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Abbaszadeh M, Naseri B, Taghizadeh-Teymorloei M, Mardi A, Javan MR, Masoumi J, Ghorbaninezhad F, Hatami‐Sadr A, Tural Ş, Baradaran B, Sadeghi MR. Overview of dendritic cells subsets and their involvement in immune-related pathological disease. BIOIMPACTS : BI 2025; 15:30671. [PMID: 40256217 PMCID: PMC12008504 DOI: 10.34172/bi.30671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/01/2024] [Accepted: 11/19/2024] [Indexed: 04/22/2025]
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) in linking innate and adaptive immune responses. In addition to presenting antigens to T cells, DCs must also provide co-stimulatory signals along with cytokines for T cells to induce an appropriate cellular immune response. Tolerance is also established and maintained by DCs under homeostatic circumstances. There is remarkable phenotypic heterogeneity in DCs, each with different functional flexibility and specific expression of various markers. The three primary categories of DCs comprise conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). Langerhans cells (LCs) are another type of DCs, which are found in the skin's epidermal layer. DCs may be positioned or triggered inappropriately as a result of dysregulation of DC. This phenomenon can cause an imbalance in immune responses and even immune-related pathological disorders, i.e., autoimmune diseases and malignancies. Herein, by reviewing the ontogeny, biology, characteristics, and function of DCs subsets in immune system, we discuss the contribution of these cells in the mentioned immune-related disorders.
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Affiliation(s)
- Mohsen Abbaszadeh
- Molecular Medicine Department, Faculty of advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahar Naseri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Taghizadeh-Teymorloei
- Molecular Medicine Department, Faculty of advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amirhossein Mardi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Javan
- Department of Immunology, Faculty of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farid Ghorbaninezhad
- Department of Immunology, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Şengül Tural
- Mayis University, Faculty of Medicine, Department of Medical Biology, Samsun, Turkey
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Sadeghi
- Molecular Medicine Department, Faculty of advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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2
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Dudziak D, Heger L, Agace WW, Bakker J, de Gruijl TD, Dress RJ, Dutertre C, Fenton TM, Fransen MF, Ginhoux F, Heyman O, Horev Y, Hornsteiner F, Kandiah V, Kles P, Lubin R, Mizraji G, Prokopi A, Saar O, Sopper S, Stoitzner P, Strandt H, Sykora MM, Toffoli EC, Tripp CH, van Pul K, van de Ven R, Wilensky A, Yona S, Zelle‐Rieser C. Guidelines for preparation and flow cytometry analysis of human nonlymphoid tissue DC. Eur J Immunol 2025; 55:e2250325. [PMID: 39668411 PMCID: PMC11739683 DOI: 10.1002/eji.202250325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 09/19/2024] [Accepted: 09/25/2024] [Indexed: 12/14/2024]
Abstract
This article is part of the Dendritic Cell Guidelines article series, which provides a collection of state-of-the-art protocols for the preparation, phenotype analysis by flow cytometry, generation, fluorescence microscopy, and functional characterization of mouse and human dendritic cells (DC) from lymphoid organs, and various nonlymphoid tissues. Within this article, detailed protocols are presented that allow for the generation of single-cell suspensions from human nonlymphoid tissues including lung, skin, gingiva, intestine as well as from tumors and tumor-draining lymph nodes with a subsequent analysis of dendritic cells by flow cytometry. Further, prepared single-cell suspensions can be subjected to other applications including cellular enrichment procedures, RNA sequencing, functional assays, etc. While all protocols were written by experienced scientists who routinely use them in their work, this article was also peer-reviewed by leading experts and approved by all co-authors, making it an essential resource for basic and clinical DC immunologists.
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Affiliation(s)
- Diana Dudziak
- Institute of ImmunologyJena University HospitalFriedrich‐Schiller‐UniversityJenaGermany
- Laboratory of Dendritic Cell BiologyDepartment of DermatologyUniversity Hospital ErlangenErlangenGermany
| | - Lukas Heger
- Laboratory of Dendritic Cell BiologyDepartment of DermatologyUniversity Hospital ErlangenErlangenGermany
- Department of Transfusion Medicine and HemostaseologyUniversity Hospital ErlangenErlangenGermany
| | - William W Agace
- LEO Foundation Skin Immunology Research CenterDepartment of Immunology and MicrobiologyUniversity of CopenhagenCopenhagenDenmark
- Immunology SectionLund UniversityLundSweden
| | - Joyce Bakker
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Tanja D. de Gruijl
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Regine J. Dress
- Institute of Systems ImmunologyHamburg Center for Translational Immunology (HCTI)University Medical Center Hamburg‐EppendorfHamburgGermany
| | | | | | - Marieke F. Fransen
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Department of Pulmonary DiseasesAmsterdam UMC location Vrije UniversiteitAmsterdamThe Netherlands
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and ResearchSingaporeSingapore
- Department of Immunology and MicrobiologyShanghai Institute of ImmunologyShanghai Jiao Tong University School of MedicineShanghaiChina
- SingHealth Duke‐NUS Academic Medical CentreTranslational Immunology InstituteSingaporeSingapore
- INSERM U1015, Gustave Roussy Cancer CampusVillejuifFrance
| | - Oded Heyman
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Yael Horev
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Florian Hornsteiner
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
| | - Vinitha Kandiah
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Paz Kles
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Ruth Lubin
- Faculty of Dental MedicineThe Institute of Biomedical and Oral ResearchHebrew University of JerusalemIsrael
| | - Gabriel Mizraji
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Anastasia Prokopi
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Or Saar
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Sieghart Sopper
- Internal Medicine V, Hematology and OncologyMedical University of InnsbruckInnsbruckAustria
- Tyrolean Cancer Research CenterInnsbruckAustria
| | - Patrizia Stoitzner
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
| | - Helen Strandt
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
| | - Martina M Sykora
- Internal Medicine V, Hematology and OncologyMedical University of InnsbruckInnsbruckAustria
- Tyrolean Cancer Research CenterInnsbruckAustria
| | - Elisa C. Toffoli
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Christoph H. Tripp
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
| | - Kim van Pul
- Institute for Infection and ImmunologyCancer ImmunologyAmsterdamThe Netherlands
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
| | - Rieneke van de Ven
- Cancer Center AmsterdamCancer ImmunologyAmsterdamThe Netherlands
- Amsterdam UMC location Vrije UniversiteitMedical OncologyAmsterdamThe Netherlands
- Department of Otolaryngology, Head and Neck SurgeryAmsterdam UMC location Vrije UniversiteitAmsterdamThe Netherlands
| | - Asaf Wilensky
- Department of PeriodontologyHadassah Medical CenterFaculty of Dental MedicineHebrew University of JerusalemIsrael
| | - Simon Yona
- Faculty of Dental MedicineThe Institute of Biomedical and Oral ResearchHebrew University of JerusalemIsrael
| | - Claudia Zelle‐Rieser
- Department of Dermatology, Venereology & AllergologyMedical University of InnsbruckInnsbruckAustria
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Xu J, Cao S, Xu Y, Chen H, Nian S, Li L, Liu Q, Xu W, Ye Y, Yuan Q. The role of DC subgroups in the pathogenesis of asthma. Front Immunol 2024; 15:1481989. [PMID: 39530090 PMCID: PMC11550972 DOI: 10.3389/fimmu.2024.1481989] [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] [Scholar Register] [Received: 08/17/2024] [Accepted: 10/09/2024] [Indexed: 11/16/2024] Open
Abstract
Dendritic cells (DCs), specialized antigen-presenting cells of the immune system, act as immunomodulators in diseases of the immune system, including asthma. The understanding of DC biology has evolved over the years to include multiple subsets of DCs with distinct functions in the initiation and maintenance of asthma. Moreover, most strategies for treating asthma with relevant therapeutic agents that target DCs have been initiated from the study of DC function. We discussed the pathogenesis of asthma (including T2-high and T2-low), the roles played by different DC subpopulations in the pathogenesis of asthma, and the therapeutic strategies centered around DCs. This study will provide a scientific theoretical basis for current asthma treatment, provide theoretical guidance and research ideas for developing and studying therapeutic drugs targeting DC, and provide more therapeutic options for the patient population with poorly controlled asthma symptoms.
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Affiliation(s)
- Jiangang Xu
- School of Basic Medical Sciences, Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, China
| | - Shuxian Cao
- School of Basic Medical Sciences, Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, China
| | - Youhua Xu
- School of Basic Medical Sciences, Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, China
| | - Han Chen
- School of Stomatology, Southwest Medical University, Luzhou, Sichuan, China
| | - Siji Nian
- School of Basic Medical Sciences, Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, China
| | - Lin Li
- School of Basic Medical Sciences, Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, China
| | - Qin Liu
- School of Basic Medical Sciences, Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, China
| | - Wenfeng Xu
- School of Basic Medical Sciences, Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, China
| | - Yingchun Ye
- School of Basic Medical Sciences, Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, China
| | - Qing Yuan
- School of Basic Medical Sciences, Public Center of Experimental Technology, Southwest Medical University, Luzhou, Sichuan, China
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Abacar K, Macleod T, Direskeneli H, McGonagle D. How underappreciated autoinflammatory (innate immunity) mechanisms dominate disparate autoimmune disorders. Front Immunol 2024; 15:1439371. [PMID: 39372419 PMCID: PMC11449752 DOI: 10.3389/fimmu.2024.1439371] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 09/04/2024] [Indexed: 10/08/2024] Open
Abstract
Historically inflammation against self was considered autoimmune which stems back to the seminal observations by Ehrlich who described serum factors, now known to be autoantibodies produced by B lineage cells that mediate "horror autotoxicus". The 20th century elucidation of B- and T-cell adaptive immune responses cemented the understanding of the key role of adaptive immune responses in mediating pathology against self. However, Mechnikov shared the Nobel Prize for the discovery of phagocytosis, the most rudimentary aspect of innate immunity. Fast forward some 100 years and an immunogenetic understanding of innate immunity led to the categorising of innate immunopathology under the umbrella term 'auto inflammation' and terminology such as "horror autoinflammaticus" to highlight the schism from the classical adaptive immune understanding of autoimmunity. These concepts lead to calls for a two-tiered classification of inflammation against self, but just as innate and adaptive immunity are functionally integrated, so is immunopathology in many settings and the concept of an autoimmune to autoinflammation continuum emerged with overlaps between both. Herein we describe several historically designated disorders of adaptive immunity where innate immunity is key, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) where the immunopathology phenotype is strongly linked to major histocompatibility complex (MHC) class II associations and responds to drugs that target T-cells. We also consider MHC-I-opathies including psoriasis and Behcet's disease(BD) that are increasingly viewed as archetype CD8 T-cell related disorders. We also briefly review the key role of barrier dysfunction in eczema and ulcerative colitis (UC) where innate tissue permeability barrier dysfunction and microbial dysbiosis contributes to prominent adaptive immune pathological mechanisms. We also highlight the emerging roles of intermediate populations of lymphocytes including gamma delta (γδ) and mucosal-associated invariant T (MAIT) cells that represent a blend of adaptive immune plasticity and innate immune rapid responders that may also determine site specific patterns of inflammation.
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Affiliation(s)
- Kerem Abacar
- Department of Internal Medicine, Division of Rheumatology, Marmara University School of Medicine, Istanbul, Türkiye
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
| | - Tom Macleod
- Department of Internal Medicine, Division of Rheumatology, Marmara University School of Medicine, Istanbul, Türkiye
| | - Haner Direskeneli
- Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom
| | - Dennis McGonagle
- Department of Internal Medicine, Division of Rheumatology, Marmara University School of Medicine, Istanbul, Türkiye
- National Institute for Health Research, Leeds Biomedical Research Centre, Leeds Teaching Hospitals, Leeds, United Kingdom
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Li Y, Quan X, Tai Y, Wu YT, Wei B, Wu H. Causal association between 731 immunocyte phenotypes and liver cirrhosis: A bidirectional two-sample mendelian randomization analysis. World J Hepatol 2024; 16:1156-1166. [PMID: 39221101 PMCID: PMC11362904 DOI: 10.4254/wjh.v16.i8.1156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 07/24/2024] [Accepted: 08/02/2024] [Indexed: 08/21/2024] Open
Abstract
BACKGROUND Liver cirrhosis is a progressive hepatic disease whose immunological basis has attracted increasing attention. However, it remains unclear whether a concrete causal association exists between immunocyte phenotypes and liver cirrhosis. AIM To explore the concrete causal relationships between immunocyte phenotypes and liver cirrhosis through a mendelian randomization (MR) study. METHODS Data on 731 immunocyte phenotypes were obtained from genome-wide association studies. Liver cirrhosis data were derived from the Finn Gen dataset, which included 214403 individuals of European ancestry. We used inverse variable weighting as the primary analysis method to assess the causal relationship. Sensitivity analyses were conducted to evaluate heterogeneity and horizontal pleiotropy. RESULTS The MR analysis demonstrated that 11 immune cell phenotypes have a positive association with liver cirrhosis [P < 0.05, odds ratio (OR) > 1] and that 9 immunocyte phenotypes were negatively correlated with liver cirrhosis (P < 0.05, OR < 1). Liver cirrhosis was positively linked to 9 immune cell phenotypes (P < 0.05, OR > 1) and negatively linked to 10 immune cell phenotypes (P < 0.05; OR < 1). None of these associations showed heterogeneity or horizontally pleiotropy (P > 0.05). CONCLUSION This bidirectional two-sample MR study demonstrated a concrete causal association between immunocyte phenotypes and liver cirrhosis. These findings offer new directions for the treatment of liver cirrhosis.
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Affiliation(s)
- Ying Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Xin Quan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yang Tai
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yu-Tong Wu
- Department of Clinical Medicine, Chongqing Medical University, Chongqing 400016, China
| | - Bo Wei
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hao Wu
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
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Mazzoccoli L, Liu B. Dendritic Cells in Shaping Anti-Tumor T Cell Response. Cancers (Basel) 2024; 16:2211. [PMID: 38927916 PMCID: PMC11201542 DOI: 10.3390/cancers16122211] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/07/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
Among professional antigen-presenting cells, dendritic cells (DCs) orchestrate innate and adaptive immunity and play a pivotal role in anti-tumor immunity. DCs are a heterogeneous population with varying functions in the tumor microenvironment (TME). Tumor-associated DCs differentiate developmentally and functionally into three main subsets: conventional DCs (cDCs), plasmacytoid DCs (pDCs), and monocyte-derived DCs (MoDCs). There are two major subsets of cDCs in TME, cDC1 and cDC2. cDC1 is critical for cross-presenting tumor antigens to activate cytotoxic CD8+ T cells and is also required for priming earlier CD4+ T cells in certain solid tumors. cDC2 is vital for priming anti-tumor CD4+ T cells in multiple tumor models. pDC is a unique subset of DCs and produces type I IFN through TLR7 and TLR9. Studies have shown that pDCs are related to immunosuppression in the TME through the secretion of immunosuppressive cytokines and by promoting regulatory T cells. MoDCs differentiate separately from monocytes in response to inflammatory cues and infection. Also, MoDCs can cross-prime CD8+ T cells. In this review, we summarize the subsets and functions of DCs. We also discuss the role of different DC subsets in shaping T cell immunity in TME and targeting DCs for potential immunotherapeutic benefits against cancer.
