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Peltier D, Anh Do-Thi V, Devos T, Blazar BR, Toubai T. Cellular therapies for the prevention and treatment of acute graft-versus-host disease. Stem Cells 2025; 43:sxaf009. [PMID: 40117296 PMCID: PMC12111709 DOI: 10.1093/stmcls/sxaf009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 11/14/2024] [Indexed: 03/23/2025]
Abstract
Acute graft-versus-host disease (aGVHD) is a major complication of allogeneic hematopoietic cell transplantation (allo-HCT) that is caused by donor immune cells attacking and damaging host tissues. Immune suppressive small molecule and protein-based therapeutics targeting donor anti-host immune cells are currently used for GVHD prophylaxis and treatment. Even with these therapies, aGVHD progresses to life-threatening steroid-refractory aGVHD (SR-aGVHD) in up to 50% of cases and is a risk factor for the subsequent development of debilitating chronic GVHD. To improve aGVHD-related outcomes, donor graft engineering techniques and adoptive transfer of immune modulatory cells have been explored. Highly rigorous donor graft T-cell depletion approaches have revealed that mitigation of aGVHD can be accompanied by slow immune recovery post-allo-HCT and reduction in anti-microbial and anti-leukemia responses resulting in increased relapse and infection rates, respectively. Recent T-cell separation techniques allowing for precision graft engineering by selectively eliminating aGVHD-causing T-cells (eg, naïve T-cells) without loss of T-cells with beneficial functions and retaining and/or enriching immune regulatory populations (eg, regulatory T-cells (Tregs) or myeloid-derived suppressor cells) have been tested and will continue to improve. Clinical cell-based regulatory therapies have been employed for targeting SR-aGVHD, particularly mesenchymal stem cells (MSCs) and more recently, Tregs. In this review, we summarize aGVHD pathophysiology, highlight newly discovered aGVHD mechanisms, and discuss current and emerging cellular and graft manipulation approaches for aGVHD prevention and treatment.
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Affiliation(s)
- Daniel Peltier
- Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Herman B. Wells Center for Pediatric Research, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Van Anh Do-Thi
- Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Herman B. Wells Center for Pediatric Research, Melvin and Bren Simon Comprehensive Cancer Center, Indiana University School of Medicine, Indianapolis, IN 46202, United States
| | - Timothy Devos
- Department of Hematology, University Hospitals Leuven and Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven 3000, Belgium
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN 55455, United States
| | - Tomomi Toubai
- Department of Internal Medicine III, Division of Hematology and Cell Therapy, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan
- Clinical Research and Trial Center, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo City, Tokyo 113-8677, Japan
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2
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Liu Y, Ren Y, Luo R, Li X, Xie L, Kang H, Li Y, Dong X, He Y. FK506 prolongs corneal allograft survival and prevents dendritic cell infiltration in an MDSC-dependent manner. Am J Transplant 2025:S1600-6135(25)00272-2. [PMID: 40398562 DOI: 10.1016/j.ajt.2025.05.018] [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: 11/24/2024] [Revised: 05/08/2025] [Accepted: 05/11/2025] [Indexed: 05/23/2025]
Abstract
FK506 (a.k.a. Tacrolimus) is one of most widely used immunosuppressive drugs in the postsurgery management of transplantation. To date, the cellular mechanism by which FK506 suppresses immune activation and elongates allograft survival remains largely unclear. Here, we employed a mouse model for corneal penetrating keratoplasty to interrogate this critical question. Administration of FK506 led to increased expansion myeloid-derived suppressor cells (MDSC) in recipient mice and prolonged survival of corneal allografts. In contrast, antibody-mediated depletion of MDSC abolished the FK506-mediated beneficial effects, which is associated with increased dendritic cell (DC) activation and recruitment to the graft bed and allografts. Of note, unlike continuous depletion and temporary early depletion (in the first week), delayed depletion of MDSC that started on day 8 posttransplant failed to disrupt the FK506-induced elongation of corneal allograft survival. Single-cell RNA sequencing analysis and immunofluorescence staining of corneal grafts reveal that FK506 reduced graft infiltration of immune cells including DC and T cells in an MDSC-dependent and temporal fashion. Moreover, depletion of MDSC reverted the FK506's suppression of DC maturation in the draining lymph node on day 7. Taken together, these findings indicate that FK506 prolongs allograft survival through induction of MDSC-mediated suppression of early DC activation.
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Affiliation(s)
- Yingyi Liu
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University; Beijing Key Laboratory of Ophthalmology & Visual Sciences, Beijing 100730, China
| | - Yuerong Ren
- Department of Ophthalmology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; Hunan Clinical Research Center of Ophthalmic Disease, Changsha, Hunan 410011, China
| | - Runxi Luo
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
| | - Xiujuan Li
- School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 511436, China
| | - Limin Xie
- National Clinical Research Center for Metabolic Diseases, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, China
| | - Huanmin Kang
- Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yang Li
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University; Beijing Key Laboratory of Ophthalmology & Visual Sciences, Beijing 100730, China
| | - Xiaonan Dong
- State Key Laboratory of Respiratory Disease, Department of Organ transplantation, Advanced Interdisciplinary Studies Center, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510120, China; Institute of Infection and Health, Fudan University, Shanghai 200438, China; Guangzhou National Laboratory, Guangzhou, Guangdong 510005, China.
| | - Yan He
- Beijing Tongren Eye Center, Beijing Tongren Hospital, Capital Medical University; Beijing Key Laboratory of Ophthalmology & Visual Sciences, Beijing 100730, China.
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3
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Alhajahjeh A, Stahl M, Kim TK, Kewan T, Stempel JM, Zeidan AM, Bewersdorf JP. Contemporary understanding of myeloid-derived suppressor cells in the acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) tumor microenvironment. Expert Rev Anticancer Ther 2025; 25:435-456. [PMID: 40122075 DOI: 10.1080/14737140.2025.2483855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/01/2025] [Accepted: 03/20/2025] [Indexed: 03/25/2025]
Abstract
INTRODUCTION Myeloid-derived suppressor cells (MDSCs) are a key immunosuppressive component in the tumor microenvironment, contributing to immune evasion and disease progression in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). AREAS COVERED We searched PubMed for literature that evaluated the effect of MDSCs in myeloid diseases. MDSCs impact outcomes by facilitating leukemic stem cell survival, impairing immune checkpoint efficacy, and modulating the bone marrow niche. While these immunosuppressive properties can mitigate graft-versus-host disease post-transplantation, sustained MDSC-mediated immunosuppression can also increase the risk of leukemia relapse.We review MDSC development and function, including metabolic reprogramming, epigenetic modifications, and cytokine-mediated pathways. Therapeutic strategies targeting MDSCs, such as depletion, functional reprogramming, and inhibition of key metabolic and immune pathways, show promising data in preclinical models. However, clinical translation remains hindered by challenges in MDSC quantification and standardization of functional assays. This review underscores the potential of combining MDSC-targeted therapies with conventional and novel treatments to improve patient outcomes in AML and MDS. EXPERT OPINION Future studies should focus on standardizing MDSC assessment, elucidate their dynamic roles in therapy, and optimize combination approaches for clinical application.
