pingale
- Department of Radiation Oncology, Biologic Therapeutics Center, Washington University School of Medicine, St. Louis, MO, USA
| | - David T Curiel
- Department of Radiation Oncology, Biologic Therapeutics Center, Washington University School of Medicine, St. Louis, MO, USA.
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14
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Panek I, Liczek M, Gabryelska A, Rakoczy I, Kuna P, Panek M. Inflammasome signalling pathway in the regulation of inflammation - its involvement in the development and exacerbation of asthma and chronic obstructive pulmonary disease. Postepy Dermatol Alergol 2023; 40:487-495. [PMID: 37692274 PMCID: PMC10485761 DOI: 10.5114/ada.2022.118077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/10/2021] [Accepted: 09/13/2021] [Indexed: 09/12/2023] Open
Abstract
Inflammasomes are multiprotein oligomers, whose main function is the recruitment and activation of caspase-1, which cleaves the precursor forms of interleukin (IL)-1β and IL-18, generating biologically active cytokines. Activation of inflammasome is an essential component of the innate immune response, and according to recent reports it is involved in epithelial homeostasis and type 2 T helper cell (Th2) differentiation. In recent years, the contribution of inflammasome dependent signalling pathways to the development of inflammatory diseases became a topic of multiple research studies. Asthma and chronic obstructive pulmonary disease (COPD) are the most prevalent obstructive lung diseases. Recent studies have focused on inflammatory aspects of asthma and COPD development, demonstrating the key role of inflammasome-dependent processes. Factors responsible for activation of inflammasome complex are similar in both asthma and COPD and include bacteria, viruses, cigarette smoke, and particulate matter. Some recent studies have revealed that NLRP3 inflammasome plays a crucial role, particularly in the development of acute exacerbations of COPD (AECOPD). Activation of NLRP3 inflammasome has been linked with neutrophilic severe steroid-resistant asthma. Although most of the studies on inflammasomes in asthma and COPD focused on the NLRP3 inflammasome, there are scarce scientific reports linking other inflammasomes such as AIM2 and NLRP1 with obstructive lung diseases. In this mini review we focus on the role of molecular pathways associated with inflammasome in the most prevalent lung diseases such as asthma and COPD. Furthermore, we will try to answer the question of whether inhibition of inflammasome can occur as a modern therapy in these diseases.
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Affiliation(s)
- Iga Panek
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Lodz, Poland
| | - Maciej Liczek
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Lodz, Poland
| | - Agata Gabryelska
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Lodz, Poland
| | - Igor Rakoczy
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Lodz, Poland
| | - Piotr Kuna
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Lodz, Poland
| | - Michał Panek
- Department of Internal Medicine, Asthma and Allergy, Medical University of Lodz, Lodz, Poland
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15
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Mazgaeen L, Yorek M, Saini S, Vogel P, Meyerholz DK, Kanneganti TD, Gurung P. CD47 halts Ptpn6-deficient neutrophils from provoking lethal inflammation. SCIENCE ADVANCES 2023; 9:eade3942. [PMID: 36608128 PMCID: PMC9821860 DOI: 10.1126/sciadv.ade3942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 05/06/2023]
Abstract
Mice with SHP1 proteins, which have a single amino acid substitution from tyrosine-208 residue to asparagine (hereafter Ptpn6spin mice), develop an autoinflammatory disease with inflamed footpads. Genetic crosses to study CD47 function in Ptpn6spin mice bred Ptpn6spin × Cd47-/- mice that were not born at the expected Mendelian ratio. Ptpn6spin bone marrow cells, when transferred into lethally irradiated Cd47-deficient mice, caused marked weight loss and subsequent death. At a cellular level, Ptpn6-deficient neutrophils promoted weight loss and death of the lethally irradiated Cd47-/- recipients. We posited that leakage of gut microbiota promotes morbidity and mortality in Cd47-/- mice receiving Ptpn6spin cells. Colonic cell death and gut leakage were substantially increased in the diseased Cd47-/- mice. Last, IL-1 blockade using anakinra rescued the morbidity and mortality observed in the diseased Cd47-/- mice. These data together demonstrate a protective role for CD47 in tempering pathogenic neutrophils in the Ptpn6spin mice.
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Affiliation(s)
- Lalita Mazgaeen
- Inflammation Program, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
| | - Matthew Yorek
- Inflammation Program, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Saurabh Saini
- Inflammation Program, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Peter Vogel
- Animal Resources Center and the Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
| | | | | | - Prajwal Gurung
- Inflammation Program, University of Iowa, Iowa City, IA 52242, USA
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
- Interdisciplinary Graduate Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA
- Immunology Graduate Program, University of Iowa, Iowa City, IA 52241, USA
- Center for Immunology and Immune-Based Disease, University of Iowa, Iowa City, IA 52241, USA
- Corresponding author.
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16
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Wang G, Zhang Z, Zhong K, Wang Z, Yang N, Tang X, Li H, Lu Q, Wu Z, Yuan B, Zheng M, Cheng P, Tong A, Zhou L. CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma. Mol Ther 2023; 31:134-153. [PMID: 36056553 PMCID: PMC9840126 DOI: 10.1016/j.ymthe.2022.08.021] [Citation(s) in RCA: 91] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/25/2022] [Revised: 08/15/2022] [Accepted: 08/26/2022] [Indexed: 01/28/2023] Open
Abstract
Glioblastoma (GBM) is the most aggressive primary malignant brain cancer and urgently requires effective treatments. Chimeric antigen receptor T (CAR-T) cell therapy offers a potential treatment method, but it is often hindered by poor infiltration of CAR-T cells in tumors and highly immunosuppressive tumor microenvironment (TME). Here, we armed an oncolytic adenovirus (oAds) with a chemokine CXCL11 to increase the infiltration of CAR-T cells and reprogram the immunosuppressive TME, thus improving its therapeutic efficacy. In both immunodeficient and immunocompetent orthotopic GBM mice models, we showed that B7H3-targeted CAR-T cells alone failed to inhibit GBM growth but, when combined with the intratumoral administration of CXCL11-armed oAd, it achieved a durable antitumor response. Besides, oAd-CXCL11 had a potent antitumor effect and reprogramed the immunosuppressive TME in GL261 GBM models, in which increased infiltration of CD8+ T lymphocytes, natural killer (NK) cells, and M1-polarized macrophages, while decreased proportions of myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs) and M2-polarized macrophages were observed. Furthermore, the antitumor effect of the oAd-CXCL11 was CD8+ T cell dependent. Our findings thus revealed that CXCL11-armed oAd can improve immune-virotherapy and can be a promising adjuvant of CAR-T therapy for GBM.
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Affiliation(s)
- Guoqing Wang
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China
| | - Zongliang Zhang
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Kunhong Zhong
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Zeng Wang
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Nian Yang
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Xin Tang
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China
| | - Hexian Li
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Qizhong Lu
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Zhiguo Wu
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Boyang Yuan
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China
| | - Meijun Zheng
- Department of Otolaryngology, Head and Neck Surgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China
| | - Ping Cheng
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China
| | - Aiping Tong
- State Key Laboratory of Biotherapy and Cancer Center, Research Unit of Gene and Immunotherapy, Chinese Academy of Medical Sciences, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
| | - Liangxue Zhou
- Department of Neurosurgery, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, PR China.
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Abstract
PURPOSE OF REVIEW Oncolytic viruses (OVs) exert their antitumor effect through selective killing of cancer cells and induction of host anti-tumor immunity. This review aims to summarize the recent and current trials with OVs for the treatment of lung cancer. RECENT FINDINGS Several OVs have been developed for the treatment of lung cancer including adenovirus, coxsackievirus B3, reovirus, and vaccinia virus and trials have demonstrated a safe toxicity profile. Early-phase trials in lung cancer with OVs have reported antiviral immune responses and evidence of clinical benefit. However, clinical efficacy of OVs in lung cancer either as monotherapy or in combination with chemotherapy has not been confirmed in larger phase II or III trials. Development of OVs in lung cancer has been limited by difficulty in administering OVs in the tumor directly as well as achieving adequate viral load at all tumor sites with systemically administered OVs. Developing novel combinations with OVs, especially checkpoint inhibitors and other immunotherapeutics, may be a strategy to address the limited success seen thus far. Integrating appropriate biomarker studies and meaningful endpoints in future clinical trials will be imperative. Using novel viral delivery systems in addition to increasing tumor specificity through improved genetic modifications in the OVs are other strategies to improve efficacy.