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Affiliation(s)
- Luciano Mazzoccoli
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA;
- The Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Bei Liu
- Division of Hematology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA;
- The Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
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7
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Meng X, Wang Y, Li Z, Yang F, Wang J. Knowledge mapping of links between dendritic cells and allergic diseases: A bibliometric analysis (2004-2023). Heliyon 2024; 10:e30315. [PMID: 38765036 PMCID: PMC11096944 DOI: 10.1016/j.heliyon.2024.e30315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 04/23/2024] [Accepted: 04/23/2024] [Indexed: 05/21/2024] Open
Abstract
In this study, bibliometric analysis was carried out to comprehend the global research trends, hotspots, scientific frontiers, and output characteristics of the links between dendritic cells (DCs) and allergic diseases from 2004 to 2023. Publications and their recorded information were retrieved from the Web of Science Core Collection (WoSCC). VOSviewer and Citespace were used to visualize the hotspots and trends of research area. ChemBio 3D, Autodock tools, and Discovery Studio were used to visualize the molecular docking results of hotspots. A total of 4861 articles were retrieved. The number of publications (Np) was in a high and stable state. Years 2011 and 2017 were two peaks in Np. The largest contributor in terms of publications, scholars, and affiliations was the USA. The paper published in NATURE MEDICINE (IF: 82.9) and written by Trompette, A in 2006 had the highest global citation score (GCS). Keywords, such as "asthma," "t-cells," "inflammation," "expression," "atopic dermatitis," "food allergy," "gut microbiota," "murine model," and "cytokines related to immunity" appeared the most frequently. Most of the binding free energy of the key active components of Saposhnikovia divaricata docked with toll-like receptor proteins well. This bibliometric study aimed to help better comprehend the present state and make decisions from a macro viewpoint.
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Affiliation(s)
- Xianghe Meng
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Yi Wang
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Zhuqing Li
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Fan Yang
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Ji Wang
- School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
- National Institute of TCM Constitution and Preventive Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China
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Zheng LY, Duan Y, He PY, Wu MY, Wei ST, Du XH, Yao RQ, Yao YM. Dysregulated dendritic cells in sepsis: functional impairment and regulated cell death. Cell Mol Biol Lett 2024; 29:81. [PMID: 38816685 PMCID: PMC11140885 DOI: 10.1186/s11658-024-00602-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 05/21/2024] [Indexed: 06/01/2024] Open
Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Studies have indicated that immune dysfunction plays a central role in the pathogenesis of sepsis. Dendritic cells (DCs) play a crucial role in the emergence of immune dysfunction in sepsis. The major manifestations of DCs in the septic state are abnormal functions and depletion in numbers, which are linked to higher mortality and vulnerability to secondary infections in sepsis. Apoptosis is the most widely studied pathway of number reduction in DCs. In the past few years, there has been a surge in studies focusing on regulated cell death (RCD). This emerging field encompasses various forms of cell death, such as necroptosis, pyroptosis, ferroptosis, and autophagy-dependent cell death (ADCD). Regulation of DC's RCD can serve as a possible therapeutic focus for the treatment of sepsis. Throughout time, numerous tactics have been devised and effectively implemented to improve abnormal immune response during sepsis progression, including modifying the functions of DCs and inhibiting DC cell death. In this review, we provide an overview of the functional impairment and RCD of DCs in septic states. Also, we highlight recent advances in targeting DCs to regulate host immune response following septic challenge.
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Affiliation(s)
- Li-Yu Zheng
- Translational Medicine Research Center, Medical Innovation Research Division of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Yu Duan
- Department of Critical Care Medicine, Affiliated Chenzhou Hospital (the First People's Hospital of Chenzhou), Southern Medical University, Chenzhou, 423000, China
| | - Peng-Yi He
- Translational Medicine Research Center, Medical Innovation Research Division of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Meng-Yao Wu
- Translational Medicine Research Center, Medical Innovation Research Division of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Shu-Ting Wei
- Translational Medicine Research Center, Medical Innovation Research Division of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China
| | - Xiao-Hui Du
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China.
| | - Ren-Qi Yao
- Translational Medicine Research Center, Medical Innovation Research Division of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China.
- Department of General Surgery, The First Medical Center of Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China.
| | - Yong-Ming Yao
- Translational Medicine Research Center, Medical Innovation Research Division of the Chinese PLA General Hospital, 28 Fuxing Road, Haidian District, Beijing, 100853, China.
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9
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Sohrabi S, Masoumi J, Naseri B, Ghorbaninezhad F, Alipour S, Kazemi T, Ahmadian Heris J, Aghebati Maleki L, Basirjafar P, Zandvakili R, Doustvandi MA, Baradaran B. STATs signaling pathways in dendritic cells: As potential therapeutic targets? Int Rev Immunol 2024; 43:138-159. [PMID: 37886903 DOI: 10.1080/08830185.2023.2274576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 09/17/2023] [Accepted: 10/16/2023] [Indexed: 10/28/2023]
Abstract
Dendritic cells (DCs) are professional antigen-presenting cells (APCs), including heterogenous populations with phenotypic and functional diversity that coordinate bridging innate and adaptive immunity. Signal transducer and activator of transcriptions (STAT) factors as key proteins in cytokine signaling were shown to play distinct roles in the maturation and antigen presentation of DCs and play a pivotal role in modulating immune responses mediated by DCs such as differentiation of T cells to T helper (Th) 1, Th2 or regulatory T (Treg) cells. This review sheds light on the importance of STAT transcription factors' signaling pathways in different subtypes of DCs and highlights their targeting potential usages for improving DC-based immunotherapies for patients who suffer from cancer or diverse autoimmune conditions according to the type of the STAT transcription factor and its specific activating or inhibitory agent.
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Affiliation(s)
- Sepideh Sohrabi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Bahar Naseri
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Shiva Alipour
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Pedram Basirjafar
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Raziyeh Zandvakili
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | | | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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10
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Perrino M, Voulaz E, Balin S, Cazzato G, Fontana E, Franzese S, Defendi M, De Vincenzo F, Cordua N, Tamma R, Borea F, Aliprandi M, Airoldi M, Cecchi LG, Fazio R, Alloisio M, Marulli G, Santoro A, Di Tommaso L, Ingravallo G, Russo L, Da Rin G, Villa A, Della Bella S, Zucali PA, Mavilio D. Autoimmunity in thymic epithelial tumors: a not yet clarified pathologic paradigm associated with several unmet clinical needs. Front Immunol 2024; 15:1288045. [PMID: 38629065 PMCID: PMC11018877 DOI: 10.3389/fimmu.2024.1288045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 01/29/2024] [Indexed: 04/19/2024] Open
Abstract
Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against "self". In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients' life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases.
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Affiliation(s)
- Matteo Perrino
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Emanuele Voulaz
- Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Simone Balin
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
| | - Gerardo Cazzato
- Section of Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, Bari, Italy
| | - Elena Fontana
- Istituto di Ricerca Genetica e Biomedica (IRGB), National Research Council (CNR), Milan, Italy
- Human Genome and Biomedical Technologies Unit, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Sara Franzese
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Martina Defendi
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Fabio De Vincenzo
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Nadia Cordua
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Roberto Tamma
- Section of Human Anatomy and Histology, Department of Translational Biomedicine and Neurosciences (DiBraiN), University of Bari “Aldo Moro”, Bari, Italy
| | - Federica Borea
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Marta Aliprandi
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Marco Airoldi
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Luigi Giovanni Cecchi
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Roberta Fazio
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Marco Alloisio
- Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Giuseppe Marulli
- Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Armando Santoro
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Luca Di Tommaso
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
- Department of Pathology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Giuseppe Ingravallo
- Section of Pathology, Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari “Aldo Moro”, Bari, Italy
| | - Laura Russo
- Clinical Laboratory, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Giorgio Da Rin
- Clinical Laboratory, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Anna Villa
- Istituto di Ricerca Genetica e Biomedica (IRGB), National Research Council (CNR), Milan, Italy
- San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Silvia Della Bella
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
| | - Paolo Andrea Zucali
- Department of Medical Oncology and Hematology, IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Domenico Mavilio
- Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy
- Unit of Clinical and Experimental Immunology, IRCCS Humanitas Research Hospital, Milan, Italy
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11
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Galiatsatos P, Maydan DD, Macalpine E, Schleupner B, Aitchison AH, Lerner AD, Levy B, Halthore A, Eward W. Psoralen: a narrative review of current and future therapeutic uses. J Cancer Res Clin Oncol 2024; 150:130. [PMID: 38489072 PMCID: PMC10942908 DOI: 10.1007/s00432-024-05648-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 02/06/2024] [Indexed: 03/17/2024]
Abstract
Psoralen is a family of naturally occurring photoactive compounds found in plants that acquire potential cytotoxicity when activated by specific frequencies of electromagnetic waves. Psoralens penetrate the phospholipid cellular membranes and insert themselves between the pyrimidines of deoxyribonucleic acid (DNA). Psoralens are initially biologically inert and acquire photoreactivity when exposed to certain classes of electromagnetic radiation, such as ultraviolet light. Once activated, psoralens form mono- and di-adducts with DNA, leading to marked cell apoptosis. This apoptotic effect is more pronounced in tumor cells due to their high rate of cell division. Moreover, photoactivated psoralen can inhibit tyrosine kinase signaling and influence the immunogenic properties of cells. Thus, the cytotoxicity of photoactivated psoralen holds promising clinical applications from its immunogenic properties to potential anti-cancer treatments. This narrative review aims to provide an overview of the current understanding and research on psoralen and to explore its potential future pharmacotherapeutic benefits in specific diseases.
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Affiliation(s)
- Panagis Galiatsatos
- The Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins School of Medicine, 4940 Eastern Avenue, 4th Floor, Asthma & Allergy Building, Baltimore, MD, 21224, USA.
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.
| | - Daniella D Maydan
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Elle Macalpine
- Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, USA
| | - Beatrice Schleupner
- Department of Orthopaedic Surgery and Duke Cancer Institute, Duke University, Durham, NC, USA
| | | | - Andrew D Lerner
- The Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins School of Medicine, 4940 Eastern Avenue, 4th Floor, Asthma & Allergy Building, Baltimore, MD, 21224, USA
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Benjamin Levy
- The Sidney Kimmel Comprehensive Cancer Center, the Johns Hopkins School of Medicine, 4940 Eastern Avenue, 4th Floor, Asthma & Allergy Building, Baltimore, MD, 21224, USA
| | - Aditya Halthore
- Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - William Eward
- Department of Orthopaedic Surgery and Duke Cancer Institute, Duke University, Durham, NC, USA
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12
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Tan J, Ding B, Chen H, Meng Q, Li J, Yang C, Zhang W, Li X, Han D, Zheng P, Ma P, Lin J. Effects of Skeleton Structure of Mesoporous Silica Nanoadjuvants on Cancer Immunotherapy. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2024; 20:e2305567. [PMID: 37702141 DOI: 10.1002/smll.202305567] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 08/20/2023] [Indexed: 09/14/2023]
Abstract
Mesoporous silica nanoparticles (MSNs) have been widely praised as nanoadjuvants in vaccine/tumor immunotherapy thanks to their excellent biocompatibility, easy-to-modify surface, adjustable particle size, and remarkable immuno-enhancing activity. However, the application of MSNs is still greatly limited by some severe challenges including the unclear and complicated relationships of structure and immune effect. Herein, three commonly used MSNs with different skeletons including MSN with tetrasulfide bonds (TMSN), MSN containing ethoxy framework (EMSN), and pure -Si-O-Si- framework of MSN (MSN) are comprehensively compared to study the impact of chemical construction on immune effect. The results fully demonstrate that the three MSNs have great promise in improving cellular immunity for tumor immunotherapy. Moreover, the TMSN performs better than the other two MSNs in antigen loading, cellular uptake, reactive oxygen species (ROS) generation, lymph node targeting, immune activation, and therapeutic efficiency. The findings provide a new paradigm for revealing the structure-function relationship of mesoporous silica nanoadjuvants, paving the way for their future clinical application.
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Affiliation(s)
- Jia Tan
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Binbin Ding
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Hao Chen
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Qi Meng
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Jing Li
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Chunzheng Yang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Wenying Zhang
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Xinyang Li
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Di Han
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Pan Zheng
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- Key Laboratory of Superlight Materials & Surface Technology of Ministry of Education, College of Material Sciences and Chemical Engineering, Harbin Engineering University, Harbin, 150001, China
| | - Ping'an Ma
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
| | - Jun Lin
- State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, China
- School of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, 230026, China
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13
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Li Y, Arai S, Kato K, Iwabuchi S, Iwabuchi N, Muto N, Motobayashi H, Ebihara S, Tanaka M, Hashimoto S. The Potential Immunomodulatory Effect of Bifidobacterium longum subsp. longum BB536 on Healthy Adults through Plasmacytoid Dendritic Cell Activation in the Peripheral Blood. Nutrients 2023; 16:42. [PMID: 38201872 PMCID: PMC10780326 DOI: 10.3390/nu16010042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/05/2023] [Accepted: 12/18/2023] [Indexed: 01/12/2024] Open
Abstract
The interaction between the gut microbiota and the host can influence the host's immune system. Bifidobacterium, a commensal genus of gut bacteria, seems to have positive effects on host health. Our previous clinical research showed that B. longum subsp. longum BB536 enhanced innate and adaptive immune responses in elderly individuals with a lower grade of immunity, but the immunomodulatory mechanism is still unclear. In this study, dendritic cell (DC) surface markers in peripheral blood mononuclear cells isolated from healthy individuals were evaluated through coculture with heat-killed BB536. DC markers, innate immune activity and cytokine levels in plasma were also evaluated by a randomized, double-blind, placebo-controlled, parallel-group study (UMIN000045564) with 4 weeks of continuous live BB536 intake. BB536 significantly increased the expression of CD86 and HLA-DR on plasmacytoid DCs (pDCs) in vitro. Compared to placebo (n = 48), a significant increase in the expression of CD86 on peripheral pDCs was detected at week 4 of live BB536 intake (n = 49; 1 × 1010 CFU/day). Furthermore, coculture with hk-BB536 significantly increased the IFNγ expression level and demonstrated trends of increased IFNα1 and IFNβ expression. These findings suggest that consumption of BB536 has potential immunomodulatory effects on healthy individuals through the activation of peripheral pDCs.