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Affiliation(s)
- Abdulrahman Alhajahjeh
- School of Medicine, The University of Jordan, Amman, Jordan
- King Hussein Cancer Center (KHCC), Internal Medicine Department, Amman, Jordan
| | - Maximilian Stahl
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Tae K Kim
- Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Tariq Kewan
- Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Jessica M Stempel
- Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Amer M Zeidan
- Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Jan Philipp Bewersdorf
- Section of Hematology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
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4
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Wang N, Yu H, Yin J, Yu X. pH-responsive nano-vaccine combined with anti-PD-1 antibodies for enhanced immunotherapy of breast cancer. Theranostics 2025; 15:6022-6043. [PMID: 40365283 PMCID: PMC12068292 DOI: 10.7150/thno.107200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2024] [Accepted: 04/18/2025] [Indexed: 05/15/2025] Open
Abstract
Objective: This study aimed to investigate the therapeutic potential and underlying mechanisms of a novel pH-responsive nano-vaccine in combination with anti-Programmed Cell Death Protein 1 (PD-1) antibodies for the treatment of breast cancer (BC), with a focus on tumor growth inhibition, metastasis prevention, and immune microenvironment modulation. Methods: A pH-responsive amphiphilic diblock copolymer was synthesized using reversible addition-fragmentation chain transfer (RAFT) polymerization and conjugated with STING agonist ADU-S100 and mannose to specifically target dendritic cells (DCs). The nano-vaccine was further formulated with antigen peptides and polyethyleneimine (PEI) to enhance antigen delivery. Its particle size, stability, and surface charge were characterized using dynamic light scattering (DLS) and zeta potential analysis. In vitro, the immunostimulatory capacity of the nano-vaccine was evaluated via flow cytometry (FCM) analysis of DC activation markers. In vivo, mouse immune and tumor recurrence models were used to assess the its effects on T-cell activation, tumor suppression, and immune memory induction. The therapeutic efficacy of nano-vaccine/anti-PD-1 combination therapy was further assessed. Results: The nano-vaccine efficiently activated DCs and promoted antigen presentation, as indicated by increased CD80, CD86, and MHC-II expression in vitro. In mouse models, it effectively inhibited tumor growth, induced antigen-specific T-cell responses, and suppressed recurrent and metastatic tumor progression. The combination with anti-PD-1 antibodies further enhanced tumor control, immune cell infiltration, and survival rates compared to monotherapy. Conclusion: The pH-responsive nano-vaccine combined with anti-PD-1 antibodies showed remarkable synergistic effects in BC treatment, highlighting its potential to enhance immune checkpoint blockade therapy and offer a promising strategy for clinical applications in solid tumors.
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Affiliation(s)
- Ning Wang
- Department of Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Hong Yu
- Department of Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Jianqiao Yin
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Xiaopeng Yu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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5
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Braun LM, Giesler S, Andrieux G, Riemer R, Talvard-Balland N, Duquesne S, Rückert T, Unger S, Kreutmair S, Zwick M, Follo M, Hartmann A, Osswald N, Melchinger W, Chapman S, Hutchinson JA, Haferkamp S, Torster L, Kött J, Gebhardt C, Hellwig D, Karantzelis N, Wallrabenstein T, Lowinus T, Yücel M, Brehm N, Rawluk J, Pfeifer D, Bronsert P, Rogg M, Mattern S, Heikenwälder M, Fusco S, Malek NP, Singer S, Schmitt-Graeff A, Ceteci F, Greten FR, Blazar BR, Boerries M, Köhler N, Duyster J, Ihorst G, Lassmann S, Keye P, Minguet S, Schadendorf D, Ugurel S, Rafei-Shamsabadi D, Thimme R, Hasselblatt P, Bengsch B, Schell C, Pearce EL, Meiss F, Becher B, Funke-Lorenz C, Placke JM, Apostolova P, Zeiser R. Adiponectin reduces immune checkpoint inhibitor-induced inflammation without blocking anti-tumor immunity. Cancer Cell 2025; 43:269-291.e19. [PMID: 39933899 DOI: 10.1016/j.ccell.2025.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 10/30/2024] [Accepted: 01/10/2025] [Indexed: 02/13/2025]
Abstract
Immune-related adverse events (irAEs) in cancer patients receiving immune checkpoint inhibitors (ICIs) cause morbidity and necessitate cessation of treatment. Comparing irAE treatments, we find that anti-tumor immunity is preserved in mice after extracorporeal photopheresis (ECP) but reduced with glucocorticosteroids, TNFα blockade, and α4β7-integrin inhibition. Local adiponectin production elicits a tissue-specific effect by reducing pro-inflammatory T cell frequencies in the colon while sparing tumor-specific T cell development. A prospective phase-1b/2 trial (EudraCT-No.2021-002073-26) with 14 patients reveals low ECP-related toxicity. Overall response rate for all irAEs is 92% (95% confidence interval [CI]: 63.97%-99.81%); colitis-specific complete remission rate is 100% (95% CI: 63.06%-100%). Glucocorticosteroid dosages could be reduced for all patients after ECP therapy. The ECP-adiponectin axis reduces intestinal tissue-resident memory T cell activation and CD4+IFN-γ+ T cells in patients with ICI-induced colitis without evidence of loss of anti-tumor immunity. In conclusion, we identify adiponectin as an immunomodulatory molecule that controls ICI-induced irAEs without blocking anti-tumor immunity.
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Affiliation(s)
- Lukas M Braun
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Sophie Giesler
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Geoffroy Andrieux
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Roxane Riemer
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Nana Talvard-Balland
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sandra Duquesne
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tamina Rückert
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Susanne Unger
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Stefanie Kreutmair
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Melissa Zwick
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Marie Follo
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Alina Hartmann
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Natascha Osswald
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Wolfgang Melchinger
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Stefanie Chapman
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - James A Hutchinson
- Department of Surgery, University Hospital Regensburg, Regensburg, Germany
| | - Sebastian Haferkamp
- Department of Dermatology, University Hospital Regensburg, Regensburg, Germany
| | - Leopold Torster
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Julian Kött
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoffer Gebhardt
- Department of Dermatology and Venereology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dirk Hellwig
- Department of Nuclear Medicine, University Hospital Regensburg, Regensburg, Germany
| | - Nikolaos Karantzelis
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Till Wallrabenstein
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Theresa Lowinus
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Mehtap Yücel
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Niklas Brehm
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Justyna Rawluk
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dietmar Pfeifer
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peter Bronsert
- Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Manuel Rogg
- Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sven Mattern
- Institute of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; M3 Research Center, Eberhard Karls University Tübingen, Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | - Stefano Fusco
- Medizinische Klinik I, Uniklinik Tübingen, Tübingen, Germany
| | - Nisar P Malek
- Medizinische Klinik I, Uniklinik Tübingen, Tübingen, Germany
| | - Stephan Singer
- Institute of Pathology, University Hospital Tübingen, 72076 Tübingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany
| | | | - Fatih Ceteci
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany
| | - Florian R Greten
- Institute for Tumor Biology and Experimental Therapy, Georg-Speyer-Haus, Frankfurt/Main, Germany
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Natalie Köhler
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - Justus Duyster
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany
| | - Gabriele Ihorst
- Clinical Trials Unit, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Silke Lassmann
- Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Philip Keye
- Eye Center, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Susana Minguet
- Signalling Research Centres BIOSS and CIBSS, Freiburg. Germany. Department of Synthetic Immunology, Faculty of Biology and Centre for Chronic Immunodeficiency (CCI), Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany; National Center for Tumor Diseases (NCT)-West, Campus Essen, & Research Alliance Ruhr, Research Center One Health, University Duisburg-Essen, Essen, Germany
| | - Selma Ugurel
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany
| | - David Rafei-Shamsabadi
- Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Robert Thimme
- Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peter Hasselblatt
- Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bertram Bengsch
- German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Department of Internal Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - Christoph Schell
- Institute of Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Erika L Pearce
- Department of Oncology, The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
| | - Frank Meiss
- Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Carolin Funke-Lorenz
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany
| | - Jan-Malte Placke
- Department of Dermatology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany, and German Cancer Consortium (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany
| | - Petya Apostolova
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Department of Oncology, The Bloomberg∼Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Department of Biomedicine, Faculty of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland; Division of Hematology, University Hospital Basel, Basel, Switzerland.