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Affiliation(s)
- Jyoti Malhotra
- Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Pavilion Building- Medical Oncology, 1500 E. Duarte Road, Duarte, CA, 91020, USA.
| | - Edward S Kim
- Medical Oncology & Therapeutics Research, City of Hope Comprehensive Cancer Center, Pavilion Building- Medical Oncology, 1500 E. Duarte Road, Duarte, CA, 91020, USA
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18
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Wang WC, Sayedahmed EE, Mittal SK. Significance of Preexisting Vector Immunity and Activation of Innate Responses for Adenoviral Vector-Based Therapy. Viruses 2022; 14:v14122727. [PMID: 36560730 PMCID: PMC9787786 DOI: 10.3390/v14122727] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/28/2022] [Revised: 12/01/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
An adenoviral (AdV)-based vector system is a promising platform for vaccine development and gene therapy applications. Administration of an AdV vector elicits robust innate immunity, leading to the development of humoral and cellular immune responses against the vector and the transgene antigen, if applicable. The use of high doses (1011-1013 virus particles) of an AdV vector, especially for gene therapy applications, could lead to vector toxicity due to excessive levels of innate immune responses, vector interactions with blood factors, or high levels of vector transduction in the liver and spleen. Additionally, the high prevalence of AdV infections in humans or the first inoculation with the AdV vector result in the development of vector-specific immune responses, popularly known as preexisting vector immunity. It significantly reduces the vector efficiency following the use of an AdV vector that is prone to preexisting vector immunity. Several approaches have been developed to overcome this problem. The utilization of rare human AdV types or nonhuman AdVs is the primary strategy to evade preexisting vector immunity. The use of heterologous viral vectors, capsid modification, and vector encapsulation are alternative methods to evade vector immunity. The vectors can be optimized for clinical applications with comprehensive knowledge of AdV vector immunity, toxicity, and circumvention strategies.
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19
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Malireddi RS, Bynigeri RR, Kancharana B, Sharma BR, Burton AR, Pelletier S, Kanneganti TD. Determining distinct roles of IL-1α through generation of an IL-1α knockout mouse with no defect in IL-1β expression. Front Immunol 2022; 13:1068230. [PMID: 36505497 PMCID: PMC9729281 DOI: 10.3389/fimmu.2022.1068230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/12/2022] [Accepted: 11/10/2022] [Indexed: 11/25/2022] Open
Abstract
Interleukin 1α (IL-1α) and IL-1β are the founding members of the IL-1 cytokine family, and these innate immune inflammatory mediators are critically important in health and disease. Early studies on these molecules suggested that their expression was interdependent, with an initial genetic model of IL-1α depletion, the IL-1α KO mouse (Il1a-KOline1), showing reduced IL-1β expression. However, studies using this line in models of infection and inflammation resulted in contrasting observations. To overcome the limitations of this genetic model, we have generated and characterized a new line of IL-1α KO mice (Il1a-KOline2) using CRISPR-Cas9 technology. In contrast to cells from Il1a-KOline1, where IL-1β expression was drastically reduced, bone marrow-derived macrophages (BMDMs) from Il1a-KOline2 mice showed normal induction and activation of IL-1β. Additionally, Il1a-KOline2 BMDMs showed normal inflammasome activation and IL-1β expression in response to multiple innate immune triggers, including both pathogen-associated molecular patterns and pathogens. Moreover, using Il1a-KOline2 cells, we confirmed that IL-1α, independent of IL-1β, is critical for the expression of the neutrophil chemoattractant KC/CXCL1. Overall, we report the generation of a new line of IL-1α KO mice and confirm functions for IL-1α independent of IL-1β. Future studies on the unique functions of IL-1α and IL-1β using these mice will be critical to identify new roles for these molecules in health and disease and develop therapeutic strategies.
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20
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Wang G, Liu Y, Liu S, Lin Y, Hu C. Oncolyic Virotherapy for Prostate Cancer: Lighting a Fire in Winter. Int J Mol Sci 2022; 23:12647. [PMID: 36293504 PMCID: PMC9603894 DOI: 10.3390/ijms232012647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/20/2022] [Revised: 09/30/2022] [Accepted: 10/07/2022] [Indexed: 11/11/2022] Open
Abstract
As the most common cancer of the genitourinary system, prostate cancer (PCa) is a global men's health problem whose treatments are an urgent research issue. Treatment options for PCa include active surveillance (AS), surgery, endocrine therapy, chemotherapy, radiation therapy, immunotherapy, etc. However, as the cancer progresses, the effectiveness of treatment options gradually decreases, especially in metastatic castration-resistant prostate cancer (mCRPC), for which there are fewer therapeutic options and which have a shorter survival period and worse prognosis. For this reason, oncolytic viral therapy (PV), with its exceptional properties of selective tumor killing, relatively good safety in humans, and potential for transgenic delivery, has attracted increasing attention as a new form of anti-tumor strategy for PCa. There is growing evidence that OV not only kills tumor cells directly by lysis but can also activate anticancer immunity by acting on the tumor microenvironment (TME), thereby preventing tumor growth. In fact, evidence of the efficacy of this strategy has been observed since the late 19th century. However, subsequently, interest waned. The renewed interest in this therapy was due to advances in biotechnological methods and innovations at the end of the 20th century, which was also the beginning of PCa therapy with OV. Moreover, in combination with chemotherapy, radiotherapy, gene therapy or immunotherapy, OV viruses can have a wide range of applications and can provide an effective therapeutic result in the treatment of PCa.
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Affiliation(s)
- Gongwei Wang
- Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Ying Liu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Shuoru Liu
- Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Yuan Lin
- Department of Pharmacology, Sun Yat-sen University, Guangzhou 528478, China
| | - Cheng Hu
- Department of Urology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
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21
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Naumenko VA, Vishnevskiy DA, Stepanenko AA, Sosnovtseva AO, Chernysheva AA, Abakumova TO, Valikhov MP, Lipatova AV, Abakumov MA, Chekhonin VP. In Vivo Tracking for Oncolytic Adenovirus Interactions with Liver Cells. Biomedicines 2022; 10:biomedicines10071697. [PMID: 35885002 PMCID: PMC9313019 DOI: 10.3390/biomedicines10071697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/09/2022] [Revised: 07/01/2022] [Accepted: 07/10/2022] [Indexed: 11/28/2022] Open
Abstract
Hepatotoxicity remains an as yet unsolved problem for adenovirus (Ad) cancer therapy. The toxic effects originate both from rapid Kupffer cell (KCs) death (early phase) and hepatocyte transduction (late phase). Several host factors and capsid components are known to contribute to hepatotoxicity, however, the complex interplay between Ad and liver cells is not fully understood. Here, by using intravital microscopy, we aimed to follow the infection and immune response in mouse liver from the first minutes up to 72 h post intravenous injection of three Ads carrying delta-24 modification (Ad5-RGD, Ad5/3, and Ad5/35). At 15–30 min following the infusion of Ad5-RGD and Ad5/3 (but not Ad5/35), the virus-bound macrophages demonstrated signs of zeiosis: the formation of long-extended protrusions and dynamic membrane blebbing with the virus release into the blood in the membrane-associated vesicles. Although real-time imaging revealed interactions between the neutrophils and virus-bound KCs within minutes after treatment, and long-term contacts of CD8+ T cells with transduced hepatocytes at 24–72 h, depletion of neutrophils and CD8+ T cells affected neither rate nor dynamics of liver infection. Ad5-RGD failed to complete replicative cycle in hepatocytes, and transduced cells remained impermeable for propidium iodide, with a small fraction undergoing spontaneous apoptosis. In Ad5-RGD-immune mice, the virus neither killed KCs nor transduced hepatocytes, while in the setting of hepatic regeneration, Ad5-RGD enhanced liver transduction. The clinical and biochemical signs of hepatotoxicity correlated well with KC death, but not hepatocyte transduction. Real-time in vivo tracking for dynamic interactions between virus and host cells provides a better understanding of mechanisms underlying Ad-related hepatotoxicity.
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Affiliation(s)
- Victor A. Naumenko
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
- Correspondence:
| | - Daniil A. Vishnevskiy
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
| | - Aleksei A. Stepanenko
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
- Department of Medical Nanobiotechnology, N.I Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
| | - Anastasiia O. Sosnovtseva
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
| | - Anastasiia A. Chernysheva
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
| | - Tatiana O. Abakumova
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, 121205 Moscow, Russia;
| | - Marat P. Valikhov
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
| | - Anastasiia V. Lipatova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia;
| | - Maxim A. Abakumov
- Department of Medical Nanobiotechnology, N.I Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
- Laboratory of Biomedical Nanomaterials, National University of Science and Technology (MISIS), 119049 Moscow, Russia
| | - Vladimir P. Chekhonin
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, 119034 Moscow, Russia; (D.A.V.); (A.A.S.); (A.O.S.); (A.A.C.); (M.P.V.); (V.P.C.)
- Department of Medical Nanobiotechnology, N.I Pirogov Russian National Research Medical University, 117997 Moscow, Russia;
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22
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Zheng N, Wang Y, Rong H, Wang K, Huang X. Human Adenovirus Associated Hepatic Injury. Front Public Health 2022; 10:878161. [PMID: 35570934 PMCID: PMC9095934 DOI: 10.3389/fpubh.2022.878161] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/17/2022] [Accepted: 03/16/2022] [Indexed: 01/08/2023] Open
Abstract
Human adenovirus (HAdV) is a common virus, but the infections it causes are relatively uncommon. At the same time, the methods for the detection of HAdV are varied, among which viral culture is still the gold standard. HAdV infection is usually self-limited but can also cause clinically symptomatic in lots of organs and tissues, of which human adenovirus pneumonia is the most common. In contrast, human adenovirus hepatitis is rarely reported. However, HAdV hepatitis has a high fatality rate once it occurs, especially in immunocompromised patients. Although human adenovirus hepatitis has some pathological and imaging features, its clinical symptoms are not typical. Therefore, HAdV hepatitis is not easy to be found in the clinic. There are kinds of treatments to treat this disease, but few are absolutely effective. In view of the above reasons, HAdV hepatitis is a disease that is difficult to be found in time. We reviewed and summarized the previously reported cases, hoping to bring some relatively common characteristics to clinicians, so as to facilitate early detection, early diagnosis, and early treatment of patients.