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Affiliation(s)
- Yiran Li
- Innovative Research Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 5-1-83, Higashihara, Zama 252-8583, Kanagawa, Japan
| | - Satoshi Arai
- Innovative Research Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 5-1-83, Higashihara, Zama 252-8583, Kanagawa, Japan
| | - Kumiko Kato
- Innovative Research Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 5-1-83, Higashihara, Zama 252-8583, Kanagawa, Japan
| | - Sadahiro Iwabuchi
- Department of Molecular Pathophysiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Wakayama, Japan
| | - Noriyuki Iwabuchi
- Innovative Research Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 5-1-83, Higashihara, Zama 252-8583, Kanagawa, Japan
| | - Natsumi Muto
- Innovative Research Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 5-1-83, Higashihara, Zama 252-8583, Kanagawa, Japan
| | - Hideki Motobayashi
- Second Department of Surgery, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Wakayama, Japan
| | - Shukuko Ebihara
- Chiyoda Paramedical Care Clinic, Daiwa Building 2F, 3-3-10 Nihonbashi Hongokucho, Chuo-ku, Tokyo 103-0021, Japan
| | - Miyuki Tanaka
- Innovative Research Institute, R&D Division, Morinaga Milk Industry Co., Ltd., 5-1-83, Higashihara, Zama 252-8583, Kanagawa, Japan
| | - Shinichi Hashimoto
- Department of Molecular Pathophysiology, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Wakayama, Japan
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14
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Sánchez‐Cerrillo I, Calzada‐Fraile D, Triguero‐Martínez A, Calvet‐Mirabent M, Popova O, Delgado‐Arévalo C, Valdivia‐Mazeyra M, Ramírez‐Huesca M, de Luis EV, Benguría A, Aceña‐Gonzalo T, Moreno‐Vellisca R, de Llano MA, de la Fuente H, Tsukalov I, Delgado‐Wicke P, Fernández‐Ruiz E, Roy‐Vallejo E, Tejedor‐Lázaro R, Ramiro A, Iborra S, Sánchez‐Madrid F, Dopazo A, Álvaro IG, Castañeda S, Martin‐Gayo E. MICa/b-dependent activation of natural killer cells by CD64 + inflammatory type 2 dendritic cells contributes to autoimmunity. EMBO J 2023; 42:e113714. [PMID: 37916875 PMCID: PMC10690448 DOI: 10.15252/embj.2023113714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 09/27/2023] [Accepted: 10/05/2023] [Indexed: 11/03/2023] Open
Abstract
Primary Sjögren's syndrome (pSS) is an inflammatory autoimmune disorder largely mediated by type I and II interferon (IFN). The potential contribution of innate immune cells, such as natural killer (NK) cells and dendritic cells (DC), to the pSS pathology remains understudied. Here, we identified an enriched CD16+ CD56hi NK cell subset associated with higher cytotoxic function, as well as elevated proportions of inflammatory CD64+ conventional dendritic cell (cDC2) subtype that expresses increased levels of MICa/b, the ligand for the activating receptor NKG2D, in pSS individuals. Circulating cDC2 from pSS patients efficiently induced activation of cytotoxic NK cells ex vivo and were found in proximity to CD56+ NK cells in salivary glands (SG) from pSS patients. Interestingly, transcriptional activation of IFN signatures associated with the RIG-I/DDX60 pathway, IFN I receptor, and its target genes regulate the expression of NKG2D ligands on cDC2 from pSS patients. Finally, increased proportions of CD64hi RAE-1+ cDC2 and NKG2D+ CD11b+ CD27+ NK cells were present in vivo in the SG after poly I:C injection. Our study provides novel insight into the contribution and interplay of NK and cDC2 in pSS pathology and identifies new potential therapy targets.
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Affiliation(s)
- Ildefonso Sánchez‐Cerrillo
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Diego Calzada‐Fraile
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
- Vascular Pathophysiology DepartmentCentro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Ana Triguero‐Martínez
- Rheumatology UnitHospital Universitario La Princesa, Instituto de Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Marta Calvet‐Mirabent
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Olga Popova
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Cristina Delgado‐Arévalo
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | | | - Marta Ramírez‐Huesca
- Vascular Pathophysiology DepartmentCentro Nacional de Investigaciones CardiovascularesMadridSpain
| | | | - Alberto Benguría
- Genomic UnitCentro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Teresa Aceña‐Gonzalo
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | | | | | - Hortensia de la Fuente
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
- CIBER Cardiovascular, Instituto de Salud Carlos IIIMadridSpain
| | - Ilya Tsukalov
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Pablo Delgado‐Wicke
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Elena Fernández‐Ruiz
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Emilia Roy‐Vallejo
- Rheumatology UnitHospital Universitario La Princesa, Instituto de Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Reyes Tejedor‐Lázaro
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Almudena Ramiro
- Vascular Pathophysiology DepartmentCentro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Salvador Iborra
- Vascular Pathophysiology DepartmentCentro Nacional de Investigaciones CardiovascularesMadridSpain
| | - Francisco Sánchez‐Madrid
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
- Vascular Pathophysiology DepartmentCentro Nacional de Investigaciones CardiovascularesMadridSpain
- CIBER Cardiovascular, Instituto de Salud Carlos IIIMadridSpain
| | - Ana Dopazo
- Vascular Pathophysiology DepartmentCentro Nacional de Investigaciones CardiovascularesMadridSpain
- Genomic UnitCentro Nacional de Investigaciones CardiovascularesMadridSpain
- CIBER Cardiovascular, Instituto de Salud Carlos IIIMadridSpain
| | - Isidoro González Álvaro
- Rheumatology UnitHospital Universitario La Princesa, Instituto de Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
| | - Santos Castañeda
- Rheumatology UnitHospital Universitario La Princesa, Instituto de Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
- Cátedra UAM‐Roche, EPID‐Future, Department of MedicineUniversidad Autónoma de Madrid (UAM)MadridSpain
| | - Enrique Martin‐Gayo
- Immunology UnitHospital Universitario La Princesa, Medicine Department, Universidad Autónoma de Madrid, Instituto Investigación Sanitaria‐Princesa IIS‐IPMadridSpain
- CIBER Enfermedades Infecciosas (CIBERINFECC), Instituto de Salud Carlos IIIMadridSpain
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15
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Eralp Y, Ates U. Clinical Applications of Combined Immunotherapy Approaches in Gastrointestinal Cancer: A Case-Based Review. Vaccines (Basel) 2023; 11:1545. [PMID: 37896948 PMCID: PMC10610904 DOI: 10.3390/vaccines11101545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/24/2023] [Accepted: 09/26/2023] [Indexed: 10/29/2023] Open
Abstract
Malignant neoplasms arising from the gastrointestinal (GI) tract are among the most common types of cancer with high mortality rates. Despite advances in treatment in a small subgroup harboring targetable mutations, the outcome remains poor, accounting for one in three cancer-related deaths observed globally. As a promising therapeutic option in various tumor types, immunotherapy with immune checkpoint inhibitors has also been evaluated in GI cancer, albeit with limited efficacy except for a small subgroup expressing microsatellite instability. In the quest for more effective treatment options, energetic efforts have been placed to evaluate the role of several immunotherapy approaches comprising of cancer vaccines, adoptive cell therapies and immune checkpoint inhibitors. In this review, we report our experience with a personalized dendritic cell cancer vaccine and cytokine-induced killer cell therapy in three patients with GI cancers and summarize current clinical data on combined immunotherapy strategies.
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Affiliation(s)
- Yesim Eralp
- Maslak Acıbadem Hospital, Acıbadem University, Istanbul 34398, Turkey
| | - Utku Ates
- Biotech4life Tissue and Cell R&D Center, Stembio Cell and Tissue Technologies, Inc., Istanbul 34398, Turkey
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16
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Pénzes Z, Alimohammadi S, Horváth D, Oláh A, Tóth BI, Bácsi A, Szöllősi AG. The dual role of cannabidiol on monocyte-derived dendritic cell differentiation and maturation. Front Immunol 2023; 14:1240800. [PMID: 37680639 PMCID: PMC10482398 DOI: 10.3389/fimmu.2023.1240800] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Accepted: 08/03/2023] [Indexed: 09/09/2023] Open
Abstract
Introduction Extracts and compounds isolated from hemp (Cannabis sativa) are increasingly gaining popularity in the treatment of a number of diseases, with topical formulations for dermatological conditions leading the way. Phytocannabinoids such as ( )-cannabidiol, ( )-cannabinol and ( )-Δ9-tetrahydrocannabivarin (CBD, CBN, and THCV, respectively), are present in variable amounts in the plant, and have been shown to have mostly anti-inflammatory effects both in vitro and in vivo, albeit dominantly in murine models. The role of phytocannabinoids in regulating responses of dendritic cells (DCs) remains unclear. Methods Our research aimed to investigate the effects of CBD, CBN, and THCV on human DCs differentiated from monocytes (moDCs). moDCs were treated with up to 10 μM of each phytocannabinoid, and their effects on viability, differentiation, and maturation were assessed both alone, and in conjunction with TLR agonists. The effects of CBD on cytokine production, T cell activation and polarization as well as the transcriptome of moDCs was also determined. Results Phytocannabinoids did not influence the viability of moDCs up to 10 μM, and only CBD had effects on maturational markers of moDCs, and neither compound influenced LPS-induced activation at 10 μM. Since only CBD had measurable effects on moDCs, in our subsequent experiments we tested the effect only of that pCB. On moDCs differentiated in the presence of CBD subsequent activation by LPS induced a markedly different, much more tolerogenic response. CBD-treated moDCs also produced significantly more interleukin (IL)-6, TNFα and, importantly, IL-10 in response to LPS, which shows a shift toward anti-inflammatory signaling, as well as a more robust secretory response in general. To rule out the possibility that these effects of CBD are specific to TLR4 signaling, we determined the effect of CBD on TLR7/8-induced maturation as well, and saw similar, although less marked responses. CBD-treated moDCs were also less efficient at activating naïve T cells after LPS stimulation, further supporting the tolerogenic effect of this phytocannabinoid on moDCs. Reactome pathway analysis showed an inflammatory response to LPS in moDCs, and to a lesser extent to CBD as well. In contrast CBD-treated moDCs responded to LPS with a shift towards a more tolerogenic phenotype, as IL-10 signaling was the most prominently induced pathway in this group. Discussion Our results show that CBD achieves an anti-inflammatory effect on adaptive immune responses only in the presence of an activating stimuli on moDCs by reprogramming cells during long-term treatment, and not through acute, short-term effects.
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Affiliation(s)
- Zsófia Pénzes
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary
| | - Shahrzad Alimohammadi
- Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary
- Department of Dermatology, School of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Dorottya Horváth
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary
| | - Attila Oláh
- Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Balázs István Tóth
- Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary
- Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
| | - Attila Bácsi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- ELKH-DE Allergology Research Group, Debrecen, Hungary
| | - Attila Gábor Szöllősi
- Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
- Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary
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Wang T, Sun S, Zeng X, Li J. ICI-based therapies: A new strategy for oral potentially malignant disorders. Oral Oncol 2023; 140:106388. [PMID: 37054586 DOI: 10.1016/j.oraloncology.2023.106388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 03/27/2023] [Indexed: 04/15/2023]
Abstract
Oral potentially malignant disorders (OPMDs) are linked with an escalated risk of developing cancers, particularly oral squamous cell carcinoma (OSCC). Since prevailing therapies cannot effectively forestall the exacerbation and recurrence of OPMDs, halting their malignant progression is paramount. The immune checkpoint serves as a cardinal regulator of the immune response and the primary cause of adaptive immunological resistance. Although the exact mechanism remains elusive, elevated expression of multiple immune checkpoints in OPMDs and OSCC relative to healthy oral mucosa has been ascertained. This review delves into the immunosuppressive microenvironment of OPMDs, the expression of diverse immune checkpoints such as programmed death receptor-1 (PD-1) and programmed death receptor-1 ligand (PD-L1) in OPMDs, and the potential application of corresponding inhibitors. In addition, synergistic strategies incorporating combined immune checkpoint inhibitors, such as cGAS-STING, costimulatory molecules, cancer vaccines, and hydrogels, are discussed to gain a more comprehensive understanding of the role and application of immune checkpoint inhibitors (ICIs) in oral carcinogenesis.
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Affiliation(s)
- Tianqing Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Silu Sun
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China
| | - Xin Zeng
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China.
| | - Jing Li
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, Research Unit of Oral Carcinogenesis and Management, Chinese Academy of Medical Sciences, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan 610041, PR China.
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El Harane S, Zidi B, El Harane N, Krause KH, Matthes T, Preynat-Seauve O. Cancer Spheroids and Organoids as Novel Tools for Research and Therapy: State of the Art and Challenges to Guide Precision Medicine. Cells 2023; 12:cells12071001. [PMID: 37048073 PMCID: PMC10093533 DOI: 10.3390/cells12071001] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/14/2023] [Accepted: 03/20/2023] [Indexed: 04/14/2023] Open
Abstract
Spheroids and organoids are important novel players in medical and life science research. They are gradually replacing two-dimensional (2D) cell cultures. Indeed, three-dimensional (3D) cultures are closer to the in vivo reality and open promising perspectives for academic research, drug screening, and personalized medicine. A large variety of cells and tissues, including tumor cells, can be the starting material for the generation of 3D cultures, including primary tissues, stem cells, or cell lines. A panoply of methods has been developed to generate 3D structures, including spontaneous or forced cell aggregation, air-liquid interface conditions, low cell attachment supports, magnetic levitation, and scaffold-based technologies. The choice of the most appropriate method depends on (i) the origin of the tissue, (ii) the presence or absence of a disease, and (iii) the intended application. This review summarizes methods and approaches for the generation of cancer spheroids and organoids, including their advantages and limitations. We also highlight some of the challenges and unresolved issues in the field of cancer spheroids and organoids, and discuss possible therapeutic applications.
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Affiliation(s)
- Sanae El Harane
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Bochra Zidi
- Department of Medicine, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Nadia El Harane
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Karl-Heinz Krause
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Thomas Matthes
- Department of Medicine, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
| | - Olivier Preynat-Seauve
- Department of Medicine, Faculty of Medicine, University of Geneva, 1206 Geneva, Switzerland
- Laboratory of Experimental Cell Therapy, Department of Diagnostics, Geneva University Hospitals, 1206 Geneva, Switzerland
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19
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Santiago KB, Conti BJ, Cardoso EDO, Conte FL, Tasca KI, Romagnoli GG, Golim MDA, Cruz MT, Sforcin JM. Propolis anti-inflammatory effects on MAGE-1 and retinoic acid-treated dendritic cells and on Th1 and T regulatory cells. J Venom Anim Toxins Incl Trop Dis 2023; 29:e20220044. [PMID: 36721426 PMCID: PMC9851646 DOI: 10.1590/1678-9199-jvatitd-2022-0044] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 12/13/2022] [Indexed: 01/15/2023] Open
Abstract
Background Propolis exhibits huge potential in the pharmaceutical industry. In the present study, its effects were investigated on dendritic cells (DCs) stimulated with a tumor antigen (MAGE-1) and retinoic acid (RA) and on T lymphocytes to observe a possible differential activation of T lymphocytes, driving preferentially to Th1 or Treg cells. Methods Cell viability, lymphocyte proliferation, gene expression (T-bet and FoxP3), and cytokine production by DCs (TNF-α, IL-10, IL-6 and IL-1β) and lymphocytes (IFN-γ and TGF-β) were analyzed. Results MAGE-1 and RA alone or in combination with propolis inhibited TNF-α production and induced a higher lymphoproliferation compared to control, while MAGE-1 + propolis induced IL-6 production. Propolis in combination with RA induced FoxP3 expression. MAGE-1 induced IFN-γ production while propolis inhibited it, returning to basal levels. RA inhibited TGF-β production, what was counteracted by propolis. Conclusion Propolis affected immunological parameters inhibiting pro-inflammatory cytokines and favoring the regulatory profile, opening perspectives for the control of inflammatory conditions.