| | - Robert Zeiser
- Department of Internal Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; German Cancer Consortium (DKTK), Partner Site Freiburg, a Partnership Between DKFZ and Medical Center - University of Freiburg, Freiburg im Breisgau, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
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6
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Awad M, Sen'kova A, Zenkova M, Markov O. The impact of cytokines and tumour-conditioned medium on the properties of murine in vitro generated myeloid-derived suppressor cells. Scand J Immunol 2025; 101:e70001. [PMID: 39865924 DOI: 10.1111/sji.70001] [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: 08/19/2024] [Revised: 11/24/2024] [Accepted: 01/10/2025] [Indexed: 01/28/2025]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells playing a critical role in immune suppression. In vitro-generated MDSCs are a convenient tool to study the properties of tumour-associated MDSCs. Here, we compared six protocols for in vitro generation of functional mouse MDSCs from bone marrow progenitors. The protocols included granulocyte-macrophage colony-stimulating factor (GM-CSF) alone or in combination with interleukin-6 (IL-6) or granulocyte colony-stimulating factor (G-CSF), with or without a tumour-conditioned medium (TCM) derived from B16-F10 melanoma. Obtained MDSCs were characterized by morphology, phenotype, gene expression of key immunosuppressive factors, and in vitro suppression of T cell proliferation. All tested protocols yielded approximately 25% monocytic and 50% polymorphonuclear MDSCs. Protocols using IL-6 generated MDSCs with reduced maturation and differentiation status, upregulated Arg1 and Nos1 mRNA expression, increased levels of Arg-1 and TGF-β proteins and enhanced ROS production compared to the other protocols. All tested protocols yielded MDSCs that efficiently inhibited T cell proliferation in vitro, with some advantage for the GM-CSF and G-CSF + GM-CSF protocols. Interestingly, a combination of protocols with B16-F10-derived TCM resulted in the generation of MDSCs with reduced immunosuppressive properties. Our results provide valuable insights into the optimal conditions for in vitro generation of MDSCs with specific immunosuppressive properties.
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Affiliation(s)
- Mona Awad
- Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia
- Faculty of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia
| | - Aleksandra Sen'kova
- Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia
| | - Marina Zenkova
- Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia
| | - Oleg Markov
- Institute of Chemical Biology and Fundamental Medicine SB RAS, Novosibirsk, Russia
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7
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Li C, Xue Y, Yinwang E, Ye Z. The Recruitment and Immune Suppression Mechanisms of Myeloid-Derived Suppressor Cells and Their Impact on Bone Metastatic Cancer. Cancer Rep (Hoboken) 2025; 8:e70044. [PMID: 39947253 PMCID: PMC11825175 DOI: 10.1002/cnr2.70044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 09/16/2024] [Accepted: 10/04/2024] [Indexed: 02/17/2025] Open
Abstract
BACKGROUND MDSCs are immature neutrophils and monocytes with immunosuppressive potentials, involving mononuclear MDSCs (M-MDSCs) and polymorphonuclear MDSCs (PMN-MDSCs). RECENT FINDINGS They are significant components of the tumor microenvironment (TME). Besides, recent studies also verified that MDSCs also facilitated the progression of bone metastasis by regulating the network of cytokines and the function of immune cells. CONCLUSION It is necessary to summarize the mechanisms of MDSC recruitment and immunosuppression, and their impact on bone metastasis.
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Affiliation(s)
- Chengyuan Li
- Department of Orthopedic Surgery, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Yucheng Xue
- Department of Orthopedic Surgery, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Eloy Yinwang
- Department of Orthopedic Surgery, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
| | - Zhaoming Ye
- Department of Orthopedic Surgery, the Second Affiliated HospitalZhejiang University School of MedicineHangzhouChina
- Orthopedics Research Institute of Zhejiang UniversityHangzhouChina
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouChina
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8
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Wang Q, Yu M, Zhang S. The characteristics of the tumor immune microenvironment in colorectal cancer with different MSI status and current therapeutic strategies. Front Immunol 2025; 15:1440830. [PMID: 39877377 PMCID: PMC11772360 DOI: 10.3389/fimmu.2024.1440830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 12/16/2024] [Indexed: 01/31/2025] Open
Abstract
Colorectal cancer (CRC) remains a significant cause of cancer-related mortality worldwide. Despite advancements in surgery, chemotherapy, and radiotherapy, the effectiveness of these conventional treatments is limited, particularly in advanced cases. Therefore, transition to novel treatment is urgently needed. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has shown promise in improving outcomes for CRC patients. Notably, patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) tumors often benefit from ICIs, while the majority of CRC cases, which exhibit proficient mismatch repair (pMMR) or microsatellite-stable (MSS) status, generally show resistance to this approach. It is assumed that the MSI phenotype cause some changes in the tumor microenvironment (TME), thus triggering antitumor immunity and leading to response to immunotherapy. Understanding these differences in the TME relative to MSI status is essential for developing more effective therapeutic strategies. This review provides an overview of the TME components in CRC and explores current approaches aimed at enhancing ICI efficacy in MSS CRC.
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Affiliation(s)
- Qingzhe Wang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Min Yu
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shuang Zhang
- Department of Targeting Therapy and Immunology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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9
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Koenderman L, Vrisekoop N. Neutrophils in cancer: from biology to therapy. Cell Mol Immunol 2025; 22:4-23. [PMID: 39653768 PMCID: PMC11686117 DOI: 10.1038/s41423-024-01244-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2024] [Accepted: 11/21/2024] [Indexed: 12/12/2024] Open
Abstract
The view of neutrophils has shifted from simple phagocytic cells, whose main function is to kill pathogens, to very complex cells that are also involved in immune regulation and tissue repair. These cells are essential for maintaining and regaining tissue homeostasis. Neutrophils can be viewed as double-edged swords in a range of situations. The potent killing machinery necessary for immune responses to pathogens can easily lead to collateral damage to host tissues when inappropriately controlled. Furthermore, some subtypes of neutrophils are potent pathogen killers, whereas others are immunosuppressive or can aid in tissue healing. Finally, in tumor immunology, many examples of both protumorigenic and antitumorigenic properties of neutrophils have been described. This has important consequences for cancer therapy, as targeting neutrophils can lead to either suppressed or stimulated antitumor responses. This review will discuss the current knowledge regarding the pro- and antitumorigenic roles of neutrophils, leading to the concept of a confused state of neutrophil-driven pro-/antitumor responses.