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Affiliation(s)
- Nan Zheng
- Department of Infectious Diseases, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Yan Wang
- Department of Infectious Diseases, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Hechen Rong
- Department of Infectious Diseases, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Kun Wang
- Department of Gastroenterology, First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xiaoping Huang
- Department of Infectious Diseases, First Affiliated Hospital of Soochow University, Suzhou, China
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23
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Cytokine Responses to Adenovirus and Adenovirus Vectors. Viruses 2022; 14:v14050888. [PMID: 35632630 PMCID: PMC9145601 DOI: 10.3390/v14050888] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/30/2022] [Revised: 04/18/2022] [Accepted: 04/20/2022] [Indexed: 12/15/2022] Open
Abstract
The expression of cytokines and chemokines in response to adenovirus infection is tightly regulated by the innate immune system. Cytokine-mediated toxicity and cytokine storm are known clinical phenomena observed following naturally disseminated adenovirus infection in immunocompromised hosts as well as when extremely high doses of adenovirus vectors are injected intravenously. This dose-dependent, cytokine-mediated toxicity compromises the safety of adenovirus-based vectors and represents a critical problem, limiting their utility for gene therapy applications and the therapy of disseminated cancer, where intravenous injection of adenovirus vectors may provide therapeutic benefits. The mechanisms triggering severe cytokine response are not sufficiently understood, prompting efforts to further investigate this phenomenon, especially in clinically relevant settings. In this review, we summarize the current knowledge on cytokine and chemokine activation in response to adenovirus- and adenovirus-based vectors and discuss the underlying mechanisms that may trigger acute cytokine storm syndrome. First, we review profiles of cytokines and chemokines that are activated in response to adenovirus infection initiated via different routes. Second, we discuss the molecular mechanisms that lead to cytokine and chemokine transcriptional activation. We further highlight how immune cell types in different organs contribute to synthesis and systemic release of cytokines and chemokines in response to adenovirus sensing. Finally, we review host factors that can limit cytokine and chemokine expression and discuss currently available and potential future interventional approaches that allow for the mitigation of the severity of the cytokine storm syndrome. Effective cytokine-targeted interventional approaches may improve the safety of systemic adenovirus delivery and thus broaden the potential clinical utility of adenovirus-based therapeutic vectors.
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24
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Nestić D, Božinović K, Drašković I, Kovačević A, van den Bosch J, Knežević J, Custers J, Ambriović-Ristov A, Majhen D. Human Adenovirus Type 26 Induced IL-6 Gene Expression in an αvβ3 Integrin- and NF-κB-Dependent Manner. Viruses 2022; 14:v14040672. [PMID: 35458402 PMCID: PMC9028149 DOI: 10.3390/v14040672] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/11/2022] [Revised: 03/16/2022] [Accepted: 03/22/2022] [Indexed: 11/17/2022] Open
Abstract
The low seroprevalent human adenovirus type 26 (HAdV26)-based vaccine vector was the first adenovirus-based vector to receive marketing authorization from European Commission. HAdV26-based vaccine vectors induce durable humoral and cellular immune responses and, as such, represent a highly valuable tool for fighting infectious diseases. Despite well-described immunogenicity in vivo, the basic biology of HAdV26 still needs some refinement. The aim of this study was to determine the pro-inflammatory cytokine profile of epithelial cells infected with HAdV26 and then investigate the underlying molecular mechanism. The expression of studied genes and proteins was assessed by quantitative polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay. Confocal microscopy was used to visualize HAdV26 cell uptake. We found that HAdV26 infection in human epithelial cells triggers the expression of pro-inflammatory cytokines and chemokines, namely IL-6, IL-8, IL-1β, and TNF-α, with the most pronounced difference shown for IL-6. We investigated the underlying molecular mechanism and observed that HAdV26-induced IL-6 gene expression is αvβ3 integrin dependent and NF-κB mediated. Our findings provide new data regarding pro-inflammatory cytokine and chemokine expression in HAdV26-infected epithelial cells, as well as details concerning HAdV26-induced host signaling pathways. Information obtained within this research increases our current knowledge of HAdV26 basic biology and, as such, can contribute to further development of HAdV26-based vaccine vectors.
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Affiliation(s)
- Davor Nestić
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.D.); (A.K.); (J.v.d.B.); (A.A.-R.)
| | - Ksenija Božinović
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.D.); (A.K.); (J.v.d.B.); (A.A.-R.)
| | - Isabela Drašković
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.D.); (A.K.); (J.v.d.B.); (A.A.-R.)
| | - Alen Kovačević
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.D.); (A.K.); (J.v.d.B.); (A.A.-R.)
| | - Jolien van den Bosch
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.D.); (A.K.); (J.v.d.B.); (A.A.-R.)
| | - Jelena Knežević
- Laboratory for Advanced Genomics, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia;
- Faculty for Dental Medicine and Health, University of Osijek, 31000 Osijek, Croatia
| | - Jerome Custers
- Janssen Vaccines and Preventions BV, 2333 CA Leiden, The Netherlands;
| | - Andreja Ambriović-Ristov
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.D.); (A.K.); (J.v.d.B.); (A.A.-R.)
| | - Dragomira Majhen
- Laboratory for Cell Biology and Signalling, Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.D.); (A.K.); (J.v.d.B.); (A.A.-R.)
- Correspondence:
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25
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Cirillo E, Esposito C, Giardino G, Azan G, Fecarotta S, Pittaluga S, Ruggiero L, Barretta F, Frisso G, Notarangelo LD, Pignata C. Case Report: Severe Rhabdomyolysis and Multiorgan Failure After ChAdOx1 nCoV-19 Vaccination. Front Immunol 2022; 13:845496. [PMID: 35371100 PMCID: PMC8968726 DOI: 10.3389/fimmu.2022.845496] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/29/2021] [Accepted: 02/28/2022] [Indexed: 12/18/2022] Open
Abstract
Background Severe skeletal muscle damage has been recently reported in patients with SARS-CoV-2 infection and as a rare vaccination complication. Case summary On Apr 28, 2021 a 68-year-old man who was previously healthy presented with an extremely severe rhabdomyolysis that occurred nine days following the first dose of SARS-CoV-2 ChAdOx1 nCov-19 vaccination. He had no risk factors, and denied any further assumption of drugs except for fermented red rice, and berberine supplement. The clinical scenario was complicated by a multi organ failure involving bone marrow, liver, lung, and kidney. For the rapid increase of the inflammatory markers, a cytokine storm was suspected and multi-target biologic immunosuppressive therapy was started, consisting of steroids, anakinra, and eculizumab, which was initially successful resulting in close to normal values of creatine phosphokinase after 17 days of treatment. Unfortunately, 48 days after the vaccination an accelerated phase of deterioration, characterized by severe multi-lineage cytopenia, untreatable hypotensive shock, hypoglycemia, and dramatic increase of procalcitonin (PCT), led to patient death. Conclusion Physicians should be aware that severe and fatal rhabdomyolysis may occur after SARS-CoV2 vaccine administration.