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Affiliation(s)
| | - Bruno José Conti
- Institute of Biosciences, São Paulo State University (UNESP),
Botucatu, SP, Brazil
| | | | - Fernanda Lopes Conte
- Institute of Biosciences, São Paulo State University (UNESP),
Botucatu, SP, Brazil
| | - Karen Ingrid Tasca
- Institute of Biosciences, São Paulo State University (UNESP),
Botucatu, SP, Brazil
| | | | | | - Maria Tereza Cruz
- Faculty of Pharmacy, Center for Neurosciences and Cellular Biology,
University of Coimbra, Coimbra, Portugal
| | - José Maurício Sforcin
- Institute of Biosciences, São Paulo State University (UNESP),
Botucatu, SP, Brazil.,Correspondence:
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Lellahi SM, Azeem W, Hua Y, Gabriel B, Paulsen Rye K, Reikvam H, Kalland KH. GM-CSF, Flt3-L and IL-4 affect viability and function of conventional dendritic cell types 1 and 2. Front Immunol 2023; 13:1058963. [PMID: 36713392 PMCID: PMC9880532 DOI: 10.3389/fimmu.2022.1058963] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 12/27/2022] [Indexed: 01/15/2023] Open
Abstract
Conventional type 1 dendritic cells (cDC1) and conventional type 2 dendritic cells (cDC2) have attracted increasing attention as alternatives to monocyte-derived dendritic cells (moDCs) in cancer immunotherapy. Use of cDCs for therapy has been hindered by their low numbers in peripheral blood. In the present study, we found that extensive spontaneous apoptosis and cDC death in culture within 24hrs represent an additional challenge. Different media conditions that maintain cDC viability and function were investigated. CD141+ cDC1 and CD1c+ cDC2 were isolated from healthy blood donor buffy coats. Low viabilities were found with CellGenix DC, RPMI-1640, and X-VIVO 15 standard culture media and with several supplements at 24hrs and 48hrs. Among multiple factors it was found that GM-CSF improved both cDC1 and cDC2 viability, whereas Flt3-L and IL-4 only increased viability of cDC1 and cDC2, respectively. Combinations of these three cytokines improved viability of both cDCs further, both at 24hrs and 48hrs time points. Although these cytokines have been extensively investigated for their role in myeloid cell differentiation, and are also used clinically, their effects on mature cDCs remain incompletely known, in particular effects on pro-inflammatory or tolerogenic cDC features. HLA-DR, CD80, CD83, CD86, PD-L1 and PD-L2 cDC membrane expressions were relatively little affected by GM-CSF, IL-4 and Flt3-L cytokine supplements compared to the strong induction following Toll-like receptor (TLR) stimulation for 24hrs. With minor exceptions the three cytokines appeared to be permissive to the TLR-induced marker expression. Allogeneic mixed leukocyte reaction showed that the cytokines promoted T-cell proliferation and revealed a potential to boost both Th1 and Th2 polarizing cytokines. GM-CSF and Flt3-L and their combination improved the capability of cDC1 for dextran uptake, while in cDC2, dextran capture was improved by GM-CSF. The data suggest that GM-CSF, IL-4 and Flt3-L and combinations might be beneficial for DC viability and function in vitro. Limited viability of cDCs could be a confounding variable experimentally and in immunotherapy.
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Affiliation(s)
- Seyed Mohammad Lellahi
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Waqas Azeem
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Immunology and Transfusion Medicine, Helse Bergen, Bergen, Norway
| | - Yaping Hua
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Benjamin Gabriel
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway
| | | | - Håkon Reikvam
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Karl-Henning Kalland
- Department of Clinical Science, University of Bergen, Bergen, Norway
- Centre for Cancer Biomarkers (CCBIO), Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Microbiology, Haukeland University Hospital, Helse Bergen, Bergen, Norway
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Ghasemi M, Abbasi L, Ghanbari Naeini L, Kokabian P, Nameh Goshay Fard N, Givtaj N. Dendritic cells and natural killer cells: The road to a successful oncolytic virotherapy. Front Immunol 2023; 13:950079. [PMID: 36703982 PMCID: PMC9871831 DOI: 10.3389/fimmu.2022.950079] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Accepted: 09/02/2022] [Indexed: 01/11/2023] Open
Abstract
Every type of cancer tissue is theoretically more vulnerable to viral infection. This natural proclivity has been harnessed as a new anti-cancer therapy by employing oncolytic viruses (OVs) to selectively infect and destroy cancer cells while providing little or no harm with no toxicity to the host. Whereas the primary oncolytic capabilities of OVs initially sparked the greatest concern, the predominant focus of research is on the association between OVs and the host immune system. Numerous OVs are potent causal agents of class I MHC pathway-related chemicals, enabling early tumor/viral immune recognition and cytokine-mediated response. The modified OVs have been studied for their ability to bind to dendritic cells (DCs) by expressing growth factors, chemokines, cytokines, and defensins inside the viral genome. OVs, like reovirus, can directly infect DCs, causing them to release chemokines and cytokines that attract and excite natural killer (NK) cells. In addition, OVs can directly alter cancer cells' sensitivity to NK by altering the expression levels of NK cell activators and inhibitors on cancerous cells. Therefore, NK cells and DCs in modulating the therapeutic response should be considered when developing and improving future OV-based therapeutics, whether modified to express transgenes or used in combination with other drugs/immunotherapies. Concerning the close relationship between NK cells and DCs in the potential of OVs to kill tumor cells, we explore how DCs and NK cells in tumor microenvironment affect oncolytic virotherapy and summarize additional information about the interaction mentioned above in detail in this work.
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Affiliation(s)
- Matin Ghasemi
- Faculty of Medicine, Tonekabon Branch, Islamic Azad University, Tonekabon, Iran
| | - Laleh Abbasi
- Guilan University of Medical Sciences, Rasht, Iran
| | | | - Pajman Kokabian
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Najmeh Nameh Goshay Fard
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Nozar Givtaj
- Rajaei Cardiovascular, Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran,*Correspondence: Nozar Givtaj,
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22
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Umbreen H, Zhang X, Tang KT, Lin CC. Regulation of Myeloid Dendritic Cells by Synthetic and Natural Compounds for the Treatment of Rheumatoid Arthritis. Int J Mol Sci 2022; 24:ijms24010238. [PMID: 36613683 PMCID: PMC9820359 DOI: 10.3390/ijms24010238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/12/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Different subsets of dendritic cells (DCs) participate in the development of rheumatoid arthritis (RA). In particular, myeloid DCs play a key role in the generation of autoreactive T and B cells. Herein, we undertook a literature review on those synthetic and natural compounds that have therapeutic efficacy/potential for RA and act through the regulation of myeloid DCs. Most of these compounds inhibit both the maturation of DCs and their secretion of inflammatory cytokines and, subsequently, alter the downstream T-cell response (suppression of Th1 and Th17 responses while expanding the Treg response). The majority of the synthetic compounds are approved for the treatment of patients with RA, which is consistent with the importance of DCs in the pathogenesis of RA. All of the natural compounds are derived from plants. Their DC-modulating effect has been demonstrated both in vitro and in vivo. In addition, these natural products ameliorate arthritis in rodents and are potential therapeutics for human RA.
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Affiliation(s)
- Hira Umbreen
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Xiang Zhang
- Department of Molecular Medicine and Surgery, Karolinska Institute, 171 76 Stockholm, Sweden
| | - Kuo-Tung Tang
- Division of Allergy, Immunology, and Rheumatology, Taichung Veterans General Hospital, Taichung 407, Taiwan
- Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Correspondence: (K.-T.T.); (C.-C.L.); Tel.: +886-4-23592525 (ext. 3334) (K.-T.T.); +886-4-23592525 (ext. 3003) (C.-C.L.); Fax: +886-4-23503285 (K.-T.T. & C.-C.L.)
| | - Chi-Chien Lin
- Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Ph.D. Program in Translational Medicine, National Chung Hsing University, Taichung 402, Taiwan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 407, Taiwan
- Institute of Biomedical Science, The iEGG and Animal Biotechnology Center, National Chung-Hsing University, Taichung 402, Taiwan
- Department of Medical Research, China Medical University Hospital, Taichung 404, Taiwan
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
- Correspondence: (K.-T.T.); (C.-C.L.); Tel.: +886-4-23592525 (ext. 3334) (K.-T.T.); +886-4-23592525 (ext. 3003) (C.-C.L.); Fax: +886-4-23503285 (K.-T.T. & C.-C.L.)
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Vedunova M, Turubanova V, Vershinina O, Savyuk M, Efimova I, Mishchenko T, Raedt R, Vral A, Vanhove C, Korsakova D, Bachert C, Coppieters F, Agostinis P, Garg AD, Ivanchenko M, Krysko O, Krysko DV. DC vaccines loaded with glioma cells killed by photodynamic therapy induce Th17 anti-tumor immunity and provide a four-gene signature for glioma prognosis. Cell Death Dis 2022; 13:1062. [PMID: 36539408 PMCID: PMC9767932 DOI: 10.1038/s41419-022-05514-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 12/12/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022]
Abstract
Gliomas, the most frequent type of primary tumor of the central nervous system in adults, results in significant morbidity and mortality. Despite the development of novel, complex, multidisciplinary, and targeted therapies, glioma therapy has not progressed much over the last decades. Therefore, there is an urgent need to develop novel patient-adjusted immunotherapies that actively stimulate antitumor T cells, generate long-term memory, and result in significant clinical benefits. This work aimed to investigate the efficacy and molecular mechanism of dendritic cell (DC) vaccines loaded with glioma cells undergoing immunogenic cell death (ICD) induced by photosens-based photodynamic therapy (PS-PDT) and to identify reliable prognostic gene signatures for predicting the overall survival of patients. Analysis of the transcriptional program of the ICD-based DC vaccine led to the identification of robust induction of Th17 signature when used as a vaccine. These DCs demonstrate retinoic acid receptor-related orphan receptor-γt dependent efficacy in an orthotopic mouse model. Moreover, comparative analysis of the transcriptome program of the ICD-based DC vaccine with transcriptome data from the TCGA-LGG dataset identified a four-gene signature (CFH, GALNT3, SMC4, VAV3) associated with overall survival of glioma patients. This model was validated on overall survival of CGGA-LGG, TCGA-GBM, and CGGA-GBM datasets to determine whether it has a similar prognostic value. To that end, the sensitivity and specificity of the prognostic model for predicting overall survival were evaluated by calculating the area under the curve of the time-dependent receiver operating characteristic curve. The values of area under the curve for TCGA-LGG, CGGA-LGG, TCGA-GBM, and CGGA-GBM for predicting five-year survival rates were, respectively, 0.75, 0.73, 0.9, and 0.69. These data open attractive prospects for improving glioma therapy by employing ICD and PS-PDT-based DC vaccines to induce Th17 immunity and to use this prognostic model to predict the overall survival of glioma patients.
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Affiliation(s)
- Maria Vedunova
- grid.28171.3d0000 0001 0344 908XInstitute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Victoria Turubanova
- grid.28171.3d0000 0001 0344 908XInstitute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia ,grid.5342.00000 0001 2069 7798Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Olga Vershinina
- grid.28171.3d0000 0001 0344 908XInstitute of Information Technology, Mathematics and Mechanics, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Maria Savyuk
- grid.28171.3d0000 0001 0344 908XInstitute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia ,grid.5342.00000 0001 2069 7798Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Iuliia Efimova
- grid.5342.00000 0001 2069 7798Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Ghent, Belgium ,grid.510942.bCancer Research Institute Ghent, Ghent, Belgium
| | - Tatiana Mishchenko
- grid.28171.3d0000 0001 0344 908XInstitute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Robrecht Raedt
- grid.5342.00000 0001 2069 77984Brain Team, Department of Head and Skin, Ghent University, Ghent, Belgium
| | - Anne Vral
- grid.5342.00000 0001 2069 7798Radiobiology Research Group, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Christian Vanhove
- grid.5342.00000 0001 2069 7798IBiTech-MEDISIP-Infinity Laboratory, Department of Electronics and Information Systems, Ghent University, Ghent, Belgium
| | - Daria Korsakova
- grid.28171.3d0000 0001 0344 908XInstitute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Claus Bachert
- grid.5342.00000 0001 2069 7798Upper Airways Research Laboratory, Department of Head and Skin, Ghent University, Ghent, Belgium
| | - Frauke Coppieters
- grid.5342.00000 0001 2069 7798Center for Medical Genetics Ghent (CMGG), Department of Biomolecular Medicine, Ghent University, Ghent, Belgium
| | - Patrizia Agostinis
- grid.5596.f0000 0001 0668 7884Laboratory of Cell Death Research & Therapy, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium ,grid.511459.dVIB Center for Cancer Biology Research, Leuven, Belgium
| | - Abhishek D. Garg
- grid.5596.f0000 0001 0668 7884Laboratory of Cell Stress & Immunity (CSI), Department of Cellular & Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Mikhail Ivanchenko
- grid.28171.3d0000 0001 0344 908XInstitute of Information Technology, Mathematics and Mechanics, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Olga Krysko
- grid.5342.00000 0001 2069 7798Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Dmitri V. Krysko
- grid.28171.3d0000 0001 0344 908XInstitute of Biology and Biomedicine, National Research Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia ,grid.5342.00000 0001 2069 7798Cell Death Investigation and Therapy (CDIT) Laboratory, Department of Human Structure and Repair, Ghent University, Ghent, Belgium ,grid.510942.bCancer Research Institute Ghent, Ghent, Belgium
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Liu C, Zhu J, Mi Y, Jin T. Impact of disease-modifying therapy on dendritic cells and exploring their immunotherapeutic potential in multiple sclerosis. J Neuroinflammation 2022; 19:298. [PMID: 36510261 PMCID: PMC9743681 DOI: 10.1186/s12974-022-02663-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022] Open
Abstract
Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs), which play a pivotal role in inducing either inflammatory or tolerogenic response based on their subtypes and environmental signals. Emerging evidence indicates that DCs are critical for initiation and progression of autoimmune diseases, including multiple sclerosis (MS). Current disease-modifying therapies (DMT) for MS can significantly affect DCs' functions. However, the study on the impact of DMT on DCs is rare, unlike T and B lymphocytes that are the most commonly discussed targets of these therapies. Induction of tolerogenic DCs (tolDCs) with powerful therapeutic potential has been well-established to combat autoimmune responses in laboratory models and early clinical trials. In contrast to in vitro tolDC induction, in vivo elicitation by specifically targeting multiple cell-surface receptors has shown greater promise with more advantages. Here, we summarize the role of DCs in governing immune tolerance and in the process of initiating and perpetuating MS as well as the effects of current DMT drugs on DCs. We then highlight the most promising cell-surface receptors expressed on DCs currently being explored as the viable pharmacological targets through antigen delivery to generate tolDCs in vivo.