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Affiliation(s)
- Leo Koenderman
- Dept. Respiratory Medicine and Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Nienke Vrisekoop
- Dept. Respiratory Medicine and Center for Translational Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
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10
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Zhu J, Yang L, Xia J, Zhou N, Zhu J, Zhu H, Chen J, Qing K, Duan CW. Interleukin-27 Promotes the Generation of Myeloid-derived Suppressor Cells to Alleviate Graft-versus-host Disease. Transplantation 2024; 108:e404-e416. [PMID: 38773837 DOI: 10.1097/tp.0000000000005069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2024]
Abstract
BACKGROUND Stimulation of myeloid-derived suppressor cell (MDSC) formation represents a potential curative therapeutic approach for graft-versus-host disease (GVHD), which significantly impacts the prognosis of allogeneic hematopoietic stem cell transplantation. However, the lack of an effective strategy for inducing MDSC production in vivo has hindered their clinical application. In our previous study, MDSC expansion was observed in interleukin (IL)-27-treated mice. METHODS In this study, we overexpressed exogenous IL-27 in mice using a recombinant adeno-associated virus vector to investigate its therapeutic and exacerbating effects in murine GVHD models. RESULTS In our study, we demonstrated that exogenous administration of IL-27 significantly suppressed GVHD development in a mouse model. We found that IL-27 treatment indirectly inhibited the proliferation and activation of donor T cells by rapidly expanding recipient and donor myeloid cells, which act as MDSCs after irradiation or under inflammatory conditions, rather than through regulatory T-cell expansion. Additionally, IL-27 stimulated MDSC expansion by enhancing granulocyte-monocyte progenitor generation. Notably, we verified that IL-27 signaling in donor T cells exerted an antagonistic effect on GVHD prevention and treatment. Further investigation revealed that combination therapy involving IL-27 and T-cell depletion exhibited remarkable preventive effects on GVHD in both mouse and xenogeneic GVHD models. CONCLUSIONS Collectively, these findings suggest that IL-27 promotes MDSC generation to reduce the incidence of GVHD, whereas targeted activation of IL-27 signaling in myeloid progenitors or its combination with T-cell depletion represents a potential strategy for GVHD therapy.
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Affiliation(s)
- Jianmin Zhu
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liting Yang
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Xia
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Neng Zhou
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayao Zhu
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hua Zhu
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Chen
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Qing
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cai-Wen Duan
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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11
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Artacho A, González-Torres C, Gómez-Cebrián N, Moles-Poveda P, Pons J, Jiménez N, Casanova MJ, Montoro J, Balaguer A, Villalba M, Chorão P, Puchades-Carrasco L, Sanz J, Ubeda C. Multimodal analysis identifies microbiome changes linked to stem cell transplantation-associated diseases. MICROBIOME 2024; 12:229. [PMID: 39511587 PMCID: PMC11542268 DOI: 10.1186/s40168-024-01948-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 10/11/2024] [Indexed: 11/15/2024]
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most efficient therapeutic options available to cure many hematological malignancies. However, severe complications derived from this procedure, including graft-versus-host disease (GVHD) and infections, can limit its success and negatively impact survival. Previous studies have shown that alterations in the microbiome are associated with the development of allo-HSCT-derived complications. However, most studies relied on single techniques that can only analyze a unique aspect of the microbiome, which hinders our ability to understand how microbiome alterations drive allo-HSCT-associated diseases. RESULTS Here, we have applied multiple "omic" techniques (16S rRNA and shotgun sequencing, targeted and un-targeted metabolomics) in combination with machine learning approaches to define the most significant microbiome changes following allo-HSCT at multiple modalities (bacterial taxa, encoded functions, and derived metabolites). In addition, multivariate approaches were applied to study interactions among the various microbiome modalities (the interactome). Our results show that the microbiome of transplanted patients exhibits substantial changes in all studied modalities. These include depletion of beneficial microbes, mainly from the Clostridiales order, loss of their bacterial encoded functions required for the synthesis of key metabolites, and a reduction in metabolic end products such as short chain fatty acids (SCFAs). These changes were followed by an expansion of bacteria that frequently cause infections after allo-HSCT, including several Staphylococcus species, which benefit from the reduction of bacteriostatic SCFAs. Additionally, we found specific alterations in all microbiome modalities that distinguished those patients who subsequently developed GVHD, including depletion of anti-inflammatory commensals, protective reactive oxygen detoxifying enzymes, and immunoregulatory metabolites such as acetate or malonate. Moreover, extensive shifts in the homeostatic relationship between bacteria and their metabolic products (e.g., Faecalibacterium and butyrate) were detected mainly in patients who later developed GVHD. CONCLUSIONS We have identified specific microbiome changes at different modalities (microbial taxa, their encoded genes, and synthetized metabolites) and at the interface between them (the interactome) that precede the development of complications associated with allo-HSCT. These identified microbial features provide novel targets for the design of microbiome-based strategies to prevent diseases associated with stem cell transplantation. Video Abstract.
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Affiliation(s)
- Alejandro Artacho
- Fundación Para El Fomento de La Investigación Sanitaria y Biomédica de La Comunitat Valenciana-FISABIO, Valencia, Spain
| | - Cintya González-Torres
- Fundación Para El Fomento de La Investigación Sanitaria y Biomédica de La Comunitat Valenciana-FISABIO, Valencia, Spain
| | - Nuria Gómez-Cebrián
- Drug Discovery Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - Paula Moles-Poveda
- Hematology Department, Hospital Universitari I Politècnic La Fe, Valencia, Spain
| | - Javier Pons
- Fundación Para El Fomento de La Investigación Sanitaria y Biomédica de La Comunitat Valenciana-FISABIO, Valencia, Spain
| | - Nuria Jiménez
- Fundación Para El Fomento de La Investigación Sanitaria y Biomédica de La Comunitat Valenciana-FISABIO, Valencia, Spain
| | | | - Juan Montoro
- Hematology Department, Hospital Universitari I Politècnic La Fe, Valencia, Spain
| | - Aitana Balaguer
- Hematology Department, Hospital Universitari I Politècnic La Fe, Valencia, Spain
| | - Marta Villalba
- Hematology Department, Hospital Universitari I Politècnic La Fe, Valencia, Spain
| | - Pedro Chorão
- Hematology Department, Hospital Universitari I Politècnic La Fe, Valencia, Spain
| | | | - Jaime Sanz
- Hematology Department, Hospital Universitari I Politècnic La Fe, Valencia, Spain.
- Departament de Medicina, Universitat de Valencia, Valencia, Spain.
- CIBERONC, Instituto Carlos III, Madrid, Spain.
| | - Carles Ubeda
- Fundación Para El Fomento de La Investigación Sanitaria y Biomédica de La Comunitat Valenciana-FISABIO, Valencia, Spain.