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Affiliation(s)
- Emilia Cirillo
- Departments of Translational Medical Sciences, Pediatric Section, Federico II University of Naples, Naples, Italy
| | - Ciro Esposito
- Department of Transplants, A. Cardarelli Hospital, Naples, Italy
| | - Giuliana Giardino
- Departments of Translational Medical Sciences, Pediatric Section, Federico II University of Naples, Naples, Italy
| | - Gaetano Azan
- Department of Transplants, A. Cardarelli Hospital, Naples, Italy
| | - Simona Fecarotta
- Departments of Translational Medical Sciences, Pediatric Section, Federico II University of Naples, Naples, Italy
| | - Stefania Pittaluga
- Laboratory of Pathology Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Lucia Ruggiero
- Department of Neuroscience, Reproductive and Odontostomatological Science, Federico II University of Naples, Naples, Italy
| | - Ferdinando Barretta
- Department of Molecular Medicine and Medical Biotechnology , Federico II University of Naples, Naples, Italy
| | - Giulia Frisso
- Department of Molecular Medicine and Medical Biotechnology , Federico II University of Naples, Naples, Italy
| | - Luigi Daniele Notarangelo
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Claudio Pignata
- Departments of Translational Medical Sciences, Pediatric Section, Federico II University of Naples, Naples, Italy
- *Correspondence: Claudio Pignata,
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26
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Enhancement of CD70-specific CAR T treatment by IFN-γ released from oHSV-1-infected glioblastoma. Cancer Immunol Immunother 2022; 71:2433-2448. [PMID: 35249119 DOI: 10.1007/s00262-022-03172-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/07/2021] [Accepted: 02/11/2022] [Indexed: 12/17/2022]
Abstract
Even with progressive combination treatments, the prognosis of patients with glioblastoma (GBM) remains extremely poor. OV is one of the new promising therapeutic strategies to treat human GBM. OVs stimulate immune cells to release cytokines such as IFN-γ during oncolysis, further improve tumor microenvironment (TME) and enhance therapeutic efficacy. IFN-γ plays vital role in the apoptosis of tumor cells and recruitment of tumor-infiltrating T cells. We hypothesized that oncolytic herpes simplex virus-1 (oHSV-1) enhanced the antitumor efficacy of novel CD70-specific chimeric antigen receptor (CAR) T cells by T cell infiltration and IFN-γ release. In this study, oHSV-1 has the potential to stimulate IFN-γ secretion of tumor cells rather than T cell secretion and lead to an increase of T cell activity, as well as CD70-specific CAR T cells can specifically recognize and kill tumor cells in vitro. Specifically, combinational therapy with CD70-specific CAR T and oHSV-1 promotes tumor degradation by enhancing pro-inflammatory circumstances and reducing anti-inflammatory factors in vitro. More importantly, combined therapy generated potent antitumor efficacy, increased the proportion of T cells and natural killer cells in TME, and reduced regulatory T cells and transformed growth factor-β1 expression in orthotopic xenotransplanted animal model of GBM. In summary, we reveal that oHSV-1 enhance the therapeutic efficacy of CD70-spefific CAR T cells by intratumoral T cell infiltration and IFN-γ release, supporting the use of CAR T therapy in GBM therapeutic strategies.
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27
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Naumenko VA, Stepanenko AA, Lipatova AV, Vishnevskiy DA, Chekhonin VP. Infection of non-cancer cells: A barrier or support for oncolytic virotherapy? MOLECULAR THERAPY - ONCOLYTICS 2022; 24:663-682. [PMID: 35284629 PMCID: PMC8898763 DOI: 10.1016/j.omto.2022.02.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 12/14/2022]
Abstract
Oncolytic viruses are designed to specifically target cancer cells, sparing normal cells. Although numerous studies demonstrate the ability of oncolytic viruses to infect a wide range of non-tumor cells, the significance of this phenomenon for cancer virotherapy is poorly understood. To fill the gap, we summarize the data on infection of non-cancer targets by oncolytic viruses with a special focus on tumor microenvironment and secondary lymphoid tissues. The review aims to address two major questions: how do attenuated viruses manage to infect normal cells, and whether it is of importance for oncolytic virotherapy.
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Affiliation(s)
- Victor A. Naumenko
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
- Corresponding author Victor A. Naumenko, PhD, V. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia.
| | - Aleksei A. Stepanenko
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
- Department of Medical Nanobiotechnology, N.I Pirogov Russian National Research Medical University, Moscow 117997, Russia
| | - Anastasiia V. Lipatova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia
| | - Daniil A. Vishnevskiy
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
| | - Vladimir P. Chekhonin
- V. Serbsky National Medical Research Center for Psychiatry and Narcology, Moscow 119034, Russia
- Department of Medical Nanobiotechnology, N.I Pirogov Russian National Research Medical University, Moscow 117997, Russia
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Adenovirus Type 6: Subtle Structural Distinctions from Adenovirus Type 5 Result in Essential Differences in Properties and Perspectives for Gene Therapy. Pharmaceutics 2021; 13:pharmaceutics13101641. [PMID: 34683934 PMCID: PMC8540711 DOI: 10.3390/pharmaceutics13101641] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/08/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 01/22/2023] Open
Abstract
Adenovirus vectors are the most frequently used agents for gene therapy, including oncolytic therapy and vaccine development. It’s hard to overestimate the value of adenoviruses during the COVID-19 pandemic as to date four out of four approved viral vector-based SARS-CoV-2 vaccines are developed on adenovirus platform. The vast majority of adenoviral vectors are based on the most studied human adenovirus type 5 (HAdV-C5), however, its immunogenicity often hampers the clinical translation of HAdV-C5 vectors. The search of less seroprevalent adenovirus types led to another species C adenovirus, Adenovirus type 6 (HAdV-C6). HAdV-C6 possesses high oncolytic efficacy against multiple cancer types and remarkable ability to induce the immune response towards carrying antigens. Being genetically very close to HAdV-C5, HAdV-C6 differs from HAdV-C5 in structure of the most abundant capsid protein, hexon. This leads to the ability of HAdV-C6 to evade the uptake by Kupffer cells as well as to distinct opsonization by immunoglobulins and other blood proteins, influencing the overall biodistribution of HAdV-C6 after systemic administration. This review describes the structural features of HAdV-C6, its interaction with liver cells and blood factors, summarizes the previous experiences using HAdV-C6, and provides the rationale behind the use of HAdV-C6 for vaccine and anticancer drugs developments.
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Macrophage Depletion via Clodronate Pretreatment Reduces Transgene Expression from AAV Vectors In Vivo. Viruses 2021; 13:v13102002. [PMID: 34696433 PMCID: PMC8538323 DOI: 10.3390/v13102002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/24/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 01/12/2023] Open
Abstract
Adeno-associated virus is a popular gene delivery vehicle for gene therapy studies. A potential roadblock to widespread clinical adoption is the high vector doses required for efficient transduction in vivo, and the potential for subsequent immune responses that may limit prolonged transgene expression. We hypothesized that the depletion of macrophages via systemic delivery of liposome-encapsulated clodronate would improve transgene expression if given prior to systemic AAV vector administration, as has been shown to be the case with adenoviral vectors. Contrary to our expectations, clodronate liposome pretreatment resulted in significantly reduced transgene expression in the liver and heart, but permitted moderate transduction of the white pulp of the spleen. There was a remarkable localization of transgene expression from the red pulp to the center of the white pulp in clodronate-treated mice compared to untreated mice. Similarly, a greater proportion of transgene expression could be observed in the medulla located in the center of the lymph node in mice treated with clodronate-containing liposomes as compared to untreated mice where transgene expression was localized primarily to the cortex. These results underscore the highly significant role that the immune system plays in influencing the distribution and relative numbers of transduced cells in the context of AAV-mediated gene delivery.
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30
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Nestić D, Božinović K, Pehar I, Wallace R, Parker AL, Majhen D. The Revolving Door of Adenovirus Cell Entry: Not All Pathways Are Equal. Pharmaceutics 2021; 13:1585. [PMID: 34683878 PMCID: PMC8540258 DOI: 10.3390/pharmaceutics13101585] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 08/28/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 01/18/2023] Open
Abstract
Adenoviruses represent exceptional candidates for wide-ranging therapeutic applications, from vectors for gene therapy to oncolytics for cancer treatments. The first ever commercial gene therapy medicine was based on a recombinant adenovirus vector, while most recently, adenoviral vectors have proven critical as vaccine platforms in effectively controlling the global coronavirus pandemic. Here, we discuss factors involved in adenovirus cell binding, entry, and trafficking; how they influence efficiency of adenovirus-based vectors; and how they can be manipulated to enhance efficacy of genetically modified adenoviral variants. We focus particularly on endocytosis and how different adenovirus serotypes employ different endocytic pathways to gain cell entry, and thus, have different intracellular trafficking pathways that subsequently trigger different host antiviral responses. In the context of gene therapy, the final goal of the adenovirus vector is to efficiently deliver therapeutic transgenes into the target cell nucleus, thus allowing its functional expression. Aberrant or inefficient endocytosis can impede this goal, therefore, it should be considered when designing and constructing adenovirus-based vectors.
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Affiliation(s)
- Davor Nestić
- Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.P.)
| | - Ksenija Božinović
- Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.P.)
| | - Isabela Pehar
- Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.P.)
| | - Rebecca Wallace
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; (R.W.); (A.L.P.)
| | - Alan L. Parker
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; (R.W.); (A.L.P.)
| | - Dragomira Majhen
- Division of Molecular Biology, Ruđer Bošković Institute, 10000 Zagreb, Croatia; (D.N.); (K.B.); (I.P.)
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31
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Biserni GB, Scarpini S, Dondi A, Biagi C, Pierantoni L, Masetti R, Sureshkumar S, Rocca A, Lanari M. Potential Diagnostic and Prognostic Biomarkers for Adenovirus Respiratory Infection in Children and Young Adults. Viruses 2021; 13:1885. [PMID: 34578465 PMCID: PMC8472906 DOI: 10.3390/v13091885] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/30/2021] [Revised: 09/05/2021] [Accepted: 09/14/2021] [Indexed: 01/03/2023] Open
Abstract
Human Adenoviruses (HAdV) are known to be potentially associated with strong inflammatory responses and morbidity in pediatric patients. Although most of the primary infections are self-limiting, the severity of clinical presentation, the elevation of the white blood cell count and inflammatory markers often mimic a bacterial infection and lead to an inappropriate use of antibiotics. In infections caused by HAdV, rapid antigen detection kits are advisable but not employed routinely; costs and feasibility of rapid syndromic molecular diagnosis may limit its use in the in-hospital setting; lymphocyte cultures and two-sampled serology are time consuming and impractical when considering the use of antibiotics. In this review, we aim to describe the principal diagnostic tools and the immune response in HAdV infections and evaluate whether markers based on the response of the host may help early recognition of HAdV and avoid inappropriate antimicrobial prescriptions in acute airway infections.