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Affiliation(s)
- Caiyun Liu
- grid.430605.40000 0004 1758 4110Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Jie Zhu
- grid.430605.40000 0004 1758 4110Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China ,grid.24381.3c0000 0000 9241 5705Department of Neurobiology, Care Sciences & Society, Division of Neurogeriatrcs, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden
| | - Yan Mi
- grid.430605.40000 0004 1758 4110Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Tao Jin
- grid.430605.40000 0004 1758 4110Neuroscience Center, Department of Neurology, The First Hospital of Jilin University, Changchun, China
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Achmad H, Saleh Ibrahim Y, Mohammed Al-Taee M, Gabr GA, Waheed Riaz M, Hamoud Alshahrani S, Alexis Ramírez-Coronel A, Turki Jalil A, Setia Budi H, Sawitri W, Elena Stanislavovna M, Gupta J. Nanovaccines in cancer immunotherapy: Focusing on dendritic cell targeting. Int Immunopharmacol 2022; 113:109434. [DOI: 10.1016/j.intimp.2022.109434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/27/2022] [Accepted: 11/03/2022] [Indexed: 11/17/2022]
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Delgado-Arévalo C, Calvet-Mirabent M, Triguero-Martínez A, Vázquez de Luis E, Benguría-Filippini A, Largo R, Calzada-Fraile D, Popova O, Sánchez-Cerrillo I, Tsukalov I, Moreno-Vellisca R, de la Fuente H, Herrero-Beaumont G, Ramiro A, Sánchez-Madrid F, Castañeda S, Dopazo A, González Álvaro I, Martin-Gayo E. NLRC4-mediated activation of CD1c+ DC contributes to perpetuation of synovitis in rheumatoid arthritis. JCI Insight 2022; 7:152886. [PMID: 36194479 DOI: 10.1172/jci.insight.152886] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 09/29/2022] [Indexed: 12/15/2022] Open
Abstract
The individual contribution of specific myeloid subsets such as CD1c+ conventional DC (cDC) to perpetuation of rheumatoid arthritis (RA) pathology remains unclear. In addition, the specific innate sensors driving pathogenic activation of CD1c+ cDC in patients with RA and their functional implications have not been characterized. Here, we assessed phenotypical, transcriptional, and functional characteristics of CD1c+ and CD141+ cDC and monocytes from the blood and synovial fluid of patients with RA. Increased levels of CCR2 and the IgG receptor CD64 on circulating CD1c+ cDC was associated with the presence of this DC subset in the synovial membrane in patients with RA. Moreover, synovial CD1c+ cDC are characterized by increased expression of proinflammatory cytokines and high abilities to induce pathogenic IFN-γ+IL-17+CD4+ T cells in vitro. Finally, we identified the crosstalk between Fcγ receptors and NLRC4 as a potential molecular mechanism mediating pathogenic activation, CD64 upregulation, and functional specialization of CD1c+ cDC in response to dsDNA-IgG in patients with RA.
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Affiliation(s)
- Cristina Delgado-Arévalo
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Marta Calvet-Mirabent
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Ana Triguero-Martínez
- Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | | | | | - Raquel Largo
- Bone and Joint Research Unit, Rheumatology Service, IIS Fundación Jiménez Díaz, Madrid, Spain
| | - Diego Calzada-Fraile
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain
| | - Olga Popova
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Ildefonso Sánchez-Cerrillo
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Ilya Tsukalov
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | | | - Hortensia de la Fuente
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain
| | | | - Almudena Ramiro
- Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain
| | - Francisco Sánchez-Madrid
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain.,Biology Laboratory, The National Centre for Cardiovascular Research, Madrid, Spain
| | - Santos Castañeda
- Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,Cátedra UAM-Roche, EPID-Future, Department of Medicine, UAM, Madrid, Spain
| | - Ana Dopazo
- Genomic Unit, The National Centre for Cardiovascular Research, Madrid, Spain.,CIBER Cardiovascular, Madrid, Spain
| | - Isidoro González Álvaro
- Rheumatology Department from Hospital Universitario La Princesa, Instituto de Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain
| | - Enrique Martin-Gayo
- Immunology Unit from Hospital Universitario La Princesa, Medicine Faculty, Autonomous University of Madrid (UAM), Instituto Investigación Sanitaria-Princesa IIS-IP, Madrid, Spain.,CIBER Infectious Diseases, Madrid, Spain
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Yaping W, Zhe W, Zhuling C, Ruolei L, Pengyu F, Lili G, Cheng J, Bo Z, Liuyin L, Guangdong H, Yaoling W, Niuniu H, Rui L. The soldiers needed to be awakened: Tumor-infiltrating immune cells. Front Genet 2022; 13:988703. [PMID: 36246629 PMCID: PMC9558824 DOI: 10.3389/fgene.2022.988703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Accepted: 08/29/2022] [Indexed: 11/18/2022] Open
Abstract
In the tumor microenvironment, tumor-infiltrating immune cells (TIICs) are a key component. Different types of TIICs play distinct roles. CD8+ T cells and natural killer (NK) cells could secrete soluble factors to hinder tumor cell growth, whereas regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) release inhibitory factors to promote tumor growth and progression. In the meantime, a growing body of evidence illustrates that the balance between pro- and anti-tumor responses of TIICs is associated with the prognosis in the tumor microenvironment. Therefore, in order to boost anti-tumor response and improve the clinical outcome of tumor patients, a variety of anti-tumor strategies for targeting TIICs based on their respective functions have been developed and obtained good treatment benefits, including mainly immune checkpoint blockade (ICB), adoptive cell therapies (ACT), chimeric antigen receptor (CAR) T cells, and various monoclonal antibodies. In recent years, the tumor-specific features of immune cells are further investigated by various methods, such as using single-cell RNA sequencing (scRNA-seq), and the results indicate that these cells have diverse phenotypes in different types of tumors and emerge inconsistent therapeutic responses. Hence, we concluded the recent advances in tumor-infiltrating immune cells, including functions, prognostic values, and various immunotherapy strategies for each immune cell in different tumors.
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Affiliation(s)
- Wang Yaping
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Wang Zhe
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Chu Zhuling
- Department of General Surgery, Eastern Theater Air Force Hospital of PLA, Nanjing, China
| | - Li Ruolei
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Fan Pengyu
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Guo Lili
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Ji Cheng
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Zhang Bo
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Liu Liuyin
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Hou Guangdong
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Wang Yaoling
- Department of Geriatrics, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hou Niuniu
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- Department of General Surgery, Eastern Theater Air Force Hospital of PLA, Nanjing, China
- *Correspondence: Hou Niuniu, ; Ling Rui,
| | - Ling Rui
- Department of Thyroid, Breast and Vascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
- *Correspondence: Hou Niuniu, ; Ling Rui,
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28
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Research progress of neoantigens in gynecologic cancers. Int Immunopharmacol 2022; 112:109236. [PMID: 36113318 DOI: 10.1016/j.intimp.2022.109236] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 09/01/2022] [Accepted: 09/04/2022] [Indexed: 11/24/2022]
Abstract
The incidence and mortality of gynecological cancers have increased over the past decade. In the absence of effective treatment strategies, many advanced patients develop resistance to conventional therapies and have poor prognosis. Neoantigens have emerged as a novel tumor-specific antigen (TSA) that arises from genomic mutations in tumor cells. With higher immunogenicity than tumor-associated antigens (TAA), they have no risk of developing autoimmune response, leading them an attractive candidate for tumor therapeutic vaccines. With the development of next-generation sequencing (NGS) technology, the identification of neoantigens has been gradually improved, and the scope of application of neoantigen vaccines has continued to expand. Combined with other therapies such as immune-checkpoint inhibitors (ICIs) or adoptive cell therapy (ACT), the application of neoantigen in gynecological cancers has extended to clinical practice. Here, we reviewed the preclinical and clinical studies of neoantigens in gynecological cancers.
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Effective innate immune response in natural HIV-1 controllers. Can mimicking lead to novel preventive and cure strategies against HIV-1? Curr Opin HIV AIDS 2022; 17:308-314. [PMID: 35938465 PMCID: PMC9415221 DOI: 10.1097/coh.0000000000000750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW HIV-1 controller individuals represents a model that can be useful for the development of novel vaccines and therapies. Initial studies pointed to the involvement of improved adaptive immunity, however, new emerging evidence suggests the contribution of innate cells to effective antiviral responses in spontaneous controllers. Therefore, understanding the alterations on innate cell subsets might be crucial to develop new effective therapeutic strategies. RECENT FINDINGS Among different innate immune cells, dendritic cell (DC) and natural killer (NK) cell are essential for effective antiviral responses. DC from controllers display improved innate detection of HIV-1 transcripts, higher induction of interferons, higher antigen presenting capacities and increased metabolism and higher capacities to induce polyfunctional CD8+ T-cell responses. Such properties have been mimicked by Toll-like receptor ligands and applied to DC-based immunotherapies in humans and in animal models. NK cells from controllers display higher expression of activating receptors promoting increased antibody-dependent cellular cytotoxicity (ADCC) and natural cytotoxicity activities. Neutralizing antibodies in combination with interleukin-15 superagonist or interferon-α can increase ADCC and cytotoxicity in NK cells from HIV-1 progressors. SUMMARY Mimicking DC and NK cell innate profiles in controllers has become a promising strategy to step forward a novel efficient immunotherapy against the HIV-1 infection.
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Pan J, Zeng W, Jia J, Shi Y, Wang D, Dong J, Fang Z, He J, Yang X, Zhang R, He M, Huang M, Fu B, Zhong B, Liu H. A Novel Therapeutic Tumor Vaccine Targeting MUC1 in Combination with PD-L1 Elicits Specific Anti-Tumor Immunity in Mice. Vaccines (Basel) 2022; 10:vaccines10071092. [PMID: 35891256 PMCID: PMC9325010 DOI: 10.3390/vaccines10071092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/26/2022] [Accepted: 06/27/2022] [Indexed: 02/04/2023] Open
Abstract
Dendritic cells (DCs), as professional antigen-presenting cells (APCs), play a key role in the initiation and regulation of humoral and cellular immunity. DC vaccines loaded with different tumor-associated antigens (TAAs) have been widely used to study their therapeutic effects on cancer. A number of clinical trials have shown that DCs are safe as an antitumor vaccine and can activate certain anti-tumor immune responses; however, the overall clinical efficacy of DC vaccine is not satisfactory, so its efficacy needs to be enhanced. MUC1 is a TAA with great potential, and the immune checkpoint PD-L1 also has great potential for tumor treatment. Both of them are highly expressed on the surface of various tumors. In this study, we generated a novel therapeutic MUC1-Vax tumor vaccine based on the method of PD-L1-Vax vaccine we recently developed; this novel PD-L1-containing MUC1-Vax vaccine demonstrated an elevated persistent anti-PD-L1 antibody production and elicited a much stronger protective cytotoxic T lymphocyte (CTL) response in immunized mice. Furthermore, the MUC1-Vax vaccine exhibited a significant therapeutic anti-tumor effect, which significantly inhibited tumor growth by expressing a high MUC1+ and PD-L1+ level of LLC and Panc02 tumor cells, and prolonged the survival of cancer-bearing animals. Taken together, our study provides a new immunotherapy strategy for improving the cross-presentation ability of therapeutic vaccine, which may be applicable to pancreatic cancer, lung cancer and for targeting other types of solid tumors that highly express MUC1 and PD-L1.
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Affiliation(s)
- Jiayi Pan
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
- Clinical Laboratory, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Science, Guangzhou 510080, China
| | - Wuyi Zeng
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Jiangtao Jia
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Yi Shi
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Danni Wang
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Jun Dong
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Zixuan Fang
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Jiashan He
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Xinyu Yang
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Rong Zhang
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Menghua He
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Maoping Huang
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
| | - Bishi Fu
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
- The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou 510260, China
| | - Bei Zhong
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
- Correspondence: (B.Z.); (H.L.); Tel./Fax: +86-020-8320-5013 (H.L.)
| | - Hui Liu
- School of Basic Medical Sciences, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People’s Hospital, Guangzhou Medical University, Guangzhou 510182, China; (J.P.); (W.Z.); (J.J.); (Y.S.); (D.W.); (J.D.); (Z.F.); (J.H.); (X.Y.); (R.Z.); (M.H.); (M.H.); (B.F.)
- The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, Guangzhou 510260, China
- Correspondence: (B.Z.); (H.L.); Tel./Fax: +86-020-8320-5013 (H.L.)
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Torres A, Vivanco S, Lavín F, Pereda C, Chernobrovkin A, Gleisner A, Alcota M, Larrondo M, López MN, Salazar-Onfray F, Zubarev RA, González FE. Haptoglobin Induces a Specific Proteomic Profile and a Mature-Associated Phenotype on Primary Human Monocyte-Derived Dendritic Cells. Int J Mol Sci 2022; 23:ijms23136882. [PMID: 35805888 PMCID: PMC9266681 DOI: 10.3390/ijms23136882] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 06/12/2022] [Accepted: 06/14/2022] [Indexed: 11/16/2022] Open
Abstract
Damage-associated molecular patterns (DAMPs) play a critical role in dendritic cells (DCs) ability to trigger a specific and efficient adaptive immune response for different physiological and pathological scenarios. We have previously identified constitutive DAMPs (HMGB1 and Calreticulin) as well as new putative inducible DAMPs such as Haptoglobin (HP), from a therapeutically used heat shock-conditioned melanoma cell lysate (called TRIMEL). Remarkably, HP was shown to be the most abundant protein in the proteomic profile of heat shock-conditioned TRIMEL samples. However, its relative contribution to the observed DCs phenotype has not been fully elucidated. Human DCs were generated from monocytes isolated from PBMC of melanoma patients and healthy donors. DC lineage was induced with rhIL-4 and rhGM-CSF. After additional stimulation with HP, the proteome of these HP-stimulated cells was characterized. In addition, DCs were phenotypically characterized by flow cytometry for canonical maturation markers and cytokine production. Finally, in vitro transmigration capacity was assessed using Transwell plates. Our results showed that the stimulation with HP was associated with the presence of exclusive and higher relative abundance of specific immune-; energy production-; lipid biosynthesis-; and DAMPs-related proteins. Importantly, HP stimulation enhanced the expression of specific DC maturation markers and pro-inflammatory and Th1-associated cytokines, and an in vitro transmigration of primary human DCs. Taken together, these data suggest that HP can be considered as a new inducible DAMP with an important role in in vitro DC activation for cancer immunotherapy.
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Affiliation(s)
- Alfredo Torres
- Laboratory of Experimental Immunology & Cancer, Faculty of Dentistry, University of Chile, Santiago 8380492, Chile; (A.T.); (S.V.); (F.L.)
- Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago 8380492, Chile;
| | - Sheilah Vivanco
- Laboratory of Experimental Immunology & Cancer, Faculty of Dentistry, University of Chile, Santiago 8380492, Chile; (A.T.); (S.V.); (F.L.)
| | - Francisca Lavín
- Laboratory of Experimental Immunology & Cancer, Faculty of Dentistry, University of Chile, Santiago 8380492, Chile; (A.T.); (S.V.); (F.L.)
| | - Cristián Pereda
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (C.P.); (A.G.); (M.N.L.); (F.S.-O.)
| | - Alexey Chernobrovkin
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE17177 Stockholm, Sweden; (A.C.); (R.A.Z.)
| | - Alejandra Gleisner
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (C.P.); (A.G.); (M.N.L.); (F.S.-O.)
| | - Marcela Alcota
- Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago 8380492, Chile;
| | - Milton Larrondo
- Blood Bank Service, University of Chile Clinical Hospital, Santiago 8380453, Chile;
| | - Mercedes N. López
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (C.P.); (A.G.); (M.N.L.); (F.S.-O.)
- Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
| | - Flavio Salazar-Onfray
- Disciplinary Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 8380453, Chile; (C.P.); (A.G.); (M.N.L.); (F.S.-O.)
- Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
| | - Roman A. Zubarev
- Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE17177 Stockholm, Sweden; (A.C.); (R.A.Z.)
| | - Fermín E. González
- Laboratory of Experimental Immunology & Cancer, Faculty of Dentistry, University of Chile, Santiago 8380492, Chile; (A.T.); (S.V.); (F.L.)
- Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, Santiago 8380492, Chile;
- Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, University of Chile, Santiago 8380453, Chile
- Correspondence: ; Tel.: +56-2-29781714
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Immunosuppressive cells in cancer: mechanisms and potential therapeutic targets. J Hematol Oncol 2022; 15:61. [PMID: 35585567 PMCID: PMC9118588 DOI: 10.1186/s13045-022-01282-8] [Citation(s) in RCA: 270] [Impact Index Per Article: 90.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 05/03/2022] [Indexed: 02/08/2023] Open
Abstract
Immunotherapies like the adoptive transfer of gene-engineered T cells and immune checkpoint inhibitors are novel therapeutic modalities for advanced cancers. However, some patients are refractory or resistant to these therapies, and the mechanisms underlying tumor immune resistance have not been fully elucidated. Immunosuppressive cells such as myeloid-derived suppressive cells, tumor-associated macrophages, tumor-associated neutrophils, regulatory T cells (Tregs), and tumor-associated dendritic cells are critical factors correlated with immune resistance. In addition, cytokines and factors secreted by tumor cells or these immunosuppressive cells also mediate the tumor progression and immune escape of cancers. Thus, targeting these immunosuppressive cells and the related signals is the promising therapy to improve the efficacy of immunotherapies and reverse the immune resistance. However, even with certain success in preclinical studies or in some specific types of cancer, large perspectives are unknown for these immunosuppressive cells, and the related therapies have undesirable outcomes for clinical patients. In this review, we comprehensively summarized the phenotype, function, and potential therapeutic targets of these immunosuppressive cells in the tumor microenvironment.
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Qiu D, Liu X, Wang W, Jiang X, Wu X, Zheng J, Zhou K, Kong X, Wu X, Jin Z. TIGIT axis: novel immune checkpoints in anti-leukemia immunity. Clin Exp Med 2022; 23:165-174. [PMID: 35419661 DOI: 10.1007/s10238-022-00817-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Accepted: 02/25/2022] [Indexed: 12/01/2022]
Abstract
Hematologic malignancy evades immune-mediated recognition through upregulating various checkpoint inhibitory receptors (IRs) on several types of lymphocytes. Immunotherapies targeting IRs have provided ample evidence supporting regulating innate and adaptive immunity and obtaining clinical benefits. Newly described IRs have received considerable attention and are under investigation in cancer immunotherapy. Specifically, T cell immunoglobulin and ITIM domain is a novel inhibitory checkpoint receptor, and its immune checkpoint axis includes additional receptors such as CD96 and CD226, which are very promising targets. However, how the dynamics and functions of these receptor networks remain unknown, this review addresses the recent findings of the relevance of this complex receptor-ligand system and discusses their potential approaches in translating these preclinical findings into novel clinical agents in anti-leukemia immunotherapy.
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Affiliation(s)
- Dan Qiu
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xiaxin Liu
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Wandi Wang
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xuan Jiang
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xiaofang Wu
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Jiamian Zheng
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Kai Zhou
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xueting Kong
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China
| | - Xiuli Wu
- Institute of Hematology, School of Medicine, Jinan University, Guangzhou, 510632, China.
| | - Zhenyi Jin
- Department of Pathology, School of Medicine, Jinan University, Guangzhou, 510632, China.
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Wang N, Chen Z, Zhang F, Zhang Q, Sun L, Lv H, Wang B, Shen J, Zhou X, Chen F, Zhang B, Meng L, Zhou H, Bai Z, Huang J. Intravenous Immunoglobulin Therapy Restores the Quantity and Phenotype of Circulating Dendritic Cells and CD4 + T Cells in Children With Acute Kawasaki Disease. Front Immunol 2022; 13:802690. [PMID: 35222381 PMCID: PMC8866170 DOI: 10.3389/fimmu.2022.802690] [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] [Scholar Register] [Received: 10/27/2021] [Accepted: 01/13/2022] [Indexed: 12/19/2022] Open
Abstract
Background Intravenous immunoglobulin (IVIG) showed its therapeutic efficacy on Kawasaki disease (KD). However, the mechanisms by which it reduces systemic inflammation are not completely understood. Dendritic cells (DCs) and T cells play critical roles in the pathogenic processes of immune disorders. Assessing the quantity of DC subsets and T cells and identifying functional molecules present on these cells, which provide information about KD, in the peripheral blood may provide new insights into the mechanisms of immunoglobulin therapy. Methods In total, 54 patients with KD and 27 age-matched healthy controls (HCs) were included in this study. The number, percentage, and phenotype of DC subsets and CD4+ T cells in peripheral blood were analyzed through flow cytometry. Results Patients with KD exhibited fewer peripheral DC subsets and CD4+ T cells than HCs. Human leucocyte antigen-DR (HLA-DR) expression was reduced on CD1c+ myeloid DCs (CD1c+ mDCs), whereas that on plasmacytoid DCs (pDCs) did not change significantly. Both pDCs and CD1c+ mDCs displayed significantly reduced expression of co-stimulatory molecules, including CD40, CD86. pDCs and CD1c+ mDCs presented an immature or tolerant phenotype in acute stages of KD. Number of circulating pDC and CD1c+ mDC significantly inversely correlated with plasma interleukin-6 (IL-6) levels in KD patients pre-IVIG treatment. No significant differences were found concerning the DC subsets and CD4+ T cells in patients with KD with and without coronary artery lesions. Importantly, these altered quantity and phenotypes on DC subsets and CD4+ T cells were restored to a great extent post-IVIG treatment. T helper (Th) subsets including Th1 and Th2 among CD4+ T cells did not show alteration pre- and post-IVIG treatment, although the Th1-related cytokine IFN-γ level in plasma increased dramatically in patients with KD pre-IVIG treatment. Conclusions pDCs and CD1c+ mDCs presented an immature or tolerant phenotype in acute stages of KD, IVIG treatment restored the quantity and functional molecules of DCs and CD4+ T cells to distinct levels in vivo, indicating the involvement of DCs and CD4+ T cells in the inflammation in KD. The findings provide insights into the immunomodulatory actions of IVIG in KD.
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Affiliation(s)
- Nana Wang
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Zhongyue Chen
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Fan Zhang
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Qianwen Zhang
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Ling Sun
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Haitao Lv
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Bo Wang
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Jie Shen
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Xufang Zhou
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Feiyan Chen
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Binwei Zhang
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
| | - Lijun Meng
- Department of Hematology, Children's Hospital of Soochow University, Suzhou, China
| | - Huiting Zhou
- Pediatric Research Institute of Soochow University, Suzhou, China
| | - ZhenJiang Bai
- Department of Pediatric Intensive Care Unit, Children Hospital of Soochow University, Suzhou, China
| | - Jie Huang
- Department of Cardiology, Children's Hospital of Soochow University, Suzhou, China
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Frutos-Rincón L, Gómez-Sánchez JA, Íñigo-Portugués A, Acosta MC, Gallar J. An Experimental Model of Neuro-Immune Interactions in the Eye: Corneal Sensory Nerves and Resident Dendritic Cells. Int J Mol Sci 2022; 23:ijms23062997. [PMID: 35328417 PMCID: PMC8951464 DOI: 10.3390/ijms23062997] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 02/28/2022] [Accepted: 03/04/2022] [Indexed: 12/04/2022] Open
Abstract
The cornea is an avascular connective tissue that is crucial, not only as the primary barrier of the eye but also as a proper transparent refractive structure. Corneal transparency is necessary for vision and is the result of several factors, including its highly organized structure, the physiology of its few cellular components, the lack of myelinated nerves (although it is extremely innervated), the tightly controlled hydration state, and the absence of blood and lymphatic vessels in healthy conditions, among others. The avascular, immune-privileged tissue of the cornea is an ideal model to study the interactions between its well-characterized and dense sensory nerves (easily accessible for both focal electrophysiological recording and morphological studies) and the low number of resident immune cell types, distinguished from those cells migrating from blood vessels. This paper presents an overview of the corneal structure and innervation, the resident dendritic cell (DC) subpopulations present in the cornea, their distribution in relation to corneal nerves, and their role in ocular inflammatory diseases. A mouse model in which sensory axons are constitutively labeled with tdTomato and DCs with green fluorescent protein (GFP) allows further analysis of the neuro-immune crosstalk under inflammatory and steady-state conditions of the eye.
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Affiliation(s)
- Laura Frutos-Rincón
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
| | - José Antonio Gómez-Sánchez
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- Correspondence: ; Tel.: +34-965-91-9594
| | - Almudena Íñigo-Portugués
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
| | - M. Carmen Acosta
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
| | - Juana Gallar
- Instituto de Neurociencias, Universidad Miguel Hernández—Consejo Superior de Investigaciones Científicas, 03550 San Juan de Alicante, Spain; (L.F.-R.); (A.Í.-P.); (M.C.A.); (J.G.)
- The European University of Brain and Technology-NeurotechEU, 03550 San Juan de Alicante, Spain
- Instituto de Investigación Biomédica y Sanitaria de Alicante, 03010 Alicante, Spain
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Papadopoulou G, Manoloudi E, Repousi N, Skoura L, Hurst T, Karamitros T. Molecular and Clinical Prognostic Biomarkers of COVID-19 Severity and Persistence. Pathogens 2022; 11:311. [PMID: 35335635 PMCID: PMC8948624 DOI: 10.3390/pathogens11030311] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/24/2022] [Accepted: 02/27/2022] [Indexed: 02/04/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), poses several challenges to clinicians, due to its unpredictable clinical course. The identification of laboratory biomarkers, specific cellular, and molecular mediators of immune response could contribute to the prognosis and management of COVID-19 patients. Of utmost importance is also the detection of differentially expressed genes, which can serve as transcriptomic signatures, providing information valuable to stratify patients into groups, based on the severity of the disease. The role of biomarkers such as IL-6, procalcitonin, neutrophil-lymphocyte ratio, white blood cell counts, etc. has already been highlighted in recently published studies; however, there is a notable amount of new evidence that has not been summarized yet, especially regarding transcriptomic signatures. Hence, in this review, we assess the latest cellular and molecular data and determine the significance of abnormalities in potential biomarkers for COVID-19 severity and persistence. Furthermore, we applied Gene Ontology (GO) enrichment analysis using the genes reported as differentially expressed in the literature in order to investigate which biological pathways are significantly enriched. The analysis revealed a number of processes, such as inflammatory response, and monocyte and neutrophil chemotaxis, which occur as part of the complex immune response to SARS-CoV-2.
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Affiliation(s)
- Gethsimani Papadopoulou
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 115 21 Athens, Greece; (G.P.); (E.M.); (N.R.)
| | - Eleni Manoloudi
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 115 21 Athens, Greece; (G.P.); (E.M.); (N.R.)
| | - Nikolena Repousi
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 115 21 Athens, Greece; (G.P.); (E.M.); (N.R.)
| | - Lemonia Skoura
- Department of Microbiology, AHEPA University Hospital, Medical School, Aristotle University of Thessaloniki, 546 36 Thessaloniki, Greece;
| | - Tara Hurst
- School of Health Sciences, Birmingham City University, Birmingham B15 3TN, UK;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 115 21 Athens, Greece; (G.P.); (E.M.); (N.R.)
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Kubiszewska I, Gackowska L, Obrycki Ł, Wierzbicka A, Helmin-Basa A, Kułaga Z, Wiese-Szadkowska M, Michałkiewicz J, Litwin M. Distribution and maturation state of peripheral blood dendritic cells in children with primary hypertension. Hypertens Res 2022; 45:401-413. [PMID: 34916664 DOI: 10.1038/s41440-021-00809-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 10/18/2021] [Accepted: 10/28/2021] [Indexed: 11/09/2022]
Abstract
Dendritic cells (DCs) play an important role in T cell alterations in primary hypertension (PH). We determined the numbers and maturation markers of peripheral blood total DCs (tDCs), myeloid cells (mDCs), and plasmacytoid cells (pDCs) and their association with hypertension-mediated organ damage (HMOD) markers and selected immune parameters in 30 adolescents with white coat hypertension (WCH), 25 adolescents with PH and a group of 35 age- and sex-matched children with normotension. Using multicolor flow cytometry, expression of maturation markers (CD86 and CD83) in tDCs (Lin1-/HLA-DR+), myeloid DCs (Lin1-/HLA-DR+/CD11c+) (mDCs), and plasmacytoid DCs (Lin1-/HLA-DR+/CD123+) (pDCs) and the distribution of peripheral Th17-bearing and T-reg cells were defined. In subjects with hypertension, carotid intima-media thickness (cIMT), left ventricular mass index (LVMI), and pulse wave velocity (PWV) were assessed. Compared with WCH and subjects with normotension, subjects with hypertension had reduced tDC and pDC numbers, an increased percentage of mDC subsets, an elevated mDC/pDC ratio, an increased population of mature mDC and pDC subsets bearing CD83 of high density, a decreased subset of CD86-bearing pDCs, and increased expression of DC activation markers (HLA-DR, CD86), as well as CD11c (mDCs) and CD123 (pDCs). PWV, LVMI, and cIMT values correlated negatively with tDCs and pDCs and positively with mDC numbers. Expression of DC maturation/activation markers (CD83, CD86, HLA-DR, CD11c, and CD123) correlated positively with PWV. Certain DC characteristics of WCH subjects resembled those of PH subjects (decreased tDC frequency and upregulation of activation marker expression). These changes correlated with HMOD. WCH subjects presented a DC phenotype that was intermediate between the normotensive and hypertensive phenotypes.
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Affiliation(s)
- Izabela Kubiszewska
- Department of Immunology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Lidia Gackowska
- Department of Immunology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Łukasz Obrycki
- Department of Nephrology, Kidney Transplantation and Arterial Hypertension, The Children's Memorial Health Institute, Warsaw, Poland
| | - Aldona Wierzbicka
- Department of Biochemistry and Experimental Medicine, The Children's Memorial Health Institute, Warsaw, Poland
| | - Anna Helmin-Basa
- Department of Immunology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Zbigniew Kułaga
- Department of Public Health, The Children's Memorial Health Institute, Warsaw, Poland
| | - Małgorzta Wiese-Szadkowska
- Department of Immunology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland
| | - Jacek Michałkiewicz
- Department of Immunology, Faculty of Pharmacy, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Torun, Torun, Poland.,Department of Microbiology and Clinical Immunology, The Children's Memorial Health Institute, Warsaw, Poland
| | - Mieczysław Litwin
- Department of Nephrology, Kidney Transplantation and Arterial Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.