- Centers of Biomedical Research Network (CIBER) in Epidemiology and Public Health, Madrid, Spain.
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12
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Yang PJ, Zhao XY, Kou YH, Liu J, Ren XY, Zhang YY, Wang ZD, Ge Z, Yuan WX, Qiu C, Tan B, Liu Q, Shi YN, Jiang YQ, Qiu C, Guo LH, Li JY, Huang XJ, Yu LY. Human amniotic epithelial stem cell is a cell therapy candidate for preventing acute graft-versus-host disease. Acta Pharmacol Sin 2024; 45:2339-2353. [PMID: 38802569 PMCID: PMC11489431 DOI: 10.1038/s41401-024-01283-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2023] [Accepted: 04/01/2024] [Indexed: 05/29/2024]
Abstract
Graft-versus-host disease (GVHD), an immunological disorder that arises from donor T cell activation through recognition of host alloantigens, is the major limitation in the application of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Traditional immunosuppressive agents can relieve GVHD, but they induce serious side effects. It is highly required to explore alternative therapeutic strategy. Human amniotic epithelial stem cells (hAESCs) were recently considered as an ideal source for cell therapy with special immune regulatory property. In this study, we evaluated the therapeutic role of hAESCs in the treatment of GVHD, based on our previous developed cGMP-grade hAESCs product. Humanized mouse model of acute GVHD (aGVHD) was established by injection of huPBMCs via the tail vein. For prevention or treatment of aGVHD, hAESCs were injected to the mice on day -1 or on day 7 post-PBMC infusion, respectively. We showed that hAESCs infusion significantly alleviated the disease phenotype, increased the survival rate of aGVHD mice, and ameliorated pathological injuries in aGVHD target organs. We demonstrated that hAESCs directly induced CD4+ T cell polarization, in which Th1 and Th17 subsets were downregulated, and Treg subset was elevated. Correspondingly, the levels of a series of pro-inflammatory cytokines were reduced while the levels of the anti-inflammatory cytokines were upregulated in the presence of hAESCs. We found that hAESCs regulated CD4+ subset polarization in a paracrine mode, in which TGFβ and PGE2 were selectively secreted to mediate Treg elevation and Th1/Th17 inhibition, respectively. In addition, transplanted hAESCs preserved the graft-versus-leukemia (GVL) effect by inhibiting leukemia cell growth. More intriguingly, hAESCs infusion in HSCT patients displayed potential anti-GVHD effect with no safety concerns and confirmed the immunoregulatory mechanisms in the preclinical study. We conclude that hAESCs infusion is a promising therapeutic strategy for post-HSCT GVHD without compromising the GVL effect. The clinical trial was registered at www.clinicaltrials.gov as #NCT03764228.
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Affiliation(s)
- Peng-Jie Yang
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
| | - Xiang-Yu Zhao
- Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University, Beijing, 100044, China
| | - Yao-Hui Kou
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China
| | - Jia Liu
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China
| | - Xiang-Yi Ren
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China
| | - Yuan-Yuan Zhang
- Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University, Beijing, 100044, China
| | - Zhi-Dong Wang
- Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University, Beijing, 100044, China
| | - Zhen Ge
- School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, 310013, China
| | - Wei-Xin Yuan
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China
- Shanghai iCELL Biotechnology Co. Ltd, Shanghai, 200335, China
| | - Chen Qiu
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China
| | - Bing Tan
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China
| | - Qin Liu
- Shanghai iCELL Biotechnology Co. Ltd, Shanghai, 200335, China
| | - Yan-Na Shi
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China
| | - Yuan-Qing Jiang
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China
| | - Cong Qiu
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China
| | - Li-He Guo
- Shanghai iCELL Biotechnology Co. Ltd, Shanghai, 200335, China
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Jin-Ying Li
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China.
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China.
| | - Xiao-Jun Huang
- Peking University Institute of Hematology, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University People's Hospital, Peking University, Beijing, 100044, China.
- Peking-Tsinghua Center for Life Sciences, Beijing, 100084, China.
| | - Lu-Yang Yu
- MOE Laboratory of Biosystems Homeostasis & Protection of College of Life Sciences, Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province of Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310058, China.
- College of Life Sciences-iCell Biotechnology Regenerative Biomedicine Laboratory, Joint Research Centre for Engineering Biology, Zhejiang University-University of Edinburgh Institute, Zhejiang University, Hangzhou, 314400, China.
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13
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Zeng Y, Zhang R, Jiang Y, Li D, Chen L, Dong G, Zhang R, Niu Y, Chen W, Chen S. Interactions between fibroblasts and monocyte-derived cells in chronic lung injuries induced by real-ambient particulate matter exposure. MUTATION RESEARCH. GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2024; 899:503807. [PMID: 39326935 DOI: 10.1016/j.mrgentox.2024.503807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 09/28/2024]
Abstract
Long-term exposure to fine particulate matter (PM2.5) can lead to chronic lung injury, including inflammation, idiopathic pulmonary fibrosis, and cancer. Mesenchymal cells, such as fibroblasts, myeloid-derived suppressor cells (MDSCs), and interstitial macrophages (IMs), contribute to immune regulation in lung, yet their diversity and functions upon long-term exposure to particulate matter (PM) remain inadequately characterized. In this study, we conducted a 16-week real-ambient PM exposure experiment on C57BL/6 J male mice in Shijiazhuang, China. We used single-cell RNA sequencing to analyze the cellular and molecular changes in lung tissues. Notably, we revealed a significant increase in specific fibroblast (ATX+, Col5a1+Meg3+, universal fibroblasts) and monocyte-derived cell subpopulations (monocytic-MDSCs (M-MDSCs), Lyve1loMHC-Ⅱhi IMs, Lyve1hiMHC-Ⅱlo IMs) that exhibited pro-inflammatory and pro-fibrotic functions. These cell subpopulations engaged in immunosuppressive signaling pathways and interactions with various cytokines, shaping a pulmonary microenvironment similar to those associated with cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs). This altered immune environment may promote the development of pulmonary fibrosis caused by PM exposure, underscoring the intricate roles of mesenchymal cells in chronic lung injury and highlighting the cancer-causing potential of PM2.5 exposure.
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Affiliation(s)
- Youjin Zeng
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Rui Zhang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Yue Jiang
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Daochuan Li
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Liping Chen
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Guanghui Dong
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Rong Zhang
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Yujie Niu
- Department of Toxicology, School of Public Health, Hebei Medical University, Shijiazhuang 050017, China
| | - Wen Chen
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China
| | - Shen Chen
- Department of Toxicology, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou 510080, China.