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Affiliation(s)
- Giovanni Battista Biserni
- Specialty School of Pediatrics, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (G.B.B.); (S.S.)
| | - Sara Scarpini
- Specialty School of Pediatrics, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (G.B.B.); (S.S.)
| | - Arianna Dondi
- Pediatric Emergency Unit, Scientific Institute for Research and Healthcare (IRCCS), Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy; (C.B.); (L.P.); (A.R.); (M.L.)
| | - Carlotta Biagi
- Pediatric Emergency Unit, Scientific Institute for Research and Healthcare (IRCCS), Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy; (C.B.); (L.P.); (A.R.); (M.L.)
| | - Luca Pierantoni
- Pediatric Emergency Unit, Scientific Institute for Research and Healthcare (IRCCS), Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy; (C.B.); (L.P.); (A.R.); (M.L.)
| | - Riccardo Masetti
- Pediatric Unit, Scientific Institute for Research and Healthcare (IRCCS), Sant Orsola Hospital, 40138 Bologna, Italy;
| | | | - Alessandro Rocca
- Pediatric Emergency Unit, Scientific Institute for Research and Healthcare (IRCCS), Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy; (C.B.); (L.P.); (A.R.); (M.L.)
| | - Marcello Lanari
- Pediatric Emergency Unit, Scientific Institute for Research and Healthcare (IRCCS), Azienda Ospedaliero—Universitaria di Bologna, 40138 Bologna, Italy; (C.B.); (L.P.); (A.R.); (M.L.)
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32
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Rojas JM, Sevilla N, Martín V. A New Look at Vaccine Strategies Against PPRV Focused on Adenoviral Candidates. Front Vet Sci 2021; 8:729879. [PMID: 34568477 PMCID: PMC8455998 DOI: 10.3389/fvets.2021.729879] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/24/2021] [Accepted: 08/09/2021] [Indexed: 11/28/2022] Open
Abstract
Peste des petits ruminants virus (PPRV) is a virus that mainly infects goats and sheep causing significant economic loss in Africa and Asia, but also posing a serious threat to Europe, as recent outbreaks in Georgia (2016) and Bulgaria (2018) have been reported. In order to carry out the eradication of PPRV, an objective set for 2030 by the Office International des Epizooties (OIE) and the Food and Agriculture Organization of the United Nations (FAO), close collaboration between governments, pharmaceutical companies, farmers and researchers, among others, is needed. Today, more than ever, as seen in the response to the SARS-CoV2 pandemic that we are currently experiencing, these goals are feasible. We summarize in this review the current vaccination approaches against PPRV in the field, discussing their advantages and shortfalls, as well as the development and generation of new vaccination strategies, focusing on the potential use of adenovirus as vaccine platform against PPRV and more broadly against other ruminant pathogens.
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Affiliation(s)
| | | | - Verónica Martín
- Centro de Investigación en Sanidad Animal (CISA-INIA-CSIC), Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria, Consejo Superior de Investigaciones Científicas, Madrid, Spain
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33
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Hofman L, Lawler SE, Lamfers MLM. The Multifaceted Role of Macrophages in Oncolytic Virotherapy. Viruses 2021; 13:v13081570. [PMID: 34452439 PMCID: PMC8402704 DOI: 10.3390/v13081570] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 06/22/2021] [Revised: 07/27/2021] [Accepted: 07/30/2021] [Indexed: 12/16/2022] Open
Abstract
One of the cancer hallmarks is immune evasion mediated by the tumour microenvironment (TME). Oncolytic virotherapy is a form of immunotherapy based on the application of oncolytic viruses (OVs) that selectively replicate in and induce the death of tumour cells. Virotherapy confers reciprocal interaction with the host’s immune system. The aim of this review is to explore the role of macrophage-mediated responses in oncolytic virotherapy efficacy. The approach was to study current scientific literature in this field in order to give a comprehensive overview of the interactions of OVs and macrophages and their effects on the TME. The innate immune system has a central influence on the TME; tumour-associated macrophages (TAMs) generally have immunosuppressive, tumour-supportive properties. In the context of oncolytic virotherapy, macrophages were initially thought to predominantly contribute to anti-viral responses, impeding viral spread. However, macrophages have now also been found to mediate transport of OV particles and, after TME infiltration, to be subjected to a phenotypic shift that renders them pro-inflammatory and tumour-suppressive. These TAMs can present tumour antigens leading to a systemic, durable, adaptive anti-tumour immune response. After phagocytosis, they can recirculate carrying tissue-derived proteins, which potentially enables the monitoring of OV replication in the TME. Their role in therapeutic efficacy is therefore multifaceted, but based on research applying relevant, immunocompetent tumour models, macrophages are considered to have a central function in anti-cancer activity. These novel insights hold important clinical implications. When optimised, oncolytic virotherapy, mediating multifactorial inhibition of cancer immune evasion, could contribute to improved patient survival.
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Affiliation(s)
- Laura Hofman
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands;
| | - Sean E. Lawler
- Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115, USA;
| | - Martine L. M. Lamfers
- Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Wytemaweg 80, 3015 CN Rotterdam, The Netherlands;
- Correspondence: ; Tel.: +31-010-703-5993
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34
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Daussy CF, Pied N, Wodrich H. Understanding Post Entry Sorting of Adenovirus Capsids; A Chance to Change Vaccine Vector Properties. Viruses 2021; 13:1221. [PMID: 34202573 PMCID: PMC8310329 DOI: 10.3390/v13071221] [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] [Academic Contribution Register] [Received: 05/14/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/25/2022] Open
Abstract
Adenovirus vector-based genetic vaccines have emerged as a powerful strategy against the SARS-CoV-2 health crisis. This success is not unexpected because adenoviruses combine many desirable features of a genetic vaccine. They are highly immunogenic and have a low and well characterized pathogenic profile paired with technological approachability. Ongoing efforts to improve adenovirus-vaccine vectors include the use of rare serotypes and non-human adenoviruses. In this review, we focus on the viral capsid and how the choice of genotypes influences the uptake and subsequent subcellular sorting. We describe how understanding capsid properties, such as stability during the entry process, can change the fate of the entering particles and how this translates into differences in immunity outcomes. We discuss in detail how mutating the membrane lytic capsid protein VI affects species C viruses' post-entry sorting and briefly discuss if such approaches could have a wider implication in vaccine and/or vector development.
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Affiliation(s)
| | | | - Harald Wodrich
- Microbiologie Fondamentale et Pathogénicité, MFP CNRS UMR 5234, University of Bordeaux, 146 rue Leo Saignat, CEDEX, 33076 Bordeaux, France; (C.F.D.); (N.P.)
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35
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Atasheva S, Emerson CC, Yao J, Young C, Stewart PL, Shayakhmetov DM. Systemic cancer therapy with engineered adenovirus that evades innate immunity. Sci Transl Med 2021; 12:12/571/eabc6659. [PMID: 33239388 DOI: 10.1126/scitranslmed.abc6659] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/06/2020] [Accepted: 08/21/2020] [Indexed: 12/12/2022]
Abstract
Oncolytic virus therapy is a cancer treatment modality that has the potential to improve outcomes for patients with currently incurable malignancies. Although intravascular delivery of therapeutic viruses provides access to disseminated tumors, this delivery route exposes the virus to opsonizing and inactivating factors in the blood, which limit the effective therapeutic virus dose and contribute to activation of systemic toxicities. When human species C adenovirus HAdv-C5 is delivered intravenously, natural immunoglobulin M (IgM) antibodies and coagulation factor X rapidly opsonize HAdv-C5, leading to virus sequestration in tissue macrophages and promoting infection of liver cells, triggering hepatotoxicity. Here, we showed that natural IgM antibody binds to the hypervariable region 1 (HVR1) of the main HAdv-C5 capsid protein hexon. Using compound targeted mutagenesis of hexon HVR1 loop and other functional sites that mediate virus-host interactions, we engineered and obtained a high-resolution cryo-electron microscopy structure of an adenovirus vector, Ad5-3M, which resisted inactivation by blood factors, avoided sequestration in liver macrophages, and failed to trigger hepatotoxicity after intravenous delivery. Systemic delivery of Ad5-3M to mice with localized or disseminated lung cancer led to viral replication in tumor cells, suppression of tumor growth, and prolonged survival. Thus, compound targeted mutagenesis of functional sites in the virus capsid represents a generalizable approach to tailor virus interactions with the humoral and cellular arms of the immune system, enabling generation of "designer" viruses with improved therapeutic properties.