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Plesca I, Müller L, Böttcher JP, Medyouf H, Wehner R, Schmitz M. Tumor-associated human dendritic cell subsets: phenotype, functional orientation, and clinical relevance. Eur J Immunol 2022; 52:1750-1758. [PMID: 35106759 DOI: 10.1002/eji.202149487] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 12/15/2021] [Accepted: 01/24/2022] [Indexed: 11/09/2022]
Abstract
Dendritic cells (DCs) play a pivotal role in orchestrating innate and adaptive antitumor immunity. Activated DCs can produce large amounts of various proinflammatory cytokines, initiate T cell responses, and exhibit direct cytotoxicity against tumor cells. They also efficiently enhance the antitumoral properties of natural killer cells and T lymphocytes. Based on these capabilities, immunogenic DCs promote tumor elimination and are associated with improved survival of patients. Furthermore, they can essentially contribute to the clinical efficacy of immunotherapeutic strategies for cancer patients. However, depending on their intrinsic properties and the tumor microenvironment, DCs can be rendered dysfunctional and mediate tolerance by producing immunosuppressive cytokines and activating regulatory T cells. Such tolerogenic DCs can foster tumor progression and are linked to poor prognosis of patients. Here, we focus on recent studies exploring the phenotype, functional orientation, and clinical relevance of tumor-infiltrating conventional DC1, conventional DC2, plasmacytoid DCs, and monocyte-derived DCs in translational and clinical settings. In addition, recent findings demonstrating the influence of DCs on the efficacy of immunotherapeutic strategies are summarized. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Ioana Plesca
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Luise Müller
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - Jan P Böttcher
- Institute of Molecular Immunology and Experimental Oncology, Klinikum Rechts der Isar, School of Medicine, Technical University of Munich (TUM), Munich, Germany
| | - Hind Medyouf
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany.,Frankfurt Cancer Institute, Frankfurt am Main, Germany.,German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Rebekka Wehner
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Marc Schmitz
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.,National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany.,German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
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Peil J, Bock F, Kiefer F, Schmidt R, Heindl LM, Cursiefen C, Schlereth SL. New Therapeutic Approaches for Conjunctival Melanoma-What We Know So Far and Where Therapy Is Potentially Heading: Focus on Lymphatic Vessels and Dendritic Cells. Int J Mol Sci 2022; 23:1478. [PMID: 35163401 PMCID: PMC8835854 DOI: 10.3390/ijms23031478] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 11/25/2022] Open
Abstract
Conjunctival melanoma (CM) accounts for 5% of all ocular melanomas and arises from malignantly transformed melanocytes in the conjunctival epithelium. Current therapies using surgical excision in combination with chemo- or cryotherapy still have high rates for recurrences and metastatic disease. Lately, novel signal transduction-targeted and immune checkpoint inhibitors like cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, programmed cell death protein-1 (PD-1) receptor inhibitors, BRAF- or MEK-inhibitors for systemic treatment of melanoma have improved the outcome even for unresectable cutaneous melanoma, improving patient survival dramatically. The use of these therapies is now also recommended for CM; however, the immunological background of CM is barely known, underlining the need for research to better understand the immunological basics when treating CM patients with immunomodulatory therapies. Immune checkpoint inhibitors activate tumor defense by interrupting inhibitory interactions between tumor cells and T lymphocytes at the so-called checkpoints. The tumor cells exploit these inhibitory targets on T-cells that are usually used by dendritic cells (DCs). DCs are antigen-presenting cells at the forefront of immune response induction. They contribute to immune tolerance and immune defense but in the case of tumor development, immune tolerance is often prevalent. Enhancing the immune response via DCs, interfering with the lymphatic pathways during immune cell migration and tumor development and specifically targeting tumor cells is a major therapeutic opportunity for many tumor entities including CM. This review summarizes the current knowledge on the function of lymphatic vessels in tumor growth and immune cell transport and continues to compare DC subsets in CM with related melanomas, such as cutaneous melanoma and mucosal melanoma.
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Affiliation(s)
- Jennifer Peil
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (J.P.); (F.B.); (L.M.H.); (C.C.)
| | - Felix Bock
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (J.P.); (F.B.); (L.M.H.); (C.C.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
| | - Friedemann Kiefer
- European Institute for Molecular Imaging (EIMI), University of Münster, 48149 Münster, Germany;
| | - Rebecca Schmidt
- Department of Oral, Maxillofacial and Plastic Facial Surgery, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, 40225 Düsseldorf, Germany;
| | - Ludwig M. Heindl
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (J.P.); (F.B.); (L.M.H.); (C.C.)
| | - Claus Cursiefen
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (J.P.); (F.B.); (L.M.H.); (C.C.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
| | - Simona L. Schlereth
- Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany; (J.P.); (F.B.); (L.M.H.); (C.C.)
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50937 Cologne, Germany
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de Almeida Baptista MV, da Silva LT, Samer S, Oshiro TM, Shytaj IL, Giron LB, Pena NM, Cruz N, Gosuen GC, Ferreira PRA, Cunha-Neto E, Galinskas J, Dias D, Sucupira MCA, de Almeida-Neto C, Salomão R, da Silva Duarte AJ, Janini LM, Hunter JR, Savarino A, Juliano MA, Diaz RS. Immunogenicity of personalized dendritic-cell therapy in HIV-1 infected individuals under suppressive antiretroviral treatment: interim analysis from a phase II clinical trial. AIDS Res Ther 2022; 19:2. [PMID: 35022035 PMCID: PMC8753935 DOI: 10.1186/s12981-021-00426-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 12/16/2021] [Indexed: 11/12/2022] Open
Abstract
Background We developed a personalized Monocyte-Derived Dendritic-cell Therapy (MDDCT) for HIV-infected individuals on suppressive antiretroviral treatment and evaluated HIV-specific T-cell responses. Methods PBMCs were obtained from 10 HIV+ individuals enrolled in trial NCT02961829. Monocytes were differentiated into DCs using IFN-α and GM-CSF. After sequencing each patient’s HIV-1 Gag and determining HLA profiles, autologous Gag peptides were selected based on the predicted individual immunogenicity and used to pulse MDDCs. Three doses of the MDDCT were administered every 15 days. To assess immunogenicity, patients’ cells were stimulated in vitro with autologous peptides, and intracellular IL-2, TNF, and interferon-gamma (IFN-γ) production were measured in CD4+ and CD8+ T-cells. Results The protocol of ex-vivo treatment with IFN-α and GM-CSF was able to induce maturation of MDDCs, as well as to preserve their viability for reinfusion. MDDCT administration was associated with increased expression of IL-2 in CD4+ and CD8+ T-cells at 15 and/or 30 days after the first MDDCT administration. Moreover, intracellular TNF and IFN-γ expression was significantly increased in CD4+ T-cells. The number of candidates that increased in vitro the cytokine levels in CD4+ and CD8+ T cells upon stimulation with Gag peptides from baseline to day 15 and from baseline to day 30 and day 120 after MDDCT was significant as compared to Gag unstimulated response. This was accompanied by an increasing trend in the frequency of polyfunctional T-cells over time, which was visible when considering both cells expressing two and three out of the three cytokines examined. Conclusions MDDC had a mature profile, and this MDDCT promoted in-vitro T-cell immune responses in HIV-infected patients undergoing long-term suppressive antiretroviral treatment. Trial registration NCT02961829: (Multi Interventional Study Exploring HIV-1 Residual Replication: a Step Towards HIV-1 Eradication and Sterilizing Cure, https://www.clinicaltrials.gov/ct2/show/NCT02961829, posted November 11th, 2016) Supplementary Information The online version contains supplementary material available at 10.1186/s12981-021-00426-z.
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Iseghohi F, Yahemba AP, Rowaiye AB, Oli AN. Dendritic cells as vaccine targets. VACCINOLOGY AND METHODS IN VACCINE RESEARCH 2022:57-94. [DOI: 10.1016/b978-0-323-91146-7.00010-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Calvet-Mirabent M, Claiborne DT, Deruaz M, Tanno S, Serra C, Delgado-Arévalo C, Sánchez-Cerrillo I, de Los Santos I, Sanz J, García-Fraile L, Sánchez-Madrid F, Alfranca A, Muñoz-Fernández MÁ, Allen TM, Buzón MJ, Balazs A, Vrbanac V, Martín-Gayo E. Poly I:C and STING agonist-primed DC increase lymphoid tissue polyfunctional HIV-1-specific CD8 + T cells and limit CD4 + T cell loss in BLT mice. Eur J Immunol 2021; 52:447-461. [PMID: 34935145 DOI: 10.1002/eji.202149502] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 11/19/2021] [Accepted: 12/14/2021] [Indexed: 11/11/2022]
Abstract
Effective function of CD8+ T cells and enhanced innate activation of dendritic cells (DC) in response to HIV-1 is linked to protective antiviral immunity in controllers. Manipulation of DC targeting the master regulator TANK-binding Kinase 1 (TBK1) might be useful to acquire controller-like properties. Here, we evaluated the impact of the combination of 2´3´-c´diAM(PS)2 and Poly I:C as potential adjuvants capable of potentiating DC´s abilities to induce polyfunctional HIV-1 specific CD8+ T cell responses in vitro and in vivo using a humanized BLT mouse model. Adjuvant combination enhanced TBK-1 phosphorylation and IL-12 and IFNβ expression on DC and increased their ability to activate polyfunctional HIV-1-specific CD8+ T cells in vitro. Moreover, higher proportions of hBLT mice vaccinated with ADJ-DC exhibited less severe CD4+ T cell depletion following HIV-1 infection compared to control groups. This was associated with infiltration of CD8+ T cells in the white pulp from the spleen, reduced spread of infected p24+ cells to lymph node and with preserved abilities of CD8+ T cells from the spleen and blood of vaccinated animals to induce specific polyfunctional responses upon antigen stimulation. Therefore, priming of DC with Poly I:C and STING agonists might be useful for future HIV-1 vaccine studies. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Marta Calvet-Mirabent
- Immunology Unit from Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa.,Universidad Autónoma of Madrid, Medicine Department Spain
| | | | - Maud Deruaz
- Human Immune System Mouse Program from Massachusetts General Hospital, Boston.,Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Serah Tanno
- Ragon Institute of MGH, MIT and Harvard.,Human Immune System Mouse Program from Massachusetts General Hospital, Boston
| | - Carla Serra
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona
| | - Cristina Delgado-Arévalo
- Immunology Unit from Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa.,Universidad Autónoma of Madrid, Medicine Department Spain
| | - Ildefonso Sánchez-Cerrillo
- Immunology Unit from Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa
| | - Ignacio de Los Santos
- Infectious Diseases Unit from Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa
| | - Jesús Sanz
- Infectious Diseases Unit from Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa
| | - Lucio García-Fraile
- Infectious Diseases Unit from Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa
| | - Francisco Sánchez-Madrid
- Immunology Unit from Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa.,Universidad Autónoma of Madrid, Medicine Department Spain
| | - Arantzazu Alfranca
- Immunology Unit from Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa
| | - María Ángeles Muñoz-Fernández
- Immunology Section, Instituto Investigación Sanitaria Gregorio Marañón (IiSGM), Hospital General Universitario Gregorio Marañón. Madrid, Spain
| | | | - Maria J Buzón
- Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona
| | - Alejandro Balazs
- Ragon Institute of MGH, MIT and Harvard.,Human Immune System Mouse Program from Massachusetts General Hospital, Boston
| | - Vladimir Vrbanac
- Ragon Institute of MGH, MIT and Harvard.,Human Immune System Mouse Program from Massachusetts General Hospital, Boston
| | - Enrique Martín-Gayo
- Immunology Unit from Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa.,Universidad Autónoma of Madrid, Medicine Department Spain
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Kwiecień I, Rutkowska E, Raniszewska A, Rzepecki P, Domagała-Kulawik J. Modulation of the immune response by heterogeneous monocytes and dendritic cells in lung cancer. World J Clin Oncol 2021; 12:966-982. [PMID: 34909393 PMCID: PMC8641004 DOI: 10.5306/wjco.v12.i11.966] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 08/02/2021] [Accepted: 11/05/2021] [Indexed: 02/06/2023] Open
Abstract
Different subpopulations of monocytes and dendritic cells (DCs) may have a key impact on the modulation of the immune response in malignancy. In this review, we summarize the monocyte and DCs heterogeneity and their function in the context of modulating the immune response in cancer. Subgroups of monocytes may play opposing roles in cancer, depending on the tumour growth and progression as well as the type of cancer. Monocytes can have pro-tumour and anti-tumour functions and can also differentiate into monocyte-derived DCs (moDCs). MoDCs have a similar antigen presentation ability as classical DCs, including cross-priming, a process by which DCs activate CD8 T-cells by cross-presenting exogenous antigens. DCs play a critical role in generating anti-tumour CD8 T-cell immunity. DCs have plastic characteristics and show distinct phenotypes depending on their mature state and depending on the influence of the tumour microenvironment. MoDCs and other DC subsets have been attracting increased interest owing to their possible beneficial effects in cancer immunotherapy. This review also highlights key strategies deploying specific DC subpopulations in combination with other therapies to enhance the anti-tumour response and summarizes the latest ongoing and completed clinical trials using DCs in lung cancer.
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Affiliation(s)
- Iwona Kwiecień
- Department of Internal Medicine and Hematology, Laboratory of Hematology and Flow Cytometry, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Elżbieta Rutkowska
- Department of Internal Medicine and Hematology, Laboratory of Hematology and Flow Cytometry, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Agata Raniszewska
- Department of Internal Medicine and Hematology, Laboratory of Hematology and Flow Cytometry, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Piotr Rzepecki
- Department of Internal Medicine and Hematology, Military Institute of Medicine, Warsaw 04-141, Poland
| | - Joanna Domagała-Kulawik
- Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw 02-091, Poland
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Zurmühl N, Schmitt A, Formentini U, Weiss J, Appel H, Debatin KM, Fabricius D. Differential uptake of three clinically relevant allergens by human plasmacytoid dendritic cells. Clin Mol Allergy 2021; 19:23. [PMID: 34789269 PMCID: PMC8597288 DOI: 10.1186/s12948-021-00163-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 11/10/2021] [Indexed: 11/20/2022] Open
Abstract
Background Human plasmacytoid dendritic cells (pDC) have a dual role as interferon-producing and antigen-presenting cells. Their relevance for allergic diseases is controversial. and the impact of pDC on allergic immune responses is poorly understood. Methods This in vitro study on human pDC isolated from peripheral blood was designed to compare side by side the uptake of three clinically relevant representative allergens: fluorochrome-labeled house dust mite Der p 1, Bee venom extract from Apis mellifera (Api) and the food allergen OVA analyzed flow cytometry and confocal microscopy. Results We found that the internalization and its regulation by TLR9 ligation was significantly different between allergens in terms of time course and strength of uptake. Api and OVA uptake in pDC of healthy subjects was faster and reached higher levels than Der p 1 uptake. CpG ODN 2006 suppressed OVA uptake and to a lesser extent Der p 1, while Api internalization was not affected. All allergens colocalized with LAMP1 and EEA1, with Api being internalized particularly fast and reaching highest intracellular levels in pDC. Of note, we could not determine any specific differences in antigen uptake in allergic compared with healthy subjects. Conclusions To our knowledge this is the first study that directly compares uptake regulation of clinically relevant inhalative, injective and food allergens in pDC. Our findings may help to explain differences in the onset and severity of allergic reactions as well as in the efficiency of AIT. Supplementary Information The online version contains supplementary material available at 10.1186/s12948-021-00163-8.