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14
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Guan Q, Gilpin SG, Doerksen J, Bath L, Lam T, Li Y, Lambert P, Wall DA. The Interactions of T Cells with Myeloid-Derived Suppressor Cells in Peripheral Blood Stem Cell Grafts. Cells 2024; 13:1545. [PMID: 39329729 PMCID: PMC11429538 DOI: 10.3390/cells13181545] [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: 08/06/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/28/2024] Open
Abstract
The interaction of myeloid-derived suppressor cells (MDSCs) with T cells within G-CSF-mobilized peripheral blood stem cell (PBSC) grafts in patients undergoing autologous or allogeneic hematopoietic stem cell transplantation remains to be elucidated. Through studying allo- and auto-PBSC grafts, we observed grafts containing large numbers of T cells and MDSCs with intergraft variability in their percentage and number. T cells from autologous grafts compared to allografts expressed relative higher percentages of inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, TIGIT and BTLA. Autograft T cells had decreased cell proliferation and IFN-γ secretion, which supported the possible presence of T cell exhaustion. On the contrary, graft monocytic MDSCs (M-MDSCs) expressed multiple inhibitory receptor ligands, including PD-L1, CD86, Galectin-9, HVEM and CD155. The expression of inhibitory receptor ligands on M-MDSCs was correlated with their corresponding inhibitory receptors on T cells in the grafts. Isolated M-MDSCs had the ability to suppress T cell proliferation and IFN-γ secretion and/or promote Treg expansion. Blocking the PD-L1-PD-1 signaling pathway partially reversed the functions of M-MDSCs. Taken together, our data indicated that T cells and M-MDSCs in PBSC grafts express complementary inhibitory receptor-ligand pairing, which may impact the quality of immune recovery and clinical outcome post transplantation.
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Affiliation(s)
- Qingdong Guan
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
- Department of Immunology, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Manitoba Center for Advanced Cell and Tissue Therapy, Winnipeg, MB R3A 1R9, Canada
- Paul Albreachtsen Research Institute, CancerCare Manitoba, Winnipeg, MB R3A 1R9, Canada
| | - Scott G. Gilpin
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - James Doerksen
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Lauren Bath
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Tracy Lam
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Yun Li
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Pascal Lambert
- Department of Epidemiology and Cancer Registry, CancerCare Manitoba, Winnipeg, MB R3A 1R9, Canada;
| | - Donna A. Wall
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
- Department of Immunology, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Manitoba Center for Advanced Cell and Tissue Therapy, Winnipeg, MB R3A 1R9, Canada
- Paul Albreachtsen Research Institute, CancerCare Manitoba, Winnipeg, MB R3A 1R9, Canada
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15
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Wei C, Mi Y, Sun L, Luo J, Zhang J, Gao Y, Yu X, Ge H, Liu P. Cannabidiol alleviates suture-induced corneal pathological angiogenesis and inflammation by inducing myeloid-derived suppressor cells. Int Immunopharmacol 2024; 137:112429. [PMID: 38851157 DOI: 10.1016/j.intimp.2024.112429] [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: 04/20/2024] [Revised: 06/04/2024] [Accepted: 06/05/2024] [Indexed: 06/10/2024]
Abstract
BACKGROUND Currently, no perfect treatment for neovascularization and lymphangiogenesis exist, and each treatment method has its complications and side effects. This study aimed to investigate the anti-angiogenic and anti-inflammatory effects of cannabidiol and its mechanism of action. METHOD An in vivo corneal neovascularization (CNV) model was established using the suture method to investigate the inhibitory effects of CBD on suture-induced corneal inflammation, pathological blood vessel formation, and lymphangiogenesis. Additionally, the impact of CBD on immune cells was studied. In vitro methodologies, including cell sorting and co-culture, were employed to elucidate its mechanism of action. RESULTS Compared with the CNV group, CBD can inhibit CNV, lymphangiogenesis, and inflammation induced via the suture method. In addition, CBD specifically induced CD45+CD11b+Gr-1+ cell upregulation, which significantly inhibited the proliferation of CD4+ T lymphocytes in vitro and exhibited a CD31+ phenotype, proving that they were myeloid-derived suppressor cells (MDSCs). We administered anti-Gr-1 to mice to eliminate MDSCs in vivo and found that anti-Gr-1 partially reversed the anti-inflammatory and angiogenic effects of CBD. Furthermore, we found that compared with MDSCs in the normal group, CBD-induced MDSCs overexpress peroxisome proliferator-activated receptor-gamma (PPAR-γ). Administering PPAR-γ inhibitor in mice almost reversed the induction of MDSCs by CBD, demonstrating the role of PPAR-γ in the function of CBD. CONCLUSION This study indicates that CBD may induce MDSCs upregulation by activating the nuclear receptor PPAR-γ, exerting anti-inflammatory, antiangiogenic, and lymphangiogenic effects, and revealing potential therapeutic targets for corneal neovascularization and lymphangiogenesis.
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Affiliation(s)
- Chaoqun Wei
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, Heilongjiang, China
| | - Yu Mi
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Liyao Sun
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, Heilongjiang, China
| | - Jialin Luo
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, Heilongjiang, China; Key Laboratory of Ischemia-reperfusion, Harbin Medical University, Ministry of Education, Harbin 150001, Heilongjiang, China; Experimental Animal Centre, the Second Affiliated Hospital, Harbin Medical University, Harbin 150001, Heilongjiang, China
| | - Jiayue Zhang
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, Heilongjiang, China; Key Laboratory of Ischemia-reperfusion, Harbin Medical University, Ministry of Education, Harbin 150001, Heilongjiang, China; Experimental Animal Centre, the Second Affiliated Hospital, Harbin Medical University, Harbin 150001, Heilongjiang, China
| | - Yi Gao
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, Heilongjiang, China
| | - Xiaohan Yu
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, Heilongjiang, China
| | - Hongyan Ge
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, Heilongjiang, China.
| | - Ping Liu
- Eye Hospital, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Harbin 150001, Heilongjiang, China.
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16
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Vijayan V, Yan H, Lohmeyer JK, Prentiss KA, Patil RV, Barbarito G, Lopez I, Elezaby A, Peterson K, Baker J, Ostberg NP, Bertaina A, Negrin RS, Mochly-Rosen D, Weinberg K, Haileselassie B. Extracellular release of damaged mitochondria induced by prehematopoietic stem cell transplant conditioning exacerbates GVHD. Blood Adv 2024; 8:3691-3704. [PMID: 38701354 PMCID: PMC11284707 DOI: 10.1182/bloodadvances.2023012328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 03/07/2024] [Accepted: 04/12/2024] [Indexed: 05/05/2024] Open
Abstract
ABSTRACT Despite therapeutic advancements, graft-versus-host disease (GVHD) is a major complication of hematopoietic stem cell transplantation (HSCT). In current models of GVHD, tissue injury induced by cytotoxic conditioning regimens, along with translocation of microbes expressing pathogen-associated molecular patterns, result in activation of host antigen-presenting cells (APCs) to stimulate alloreactive donor T lymphocytes. Recent studies have demonstrated that in many pathologic states, tissue injury results in the release of mitochondria from the cytoplasm to the extracellular space. We hypothesized that extracellular mitochondria, which are related to archaebacteria, could also trigger GVHD by stimulation of host APCs. We found that clinically relevant doses of radiation or busulfan induced extracellular release of mitochondria by various cell types, including cultured intestinal epithelial cells. Conditioning-mediated mitochondrial release was associated with mitochondrial damage and impaired quality control but did not affect the viability of the cells. Extracellular mitochondria directly stimulated host APCs to express higher levels of major histocompatibility complex II (MHC-II), costimulatory CD86, and proinflammatory cytokines, resulting in increased donor T-cell activation, and proliferation in mixed lymphocyte reactions. Analyses of plasma from both experimental mice and a cohort of children undergoing HSCT demonstrated that conditioning induced extracellular mitochondrial release in vivo. In mice undergoing MHC-mismatched HSCT, administration of purified syngeneic extracellular mitochondria increased host APC activation and exacerbated GVHD. Our data suggest that pre-HSCT conditioning results in extracellular release of damaged mitochondria, which increase alloreactivity and exacerbate GVHD. Therefore, decreasing the extracellular release of damaged mitochondria after conditioning could serve as a novel strategy for GVHD prevention.