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Affiliation(s)
- Svetlana Atasheva
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Corey C Emerson
- Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Jia Yao
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Cedrick Young
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Phoebe L Stewart
- Department of Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, OH 44106, USA.
| | - Dmitry M Shayakhmetov
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA. .,Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.,Emory Center for Transplantation and Immune-mediated Disorders, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.,Discovery and Developmental Therapeutics Program, Winship Cancer Institute of Emory University, Atlanta, GA 30322, USA
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36
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Clementi N, Ghosh S, De Santis M, Castelli M, Criscuolo E, Zanoni I, Clementi M, Mancini N. Viral Respiratory Pathogens and Lung Injury. Clin Microbiol Rev 2021; 34:e00103-20. [PMID: 33789928 PMCID: PMC8142519 DOI: 10.1128/cmr.00103-20] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 12/15/2022] Open
Abstract
Several viruses target the human respiratory tract, causing different clinical manifestations spanning from mild upper airway involvement to life-threatening acute respiratory distress syndrome (ARDS). As dramatically evident in the ongoing SARS-CoV-2 pandemic, the clinical picture is not always easily predictable due to the combined effect of direct viral and indirect patient-specific immune-mediated damage. In this review, we discuss the main RNA (orthomyxoviruses, paramyxoviruses, and coronaviruses) and DNA (adenoviruses, herpesviruses, and bocaviruses) viruses with respiratory tropism and their mechanisms of direct and indirect cell damage. We analyze the thin line existing between a protective immune response, capable of limiting viral replication, and an unbalanced, dysregulated immune activation often leading to the most severe complication. Our comprehension of the molecular mechanisms involved is increasing and this should pave the way for the development and clinical use of new tailored immune-based antiviral strategies.
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Affiliation(s)
- Nicola Clementi
- Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy
- Laboratory of Microbiology and Virology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Sreya Ghosh
- Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, Massachusetts, USA
| | - Maria De Santis
- Department of Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center-IRCCS, Rozzano, Italy
| | - Matteo Castelli
- Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy
| | - Elena Criscuolo
- Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy
| | - Ivan Zanoni
- Harvard Medical School, Boston Children's Hospital, Division of Immunology, Boston, Massachusetts, USA
- Harvard Medical School, Boston Children's Hospital, Division of Gastroenterology, Boston, Massachusetts, USA
| | - Massimo Clementi
- Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy
- Laboratory of Microbiology and Virology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Nicasio Mancini
- Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy
- Laboratory of Microbiology and Virology, IRCCS San Raffaele Scientific Institute, Milan, Italy
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37
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Bellomo A, Gentek R, Golub R, Bajénoff M. Macrophage-fibroblast circuits in the spleen. Immunol Rev 2021; 302:104-125. [PMID: 34028841 DOI: 10.1111/imr.12979] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/25/2021] [Revised: 04/30/2021] [Accepted: 04/30/2021] [Indexed: 12/22/2022]
Abstract
Macrophages are an integral part of all organs in the body, where they contribute to immune surveillance, protection, and tissue-specific homeostatic functions. This is facilitated by so-called niches composed of macrophages and their surrounding stroma. These niches structurally anchor macrophages and provide them with survival factors and tissue-specific signals that imprint their functional identity. In turn, macrophages ensure appropriate functioning of the niches they reside in. Macrophages thus form reciprocal, mutually beneficial circuits with their cellular niches. In this review, we explore how this concept applies to the spleen, a large secondary lymphoid organ whose primary functions are to filter the blood and regulate immunity. We first outline the splenic micro-anatomy, the different populations of splenic fibroblasts and macrophages and their respective contribution to protection of and key physiological processes occurring in the spleen. We then discuss firmly established and potential cellular circuits formed by splenic macrophages and fibroblasts, with an emphasis on the molecular cues underlying their crosstalk and their relevance to splenic functionality. Lastly, we conclude by considering how these macrophage-fibroblast circuits might be impaired by aging, and how understanding these changes might help identify novel therapeutic avenues with the potential of restoring splenic functions in the elderly.
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Affiliation(s)
- Alicia Bellomo
- CIRI, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, École Normale Supérieure de Lyon, Univ Lyon, Lyon, France
| | - Rebecca Gentek
- Centre for Inflammation Research & Centre for Reproductive Health, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Rachel Golub
- Inserm U1223, Institut Pasteur, Paris, France.,Lymphopoiesis Unit, Institut Pasteur, Paris, France
| | - Marc Bajénoff
- Aix Marseille Univ, CNRS, INSERM, CIML, Marseille, France
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38
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Tessarollo NG, Domingues ACM, Antunes F, da Luz JCDS, Rodrigues OA, Cerqueira OLD, Strauss BE. Nonreplicating Adenoviral Vectors: Improving Tropism and Delivery of Cancer Gene Therapy. Cancers (Basel) 2021; 13:1863. [PMID: 33919679 PMCID: PMC8069790 DOI: 10.3390/cancers13081863] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/26/2021] [Revised: 04/05/2021] [Accepted: 04/06/2021] [Indexed: 12/12/2022] Open
Abstract
Recent preclinical and clinical studies have used viral vectors in gene therapy research, especially nonreplicating adenovirus encoding strategic therapeutic genes for cancer treatment. Adenoviruses were the first DNA viruses to go into therapeutic development, mainly due to well-known biological features: stability in vivo, ease of manufacture, and efficient gene delivery to dividing and nondividing cells. However, there are some limitations for gene therapy using adenoviral vectors, such as nonspecific transduction of normal cells and liver sequestration and neutralization by antibodies, especially when administered systemically. On the other hand, adenoviral vectors are amenable to strategies for the modification of their biological structures, including genetic manipulation of viral proteins, pseudotyping, and conjugation with polymers or biological membranes. Such modifications provide greater specificity to the target cell and better safety in systemic administration; thus, a reduction of antiviral host responses would favor the use of adenoviral vectors in cancer immunotherapy. In this review, we describe the structural and molecular features of nonreplicating adenoviral vectors, the current limitations to their use, and strategies to modify adenoviral tropism, highlighting the approaches that may allow for the systemic administration of gene therapy.
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Affiliation(s)
| | | | | | | | | | | | - Bryan E. Strauss
- Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of São Paulo/LIM24, University of São Paulo School of Medicine, São Paulo 01246-000, Brazil; (N.G.T.); (A.C.M.D.); (F.A.); (J.C.d.S.d.L.); (O.A.R.); (O.L.D.C.)
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39
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Chen J, Zhang H, Zhou L, Hu Y, Li M, He Y, Li Y. Enhancing the Efficacy of Tumor Vaccines Based on Immune Evasion Mechanisms. Front Oncol 2021; 10:584367. [PMID: 33614478 PMCID: PMC7886973 DOI: 10.3389/fonc.2020.584367] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 07/17/2020] [Accepted: 12/22/2020] [Indexed: 12/11/2022] Open
Abstract
Tumor vaccines aim to expand tumor-specific T cells and reactivate existing tumor-specific T cells that are in a dormant or unresponsive state. As such, there is growing interest in improving the durable anti-tumor activity of tumor vaccines. Failure of vaccine-activated T cells to protect against tumors is thought to be the result of the immune escape mechanisms of tumor cells and the intricate immunosuppressive tumor microenvironment. In this review, we discuss how tumor cells and the tumor microenvironment influence the effects of tumor infiltrating lymphocytes and summarize how to improve the efficacy of tumor vaccines by improving the design of current tumor vaccines and combining tumor vaccines with other therapies, such as metabolic therapy, immune checkpoint blockade immunotherapy and epigenetic therapy.
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Affiliation(s)
- Jianyu Chen
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Honghao Zhang
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lijuan Zhou
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuxing Hu
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Meifang Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yanjie He
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yuhua Li
- Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.,Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China
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40
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Cunliffe TG, Bates EA, Parker AL. Hitting the Target but Missing the Point: Recent Progress towards Adenovirus-Based Precision Virotherapies. Cancers (Basel) 2020; 12:E3327. [PMID: 33187160 PMCID: PMC7696810 DOI: 10.3390/cancers12113327] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/04/2020] [Revised: 10/31/2020] [Accepted: 11/09/2020] [Indexed: 12/23/2022] Open
Abstract
More people are surviving longer with cancer. Whilst this can be partially attributed to advances in early detection of cancers, there is little doubt that the improvement in survival statistics is also due to the expansion in the spectrum of treatments available for efficacious treatment. Transformative amongst those are immunotherapies, which have proven effective agents for treating immunogenic forms of cancer, although immunologically "cold" tumour types remain refractive. Oncolytic viruses, such as those based on adenovirus, have great potential as anti-cancer agents and have seen a resurgence of interest in recent years. Amongst their many advantages is their ability to induce immunogenic cell death (ICD) of infected tumour cells, thus providing the alluring potential to synergise with immunotherapies by turning immunologically "cold" tumours "hot". Additionally, enhanced immune mediated cell killing can be promoted through the local overexpression of immunological transgenes, encoded from within the engineered viral genome. To achieve this full potential requires the development of refined, tumour selective "precision virotherapies" that are extensively engineered to prevent off-target up take via native routes of infection and targeted to infect and replicate uniquely within malignantly transformed cells. Here, we review the latest advances towards this holy grail within the adenoviral field.