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Affiliation(s)
- Noelle Zurmühl
- Department of Pediatrics, University Medical Center Ulm, Eythstr. 24, 89075, Ulm, Germany
| | - Anna Schmitt
- Department of Pediatrics, University Medical Center Ulm, Eythstr. 24, 89075, Ulm, Germany
| | - Ulrike Formentini
- Department of Pediatrics, University Medical Center Ulm, Eythstr. 24, 89075, Ulm, Germany
| | - Johannes Weiss
- Department of Dermatology and Allergic Diseases, University Medical Center Ulm, Ulm, Germany
| | - Heike Appel
- Department of Otolaryngology, Ulm University, Ulm, Germany
| | - Klaus-Michael Debatin
- Department of Pediatrics, University Medical Center Ulm, Eythstr. 24, 89075, Ulm, Germany
| | - Dorit Fabricius
- Department of Pediatrics, University Medical Center Ulm, Eythstr. 24, 89075, Ulm, Germany.
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Cianga VA, Dănăilă CD, Antohe I, Oană R, Mențel M, Ivanov I, Dragoș L, Dăscălescu AS. A very rare case of FLT3-D835 positive blastic plasmacytoid dendritic cell neoplasm. Arch Clin Cases 2021; 7:57-62. [PMID: 34754929 PMCID: PMC8565708 DOI: 10.22551/2020.29.0704.10174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Blastic plasmacytoid dendritic cell neoplasms (BPDCNs) are extremely rare and aggressive hematological malignancies that derive from precursors of plasmacytoid dendritic cells (pDC) and frequently involve skin lesions and bone marrow infiltration. They mostly affect the elderly population and the prognosis is poor with the therapeutic choices currently available. Diagnosis is made with the help of tools such as immunohistochemistry and flow cytometry. Here, we present a particular case of BPDCN with a positive FLT3-D835 mutation and we discuss the possible impact this may have on the evolution of the disease and response to treatment.
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Affiliation(s)
- Vlad Andrei Cianga
- Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania.,Department of Clinical Hematology, Regional Institute of Oncology, Iasi, Romania
| | - Cătălin Doru Dănăilă
- Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania.,Department of Clinical Hematology, Regional Institute of Oncology, Iasi, Romania
| | - Ion Antohe
- Department of Clinical Hematology, Regional Institute of Oncology, Iasi, Romania
| | - Raluca Oană
- Department of Cytology, Regional Institute of Oncology, Iasi, Romania
| | - Mihaela Mențel
- Department of Immunophenotyping, Regional Institute of Oncology, Iasi, Romania
| | - Iuliu Ivanov
- Department of Molecular Diagnostics, Regional Institute of Oncology, Iasi, Romania
| | - Loredana Dragoș
- Department of Molecular Diagnostics, Regional Institute of Oncology, Iasi, Romania
| | - Angela Smaranda Dăscălescu
- Grigore T. Popa University of Medicine and Pharmacy, Iași, Romania.,Department of Clinical Hematology, Regional Institute of Oncology, Iasi, Romania
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Johnson P, Rosendahl N, Radford KJ. Conventional type 1 dendritic cells (cDC1) as cancer therapeutics: challenges and opportunities. Expert Opin Biol Ther 2021; 22:465-472. [PMID: 34654337 DOI: 10.1080/14712598.2022.1994943] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
INTRODUCTION The use of dendritic cell (DC)-based cancer vaccines over three decades has shown them to be a safe therapeutic approach against a range of hematological and solid malignancies. However, underwhelming and inconsistent results from clinical trials have seen them move in and out of favor. The limitations of ex vivo generated monocyte-derived DC (MoDC) in these therapies provide a pointed explanation for the varying and somewhat disappointing clinical outcomes. The identification of a specialized role for the rare conventional type 1 dendritic cell (cDC1) subset in orchestrating tumor immunity via the initiation of CD8+ T cell responses has led to a new concept of targeting cDC1 as a therapeutic option to address the unmet need of enhancing the immune response in cancer patients. AREAS COVERED This article reviews several current challenges and key opportunities associated with the development and use of next generation cDC1 cancer vaccines. EXPERT OPINION Manipulation of cDC1 quantity and quality holds enormous potential to improve tumor immunogenicity, as already demonstrated in preclinical models. New technologies are rapidly advancing the understanding of cDC1 in human cancer patients and facilitating the generation of these extremely rare cells in vitro, providing feasible new approaches toward clinical translation.
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Affiliation(s)
- Phillip Johnson
- Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Australia.,Queensland Cord Blood Bank At The Mater, South Brisbane, Australia
| | - Nikita Rosendahl
- Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Australia
| | - Kristen J Radford
- Mater Research Institute-The University of Queensland, Translational Research Institute, Brisbane, Australia
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47
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Orsmond A, Bereza-Malcolm L, Lynch T, March L, Xue M. Skin Barrier Dysregulation in Psoriasis. Int J Mol Sci 2021; 22:10841. [PMID: 34639182 PMCID: PMC8509518 DOI: 10.3390/ijms221910841] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023] Open
Abstract
The skin barrier is broadly composed of two elements-a physical barrier mostly localised in the epidermis, and an immune barrier localised in both the dermis and epidermis. These two systems interact cooperatively to maintain skin homeostasis and overall human health. However, if dysregulated, several skin diseases may arise. Psoriasis is one of the most prevalent skin diseases associated with disrupted barrier function. It is characterised by the formation of psoriatic lesions, the aberrant differentiation and proliferation of keratinocytes, and excessive inflammation. In this review, we summarize recent discoveries in disease pathogenesis, including the contribution of keratinocytes, immune cells, genetic and environmental factors, and how they advance current and future treatments.
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Affiliation(s)
- Andreas Orsmond
- Sutton Arthritis Research Laboratory, Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (A.O.); (L.B.-M.)
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
| | - Lara Bereza-Malcolm
- Sutton Arthritis Research Laboratory, Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (A.O.); (L.B.-M.)
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
| | - Tom Lynch
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
| | - Lyn March
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
| | - Meilang Xue
- Sutton Arthritis Research Laboratory, Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (A.O.); (L.B.-M.)
- The Australian Arthritis and Autoimmune Biobank Collaborative (A3BC), Faculty of Medicine and Health, Institute of Bone and Joint Research, Kolling Institute, University of Sydney at Royal North Shore Hospital, St Leonards, NSW 2065, Australia; (T.L.); (L.M.)
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Gao Y, Yue Y, Xiong S. An Albumin-Binding Domain Peptide Confers Enhanced Immunoprotection Against Viral Myocarditis by CVB3 VP1 Vaccine. Front Immunol 2021; 12:666594. [PMID: 34630378 PMCID: PMC8492941 DOI: 10.3389/fimmu.2021.666594] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 09/06/2021] [Indexed: 11/13/2022] Open
Abstract
Coxsackievirus B3 (CVB3)-induced viral myocarditis is a common clinical cardiovascular disease without effective available vaccine. In this study, we tried to potentiate the immunoprotection efficacy of our previous CVB3-specific VP1 protein vaccine by introducing a streptococcal protein G-derived, draining lymph nodes (dLNs)-targeting albumin-binding domain (ABD) peptide. We found that compared with the original VP1 vaccine, ABD-fused VP1 (ABD-VP1) vaccine gained the new ability to efficiently bind murine albumin both in vitro and in vivo, possessed a much longer serum half-life in serum and exhibited more abundance in the dLNs after immunization. Accordingly, ABD-VP1 immunization not only significantly facilitated the enrichment and maturation of dendritic cells (DCs), induced higher percentages of IFN-γ+ CD8 + cells in the dLNs, but also robustly promoted VP1-induced T cell proliferation and cytotoxic T lymphocyte (CTL) responses in the spleens. More importantly, ABD-VP1 also elicited higher percentages of protective CD44hi CD62Lhi memory T cells in dLNs and spleens. Consequently, obvious protective effect against viral myocarditis was conferred by ABD-VP1 vaccine compared to the VP1 vaccine, reflected by the less body weight loss, improved cardiac function, alleviated cardiac histomorphological changes and an increased 28-day survival rate. Our results indicated that the ABD might be a promising immune-enhancing regime for vaccine design and development.
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Affiliation(s)
| | - Yan Yue
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, China
| | - Sidong Xiong
- Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Science, Soochow University, Suzhou, China
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49
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Masterman KA, Haigh OL, Tullett KM, Leal-Rojas IM, Walpole C, Pearson FE, Cebon J, Schmidt C, O'Brien L, Rosendahl N, Daraj G, Caminschi I, Gschweng EH, Hollis RP, Kohn DB, Lahoud MH, Radford KJ. Human CLEC9A antibodies deliver NY-ESO-1 antigen to CD141 + dendritic cells to activate naïve and memory NY-ESO-1-specific CD8 + T cells. J Immunother Cancer 2021; 8:jitc-2020-000691. [PMID: 32737142 PMCID: PMC7394304 DOI: 10.1136/jitc-2020-000691] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/19/2020] [Indexed: 12/14/2022] Open
Abstract
Background Dendritic cells (DCs) are crucial for the efficacy of cancer vaccines, but current vaccines do not harness the key cDC1 subtype required for effective CD8+ T-cell-mediated tumor immune responses. Vaccine immunogenicity could be enhanced by specific delivery of immunogenic tumor antigens to CD141+ DCs, the human cDC1 equivalent. CD141+ DCs exclusively express the C-type-lectin-like receptor CLEC9A, which is important for the regulation of CD8+ T cell responses. This study developed a new vaccine that harnesses a human anti-CLEC9A antibody to specifically deliver the immunogenic tumor antigen, NY-ESO-1 (New York esophageal squamous cell carcinoma 1), to human CD141+ DCs. The ability of the CLEC9A-NY-ESO-1 antibody to activate NY-ESO-1-specific naïve and memory CD8+ T cells was examined and compared with a vaccine comprised of a human DEC-205-NY-ESO-1 antibody that targets all human DCs. Methods Human anti-CLEC9A, anti-DEC-205 and isotype control IgG4 antibodies were genetically fused to NY-ESO-1 polypeptide. Cross-presentation to NY-ESO-1-epitope-specific CD8+ T cells and reactivity of T cell responses in patients with melanoma were assessed by interferon γ (IFNγ) production following incubation of CD141+ DCs and patient peripheral blood mononuclear cells with targeting antibodies. Humanized mice containing human DC subsets and a repertoire of naïve NY-ESO-1-specific CD8+ T cells were used to investigate naïve T cell priming. T cell effector function was measured by expression of IFNγ, MIP-1β, tumor necrosis factor and CD107a and by lysis of target tumor cells. Results CLEC9A-NY-ESO-1 antibodies (Abs) were effective at mediating delivery and cross-presentation of multiple NY-ESO-1 epitopes by CD141+ DCs for activation of NY-ESO-1-specific CD8+ T cells. When benchmarked to NY-ESO-1 conjugated to an untargeted control antibody or to anti-human DEC-205, CLEC9A-NY-ESO-1 was superior at ex vivo reactivation of NY-ESO-1-specific T cell responses in patients with melanoma. Moreover, CLEC9A-NY-ESO-1 induced priming of naïve NY-ESO-1-specific CD8+ T cells with polyclonal effector function and potent tumor killing capacity in vitro. Conclusions These data advocate human CLEC9A-NY-ESO-1 Ab as an attractive strategy for specific targeting of CD141+ DCs to enhance tumor immunogenicity in NY-ESO-1-expressing malignancies.
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Affiliation(s)
- Kelly-Anne Masterman
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Oscar L Haigh
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Kirsteen M Tullett
- Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Ingrid M Leal-Rojas
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Carina Walpole
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Frances E Pearson
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Jonathon Cebon
- Department of Hematology and Oncology, Olivia Newton John Cancer Research Institute, Heidelberg, Victoria, Australia
| | - Christopher Schmidt
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Liam O'Brien
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Nikita Rosendahl
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Ghazal Daraj
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
| | - Irina Caminschi
- Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Eric H Gschweng
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA
| | - Roger P Hollis
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA
| | - Donald B Kohn
- Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, USA
| | - Mireille H Lahoud
- Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
| | - Kristen J Radford
- Mater Research Institute, University of Queensland, Woolloongabba, Queensland, Australia
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50
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Askmyr D, Abolhalaj M, Gomez Jimenez D, Greiff L, Lindstedt M, Lundberg K. Pattern recognition receptor expression and maturation profile of dendritic cell subtypes in human tonsils and lymph nodes. Hum Immunol 2021; 82:976-981. [PMID: 34511272 DOI: 10.1016/j.humimm.2021.08.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/18/2021] [Accepted: 08/10/2021] [Indexed: 01/02/2023]
Abstract
Dendritic cells (DCs) with capacity of antigen cross-presentation are of key interest for immunotherapy against cancer as they can induce antigen-specific cytotoxic T lymphocyte (CTL) responses. This study describes frequencies of DC subtypes in human tonsils and lymph nodes, and phenotypic aspects that may be targeted by adjuvant measures. From human tonsils and neck lymph nodes, DCs were identified through flow cytometry, and subsets of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) were investigated. Maturity status was assessed and surface receptors with CTL-promoting potentials were studied. CD123+ pDCs as well as CD1c+, CD141+, and CD1c-CD141- mDCs were detected in tonsils and lymph nodes. Both sites featured a similar presence of DC subsets, with CD123+ pDC being dominant and CD141+ mDCs least frequent. Based on CD80/CD86 expression, all DC subtypes featured a low degree of maturation. Expression of pattern recognition receptors (PRRs) CD206, CD207, DC-SIGN, TLR2, and TLR4, as well as the chemokine receptor XCR1, indicated DC subset-specific receptor profiles. We conclude that tonsils and lymph nodes share common features in terms of DC subset frequency and maturation as well as PRR and XCR1 expression pattern. Our work suggests that both sites may be considered for vaccine deposition in DC-mediated immunotherapy.
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Affiliation(s)
- David Askmyr
- Department of ORL, Head & Neck Surgery, Skåne University Hospital, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
| | - Milad Abolhalaj
- Department of Immunotechnology, Lund University, Lund, Sweden.
| | | | - Lennart Greiff
- Department of ORL, Head & Neck Surgery, Skåne University Hospital, Lund, Sweden; Department of Clinical Sciences, Lund University, Lund, Sweden.
| | - Malin Lindstedt
- Department of Immunotechnology, Lund University, Lund, Sweden.
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