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Affiliation(s)
- Vijith Vijayan
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Hao Yan
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Juliane K. Lohmeyer
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Kaylin A. Prentiss
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Rachna V. Patil
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Giulia Barbarito
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Ivan Lopez
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Aly Elezaby
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA
| | - Kolten Peterson
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Jeanette Baker
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Nicolai P. Ostberg
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA
| | - Alice Bertaina
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Robert S. Negrin
- Division of Blood and Marrow Transplantation and Cellular Therapy, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Daria Mochly-Rosen
- Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA
| | - Kenneth Weinberg
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Bereketeab Haileselassie
- Division of Critical Care Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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17
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Tong X, Qiao S, Dong Z, Zhao X, Du X, Niu W. Targeting CSF1R in myeloid-derived suppressor cells: insights into its immunomodulatory functions in colorectal cancer and therapeutic implications. J Nanobiotechnology 2024; 22:409. [PMID: 38992688 PMCID: PMC11238447 DOI: 10.1186/s12951-024-02584-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 05/26/2024] [Indexed: 07/13/2024] Open
Abstract
OBJECTIVE This study aimed to investigate the critical role of MDSCs in CRC immune suppression, focusing on the CSF1R and JAK/STAT3 signaling axis. Additionally, it assessed the therapeutic efficacy of LNCs@CSF1R siRNA and anti-PD-1 in combination. METHODS Single-cell transcriptome sequencing data from CRC and adjacent normal tissues identified MDSC-related differentially expressed genes. RNA-seq analysis comprehensively profiled MDSC gene expression in murine CRC tumors. LNCs@CSF1R siRNA nanocarriers effectively targeted and inhibited CSF1R. Flow cytometry quantified changes in MDSC surface markers post-CSF1R inhibition. RNA-seq and pathway enrichment analyses revealed the impact of CSF1R on MDSC metabolism and signaling. The effect of CSF1R inhibition on the JAK/STAT3 signaling axis was validated using Colivelin and metabolic assessments. Glucose and fatty acid uptake were measured via fluorescence-based flow cytometry. The efficacy of LNCs@CSF1R siRNA and anti-PD-1, alone and in combination, was evaluated in a murine CRC model with extensive tumor section analyses. RESULTS CSF1R played a significant role in MDSC-mediated immune suppression. LNCs@CSF1R siRNA nanocarriers effectively targeted MDSCs and inhibited CSF1R. CSF1R regulated MDSC fatty acid metabolism and immune suppression through the JAK/STAT3 signaling axis. Inhibition of CSF1R reduced STAT3 activation and target gene expression, which was rescued by Colivelin. Combined treatment with LNCs@CSF1R siRNA and anti-PD-1 significantly slowed tumor growth and reduced MDSC abundance within CRC tumors. CONCLUSION CSF1R via the JAK/STAT3 axis critically regulates MDSCs, particularly in fatty acid metabolism and immune suppression. Combined therapy with LNCs@CSF1R siRNA and anti-PD-1 enhances therapeutic efficacy in a murine CRC model, providing a strong foundation for future clinical applications.
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Affiliation(s)
- Xin Tong
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, P. R. China
| | - Shifeng Qiao
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, P. R. China
| | - Zhe Dong
- Department of General Surgery, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, P. R. China
| | - Xiaohui Zhao
- Department of Medical Oncology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, P. R. China
| | - Xiaxia Du
- Department of Rehabilitation, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, P. R. China
| | - Wei Niu
- Department of Gastroenterology, The First Affiliated Hospital of Jinzhou Medical University, No. 2, Section 5, Renmin Street, Guta District, Jinzhou, Liaoning Province, 121000, P. R. China.
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18
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Wang L, Wang H, Zhu M, Ni X, Sun L, Wang W, Xie J, Li Y, Xu Y, Wang R, Han S, Zhang P, Peng J, Hou M, Hou Y. Platelet-derived TGF-β1 induces functional reprogramming of myeloid-derived suppressor cells in immune thrombocytopenia. Blood 2024; 144:99-112. [PMID: 38574321 DOI: 10.1182/blood.2023022738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/11/2024] [Accepted: 03/26/2024] [Indexed: 04/06/2024] Open
Abstract
ABSTRACT Platelet α-granules are rich in transforming growth factor β1 (TGF-β1), which is associated with myeloid-derived suppressor cell (MDSC) biology. Responders to thrombopoietin receptor agonists (TPO-RAs) revealed a parallel increase in the number of both platelets and MDSCs. Here, anti-CD61 immune-sensitized splenocytes were transferred into severe combined immunodeficient mice to establish an active murine model of immune thrombocytopenia (ITP). Subsequently, we demonstrated that TPO-RAs augmented the inhibitory activities of MDSCs by arresting plasma cells differentiation, reducing Fas ligand expression on cytotoxic T cells, and rebalancing T-cell subsets. Mechanistically, transcriptome analysis confirmed the participation of TGF-β/Smad pathways in TPO-RA-corrected MDSCs, which was offset by Smad2/3 knockdown. In platelet TGF-β1-deficient mice, TPO-RA-induced amplification and enhanced suppressive capacity of MDSCs was waived. Furthermore, our retrospective data revealed that patients with ITP achieving complete platelet response showed superior long-term outcomes compared with those who only reach partial response. In conclusion, we demonstrate that platelet TGF-β1 induces the expansion and functional reprogramming of MDSCs via the TGF-β/Smad pathway. These data indicate that platelet recovery not only serves as an end point of treatment response but also paves the way for immune homeostasis in immune-mediated thrombocytopenia.