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Affiliation(s)
| | | | - Alan L. Parker
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; (T.G.C.); (E.A.B.)
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41
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Del Papa J, Clarkin RG, Parks RJ. Use of cell fusion proteins to enhance adenoviral vector efficacy as an anti-cancer therapeutic. Cancer Gene Ther 2020; 28:745-756. [DOI: 10.1038/s41417-020-0192-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 04/30/2020] [Revised: 06/18/2020] [Accepted: 06/23/2020] [Indexed: 01/03/2023]
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42
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Coughlan L. Factors Which Contribute to the Immunogenicity of Non-replicating Adenoviral Vectored Vaccines. Front Immunol 2020; 11:909. [PMID: 32508823 PMCID: PMC7248264 DOI: 10.3389/fimmu.2020.00909] [Citation(s) in RCA: 82] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/30/2020] [Accepted: 04/20/2020] [Indexed: 01/12/2023] Open
Abstract
Adenoviral vectors are a safe and potently immunogenic vaccine delivery platform. Non-replicating Ad vectors possess several attributes which make them attractive vaccines for infectious disease, including their capacity for high titer growth, ease of manipulation, safety, and immunogenicity in clinical studies, as well as their compatibility with clinical manufacturing and thermo-stabilization procedures. In general, Ad vectors are immunogenic vaccines, which elicit robust transgene antigen-specific cellular (namely CD8+ T cells) and/or humoral immune responses. A large number of adenoviruses isolated from humans and non-human primates, which have low seroprevalence in humans, have been vectorized and tested as vaccines in animal models and humans. However, a distinct hierarchy of immunological potency has been identified between diverse Ad vectors, which unfortunately limits the potential use of many vectors which have otherwise desirable manufacturing characteristics. The precise mechanistic factors which underlie the profound disparities in immunogenicity are not clearly defined and are the subject of ongoing, detailed investigation. It has been suggested that a combination of factors contribute to the potent immunogenicity of particular Ad vectors, including the magnitude and duration of vaccine antigen expression following immunization. Furthermore, the excessive induction of Type I interferons by some Ad vectors has been suggested to impair transgene expression levels, dampening subsequent immune responses. Therefore, the induction of balanced, but not excessive stimulation of innate signaling is optimal. Entry factor binding or receptor usage of distinct Ad vectors can also affect their in vivo tropism following administration by different routes. The abundance and accessibility of innate immune cells and/or antigen-presenting cells at the site of injection contributes to early innate immune responses to Ad vaccination, affecting the outcome of the adaptive immune response. Although a significant amount of information exists regarding the tropism determinants of the common human adenovirus type-5 vector, very little is known about the receptor usage and tropism of rare species or non-human Ad vectors. Increased understanding of how different facets of the host response to Ad vectors contribute to their immunological potency will be essential for the development of optimized and customized Ad vaccine platforms for specific diseases.
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43
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Ma M, Lin B, Wang M, Liang X, Su L, Okose O, Lv W, Li J. Immunotherapy in anaplastic thyroid cancer. Am J Transl Res 2020; 12:974-988. [PMID: 32269728 PMCID: PMC7137046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/12/2019] [Accepted: 02/13/2020] [Indexed: 06/11/2023]
Abstract
Anaplastic thyroid cancer (ATC) is one of the worst human malignancies, with an associated median survival of only 5 months. It is resistant to conventional thyroid cancer therapies, including radioiodine and thyroid-stimulating hormone suppression. Cancer immunotherapy has emerged over the past few decades as a transformative approach to treating a wide variety of cancers. However, immunotherapy for ATC is still in the experimental stage. This review will cover several strategies of immunotherapy and discuss the possible application of these strategies in the treatment of ATC (such as targeted therapy for tumor-associated macrophages, cancer vaccines, adoptive immunotherapy, monoclonal antibodies and immune checkpoint blockade) with the hope of improving the prognosis of ATC in the future.
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Affiliation(s)
- Maoguang Ma
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Bo Lin
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Mingdian Wang
- State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer CenterGuangzhou, China
| | - Xiaoli Liang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Lei Su
- Department of Geriatrics, The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Okenwa Okose
- Texas A & M College of MedicineCollege Station, TX 77843, USA
- Division of Thyroid and Parathyroid Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical SchoolBoston, MA, USA
| | - Weiming Lv
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Jie Li
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou, China
- Division of Thyroid and Parathyroid Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical SchoolBoston, MA, USA
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Abstract
Several viral vector-based gene therapy drugs have now received marketing approval. A much larger number of additional viral vectors are in various stages of clinical trials for the treatment of genetic and acquired diseases, with many more in pre-clinical testing. Efficiency of gene transfer and ability to provide long-term therapy make these vector systems very attractive. In fact, viral vector gene therapy has been able to treat or even cure diseases for which there had been no or only suboptimal treatments. However, innate and adaptive immune responses to these vectors and their transgene products constitute substantial hurdles to clinical development and wider use in patients. This review provides an overview of the type of immune responses that have been documented in animal models and in humans who received gene transfer with one of three widely tested vector systems, namely adenoviral, lentiviral, or adeno-associated viral vectors. Particular emphasis is given to mechanisms leading to immune responses, efforts to reduce vector immunogenicity, and potential solutions to the problems. At the same time, we point out gaps in our knowledge that should to be filled and problems that need to be addressed going forward.
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Affiliation(s)
- Jamie L Shirley
- Gene Therapy Center, University of Massachusetts, Worchester, MA, USA
| | - Ype P de Jong
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Cox Terhorst
- Division of Immunology, Beth Israel Deaconess Medical Center (BIDMC), Harvard Medical School, Boston, MA, USA
| | - Roland W Herzog
- Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA.
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45
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Atasheva S, Yao J, Shayakhmetov DM. Innate immunity to adenovirus: lessons from mice. FEBS Lett 2019; 593:3461-3483. [PMID: 31769012 PMCID: PMC6928416 DOI: 10.1002/1873-3468.13696] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/01/2019] [Revised: 11/07/2019] [Accepted: 11/21/2019] [Indexed: 01/01/2023]
Abstract
Adenovirus is a highly evolutionary successful pathogen, as it is widely prevalent across the animal kingdom, infecting hosts ranging from lizards and frogs to dolphins, birds, and humans. Although natural adenovirus infections in humans rarely cause severe pathology, intravenous injection of high doses of adenovirus-based vectors triggers rapid activation of the innate immune system, leading to cytokine storm syndrome, disseminated intravascular coagulation, thrombocytopenia, and hepatotoxicity, which individually or in combination may cause morbidity and mortality. Much of the information on exactly how adenovirus activates the innate immune system has been gathered from mouse experimental systems. Intravenous administration of adenovirus to mice revealed mechanistic insights into cellular and molecular components of the innate immunity that detect adenovirus particles, activate pro-inflammatory signaling pathways and cytokine production, sequester adenovirus particles from the bloodstream, and eliminate adenovirus-infected cells. Collectively, this information greatly improved our understanding of mechanisms of activation of innate immunity to adenovirus and may pave the way for designing safer adenovirus-based vectors for therapy of genetic and acquired human diseases.
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Affiliation(s)
- Svetlana Atasheva
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Jia Yao
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
| | - Dmitry M. Shayakhmetov
- Lowance Center for Human Immunology, Departments of Pediatrics and Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
- Emory Children’s Center for Transplantation and Immuno-mediated Disorders, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA
- Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA
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46
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Shaw AR, Suzuki M. Immunology of Adenoviral Vectors in Cancer Therapy. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2019; 15:418-429. [PMID: 31890734 PMCID: PMC6909129 DOI: 10.1016/j.omtm.2019.11.001] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Indexed: 12/24/2022]
Abstract
Adenoviruses are a commonly utilized virus for gene therapy platforms worldwide. Since adenovirus components are characterized as highly immunogenic, their immunogenicity inhibits the widespread use of adenoviral vectors to treat genetic disorders. However, stimulation of the immune response can be exploited for cancer immunotherapy platforms, and thus adenoviral vectors are used for therapeutic gene transfer, vaccines, and oncolytic agents in the cancer gene therapy field. It is now accepted that the generation of anti-tumor immune responses induced by oncolytic adenovirus treatments is critical for their anti-tumor efficacy. As such, in cancer immunotherapy with adenoviral vectors, a balance must be struck between induction of anti-adenoviral and anti-tumor immune responses. The recent trend in adenoviral-based cancer gene therapy is the development of adenoviral vectors to enhance immune responses and redirect them toward tumors. This review focuses on anti-adenoviral immunity and how adenovirotherapies skew the immune response toward an anti-tumor response.
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Affiliation(s)
- Amanda Rosewell Shaw
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.,Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX, USA
| | - Masataka Suzuki
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA.,Baylor College of Medicine, Center for Cell Gene Therapy, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX, USA
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47
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van den Bossche WBL, Kleijn A, Teunissen CE, Voerman JSA, Teodosio C, Noske DP, van Dongen JJM, Dirven CMF, Lamfers MLM. Oncolytic virotherapy in glioblastoma patients induces a tumor macrophage phenotypic shift leading to an altered glioblastoma microenvironment. Neuro Oncol 2019; 20:1494-1504. [PMID: 29796615 DOI: 10.1093/neuonc/noy082] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/07/2023] Open
Abstract
Background Immunosuppressive protumoral M2 macrophages are important in pathogenesis, progression, and therapy resistance in glioblastoma (GBM) and provide a target for therapy. Recently oncolytic virotherapy in murine models was shown to change these M2 macrophages toward the pro-inflammatory and antitumoral M1 phenotype. Here we study the effects of the oncolytic virotherapy Delta24-RGD in humans, using both in vitro models and patient material. Methods Human monocyte-derived macrophages were co-cultured with Delta24-RGD-infected primary glioma stem-like cells (GSCs) and were analyzed for their immunophenotype, cytokine expression, and secretion profiles. Cerebrospinal fluid (CSF) from 18 Delta24-RGD-treated patients was analyzed for inflammatory cytokine levels, and the effects of these CSF samples on macrophage phenotype in vitro were determined. In addition, tumor macrophages in resected material from a Delta24-RGD-treated GBM patient were compared with 5 control GBM patient samples by flow cytometry. Results Human monocyte-derived M2 macrophages co-cultured with Delta24-RGD-infected GSCs shifted toward an M1-immunophenotype, coinciding with pro-inflammatory gene expression and cytokine production. This phenotypic switch was induced by the concerted effects of a change in tumor-produced soluble factors and the presence of viral particles. CSF samples from Delta24-RGD-treated GBM patients revealed cytokine levels indicative of a pro-inflammatory microenvironment. Furthermore, tumoral macrophages in a Delta24-RGD-treated patient showed significantly greater M1 characteristics than in control GBM tissue. Conclusion Together these in vitro and patient studies demonstrate that local Delta24-RGD therapy may provide a therapeutic tool to promote a prolonged shift in the protumoral M2 macrophages toward M1 in human GBM, inducing a pro-inflammatory and potentially tumor-detrimental microenvironment.
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Affiliation(s)
- Wouter B L van den Bossche
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.,Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Anne Kleijn
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Charlotte E Teunissen
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.,Department of Clinical Chemistry, Neuroscience Campus Amsterdam, Amsterdam, Netherlands
| | - Jane S A Voerman
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Cristina Teodosio
- Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
| | - David P Noske
- Department of Neurosurgery, VU University Medical Center, Amsterdam, Netherlands
| | - Jacques J M van Dongen
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.,Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, Netherlands
| | - Clemens M F Dirven
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Martine L M Lamfers
- Department of Neurosurgery, Brain Tumor Center, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
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48
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Abstract
More than 80 different adenovirus (AdV) types infect humans through the respiratory, ocular, or gastrointestinal tracts. They cause acute clinical mani-festations or persist under humoral and cell-based immunity. Immuno-suppressed individuals are at risk of death from an AdV infection. Concepts about cell entry of AdV build on strong foundations from molecular and cellular biology-and increasingly physical virology. Here, we discuss how virions enter and deliver their genome into the nucleus of epithelial cells. This process breaks open the virion at distinct sites because the particle has nonisometric mechanical strength and reacts to specific host factors along the entry pathway. We further describe how macrophages and dendritic cells resist AdV infection yet enhance productive entry into polarized epithelial cells. A deep understanding of the viral mechanisms and cell biological and biophysical principles will continue to unravel how epithelial and antigen-presenting cells respond to AdVs and control inflammation and persistence in pathology and therapy.
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Affiliation(s)
- Urs F Greber
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland;
| | - Justin W Flatt
- Institute of Biotechnology and Department of Biosciences, University of Helsinki, 00790 Helsinki, Finland;
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Zaric M, Becker PD, Hervouet C, Kalcheva P, Doszpoly A, Blattman N, A O' Neill L, Yus BI, Cocita C, Kwon SY, Baker AH, Lord GM, Klavinskis LS. Skin immunisation activates an innate lymphoid cell-monocyte axis regulating CD8 + effector recruitment to mucosal tissues. Nat Commun 2019; 10:2214. [PMID: 31101810 PMCID: PMC6525176 DOI: 10.1038/s41467-019-09969-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 09/15/2018] [Accepted: 04/08/2019] [Indexed: 02/07/2023] Open
Abstract
CD8+ T cells provide a critical defence from pathogens at mucosal epithelia including the female reproductive tract (FRT). Mucosal immunisation is considered essential to initiate this response, however this is difficult to reconcile with evidence that antigen delivered to skin can recruit protective CD8+ T cells to mucosal tissues. Here we dissect the underlying mechanism. We show that adenovirus serotype 5 (Ad5) bio-distributes at very low level to non-lymphoid tissues after skin immunisation. This drives the expansion and activation of CD3- NK1.1+ group 1 innate lymphoid cells (ILC1) within the FRT, essential for recruitment of CD8+ T-cell effectors. Interferon gamma produced by activated ILC1 is critical to licence CD11b+Ly6C+ monocyte production of CXCL9, a chemokine required to recruit skin primed CXCR3+ CD8+T-cells to the FRT. Our findings reveal a novel role for ILC1 to recruit effector CD8+ T-cells to prevent virus spread and establish immune surveillance at barrier tissues.
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Affiliation(s)
- Marija Zaric
- School of Immunobiology and Microbial Sciences, King's College London, London, SE1 9RT, UK
| | - Pablo D Becker
- School of Immunobiology and Microbial Sciences, King's College London, London, SE1 9RT, UK
| | - Catherine Hervouet
- School of Immunobiology and Microbial Sciences, King's College London, London, SE1 9RT, UK
| | - Petya Kalcheva
- School of Immunobiology and Microbial Sciences, King's College London, London, SE1 9RT, UK
| | - Andor Doszpoly
- Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | - Negin Blattman
- Biodesign Institute, Centre for Infectious Disease and Vaccinology, Arizona State University, Tempe, AZ, 85287, USA
| | - Lauren A O' Neill
- School of Immunobiology and Microbial Sciences, King's College London, London, SE1 9RT, UK
| | - Barbara Ibarzo Yus
- School of Immunobiology and Microbial Sciences, King's College London, London, SE1 9RT, UK
| | - Clement Cocita
- School of Immunobiology and Microbial Sciences, King's College London, London, SE1 9RT, UK
| | | | - Andrew H Baker
- Centre for Cardiovascular Sciences, Queens Medical Research Institute, University of Edinburgh, Edinburgh, EH16 4TJ, UK
| | - Graham M Lord
- School of Immunobiology and Microbial Sciences, King's College London, London, SE1 9RT, UK.,Faculty of Biology, Medicine and Health, University of Manchester, Manchester, M13 9PL, UK
| | - Linda S Klavinskis
- School of Immunobiology and Microbial Sciences, King's College London, London, SE1 9RT, UK.
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50
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Hu J, Xu J, Li M, Zhang Y, Yi H, Chen J, Dong L, Zhang J, Huang Z. Targeting Lymph Node Sinus Macrophages to Inhibit Lymph Node Metastasis. MOLECULAR THERAPY. NUCLEIC ACIDS 2019; 16:650-662. [PMID: 31121477 PMCID: PMC6529739 DOI: 10.1016/j.omtn.2019.04.016] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Academic Contribution Register] [Received: 10/13/2018] [Revised: 04/17/2019] [Accepted: 04/17/2019] [Indexed: 12/23/2022]
Abstract
Lymph nodes are important peripheral immune organs in which numerous important immune responses occur. During the process of lymphatic metastasis, lymph nodes are also sites through which tumor cells must pass. Therefore, it is essential to develop a drug delivery system that can specifically transfer immunostimulatory medicine into lymph nodes to block lymphatic metastasis. Here, we developed a nucleic acid drug delivery system containing cationic agarose (C-agarose) and CpG oligodeoxynucleotides. C-agarose has a high affinity for Siglec-1 on the surface of lymph node sinus macrophages, which have a high specificity for targeting lymph nodes. Subcutaneous implantation of C-agarose+CpG gel caused the accumulation of CpG in the lymph node sinus macrophages and generated antitumor immune responses in the lymph node. C-agarose+CpG gel treatment decreased the metastasis size in the tumor-draining lymph node (TDLN) and lung metastatic nodules and suppressed tumor growth in both a mouse 4T1 breast cancer model and a B16F10 melanoma model. On this basis, this study proposes a nonsurgical invasive lymph node targeting immunotherapy concept that may provide a new approach for antitumor metastasis.
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Affiliation(s)
- Junqing Hu
- State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China
| | - Jinhao Xu
- State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China
| | - Mingyue Li
- State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China
| | - Yanping Zhang
- State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China
| | - Huaiqiang Yi
- State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China
| | - Jiangning Chen
- State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China
| | - Lei Dong
- State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China
| | - Junfeng Zhang
- State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China.
| | - Zhen Huang
- State Key Laboratory of Analytical Chemistry for Life Sciences and Collaborative Innovation Center of Chemistry for Life Sciences, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210023, P.R. China.
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