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Affiliation(s)
- Lingjun Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Haoyi Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Mingfang Zhu
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Xiaofei Ni
- Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Lu Sun
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Wanru Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Jie Xie
- Department of Hematology, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yubin Li
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Yitong Xu
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Ruting Wang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Shouqing Han
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Ping Zhang
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Jun Peng
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Ming Hou
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
| | - Yu Hou
- Department of Hematology, Qilu Hospital of Shandong University, Shandong University, Jinan, China
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19
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Notarantonio AB, Bertrand A, Piucco R, Fievet G, Sartelet H, Boulangé L, de Isla N, De Carvalho Bittencourt M, Hergalant S, Rubio MT, D'Aveni M. Highly immunosuppressive myeloid cells correlate with early relapse after allogeneic stem cell transplantation. Exp Hematol Oncol 2024; 13:50. [PMID: 38734654 PMCID: PMC11088072 DOI: 10.1186/s40164-024-00516-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for myeloid malignancies such as some acute myeloid leukemias (AML) and high-risk myelodysplastic syndromes (MDS). It aims to eradicate the malignant clone using immunocompetent donor cells (graft-versus-leukemia effect, GVL). Unfortunately, relapse is the primary cause of transplant failure mainly related on HLA loss or downregulation and upregulation of inhibitory ligands on blasts which result in donor immune effector dysfunctions. METHODS Between 2018 and 2021, we conducted a monocentric prospective study including 61 consecutive patients transplanted for AML or high-risk MDS. We longitudinally investigated immune cells at days + 30, + 90 and + 180 post-transplant from bone marrow and peripheral blood. We assessed the dynamics between myeloid derived suppressor cells (MDSCs) and T-cells. RESULTS Among the 61 patients, 45 did not relapse over the first 12 months while 16 relapsed during the first year post-transplant. Through months 1 to 6, comparison with healthy donors revealed an heterogenous increase in MDSC frequency. In all recipients, the predominant MDSC subset was granulocytic with no specific phenotypic relapse signature. However, in relapsed patients, in vitro and in vivo functional analyses revealed that MDSCs from peripheral blood were highly immunosuppressive from day + 30 onwards, with an activated NLRP3 inflammasome signature. Only circulating immunosuppressive MDSCs were statistically correlated to circulating double-positive Tim3+LAG3+ exhausted T cells. CONCLUSION Our simple in vitro functional assay defining MDSC immunosuppressive properties might serve as an early biomarker of relapse and raise the question of new preventive treatments targeting MDSCs in the future. Trial registration NCT03357172.
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Affiliation(s)
- Anne-Béatrice Notarantonio
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
- Hematology Department, CHRU Nancy, Université de Lorraine, 54000, Nancy, France
| | - Allan Bertrand
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
| | - Romain Piucco
- Inserm UMR_S 1256 NGERE, Université de Lorraine, 54500, Vandœuvre-les-Nancy, France
| | - Ghislain Fievet
- Inserm UMR_S 1256 NGERE, Université de Lorraine, 54500, Vandœuvre-les-Nancy, France
| | - Hervé Sartelet
- Anatomopathology Department, CHRU Nancy, Université de Lorraine, 54000, Nancy, France
| | - Laura Boulangé
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
| | - Natalia de Isla
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
| | - Marcelo De Carvalho Bittencourt
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
- Immunology Laboratory, CHRU Nancy, Université de Lorraine, 54000, Nancy, France
| | - Sébastien Hergalant
- Inserm UMR_S 1256 NGERE, Université de Lorraine, 54500, Vandœuvre-les-Nancy, France
| | - Marie-Thérèse Rubio
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
- Hematology Department, CHRU Nancy, Université de Lorraine, 54000, Nancy, France
| | - Maud D'Aveni
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France.
- Hematology Department, CHRU Nancy, Université de Lorraine, 54000, Nancy, France.
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20
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Czech M, Schneider S, Peltokangas N, El Khawanky N, Ghimire S, Andrieux G, Hülsdünker J, Krausz M, Proietti M, Braun LM, Rückert T, Langenbach M, Schmidt D, Martin I, Wenger V, de Vega E, Haring E, Pourjam M, Pfeifer D, Schmitt-Graeff A, Grimbacher B, Aumann K, Kircher B, Tilg H, Raffatellu M, Thiele Orberg E, Häcker G, Duyster J, Köhler N, Holler E, Nachbaur D, Boerries M, Gerner RR, Grün D, Zeiser R. Lipocalin-2 expression identifies an intestinal regulatory neutrophil population during acute graft-versus-host disease. Sci Transl Med 2024; 16:eadi1501. [PMID: 38381845 DOI: 10.1126/scitranslmed.adi1501] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 01/24/2024] [Indexed: 02/23/2024]
Abstract
Acute graft-versus-host disease (aGVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT), for which therapeutic options are limited. Strategies to promote intestinal tissue tolerance during aGVHD may improve patient outcomes. Using single-cell RNA sequencing, we identified a lipocalin-2 (LCN2)-expressing neutrophil population in mice with intestinal aGVHD. Transfer of LCN2-overexpressing neutrophils or treatment with recombinant LCN2 reduced aGVHD severity, whereas the lack of epithelial or hematopoietic LCN2 enhanced aGVHD severity and caused microbiome alterations. Mechanistically, LCN2 induced insulin-like growth factor 1 receptor (IGF-1R) signaling in macrophages through the LCN2 receptor SLC22A17, which increased interleukin-10 (IL-10) production and reduced major histocompatibility complex class II (MHCII) expression. Transfer of LCN2-pretreated macrophages reduced aGVHD severity but did not reduce graft-versus-leukemia effects. Furthermore, LCN2 expression correlated with IL-10 expression in intestinal biopsies in multiple cohorts of patients with aGVHD, and LCN2 induced IGF-1R signaling in human macrophages. Collectively, we identified a LCN2-expressing intestinal neutrophil population that reduced aGVHD severity by decreasing MHCII expression and increasing IL-10 production in macrophages. This work provides the foundation for administration of LCN2 as a therapeutic approach for aGVHD.
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Affiliation(s)
- Marie Czech
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Sophia Schneider
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Nina Peltokangas
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
- Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany
- Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg, 97078 Würzburg, Germany
| | - Nadia El Khawanky
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
- Department of Medicine III, University Hospital rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany
- TranslaTUM, Center for Translational Cancer Research, 81675 Munich, Germany
| | - Sakhila Ghimire
- Department of Internal Medicine III, Haematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Geoffroy Andrieux
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Jan Hülsdünker
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Máté Krausz
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University, 79106 Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Institute for Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Michele Proietti
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University, 79106 Freiburg, Germany
- Department of Rheumatology and Clinical Immunology, Hannover Medical School, 30625 Hannover, Germany
- RESIST-Cluster of Excellence 2155, Hannover Medical School, 30625 Hannover, Germany
| | - Lukas M Braun
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Tamina Rückert
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Marlene Langenbach
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Dominik Schmidt
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Ina Martin
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Valentin Wenger
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Enrique de Vega
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Eileen Haring
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany
| | - Mohsen Pourjam
- Core Facility Microbiome, ZIEL Institute of Food and Health, Technical University of Munich, 85354 Freising, Germany
| | - Dietmar Pfeifer
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | | | - Bodo Grimbacher
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center, Faculty of Medicine, Albert-Ludwigs-University, 79106 Freiburg, Germany
- DZIF-German Center for Infection Research, Satellite Center Freiburg, 79106 Freiburg, Germany
- RESIST-Cluster of Excellence 2155 to Hannover Medical School, Satellite Center Freiburg, Germany
- CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
| | - Konrad Aumann
- Department of Pathology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Brigitte Kircher
- Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology and Endocrinology and Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Manuela Raffatellu
- Department of Pediatrics, Division of Host-Microbe Systems and Therapeutics, University of California San Diego, La Jolla, CA 92123-0735, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA 92093, USA
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy, and Vaccines (CU-UCSD cMAV), La Jolla, CA 92093, USA
| | - Erik Thiele Orberg
- Department of Internal Medicine III, Haematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany
- German Cancer Consortium (DKTK), partner-site Munich, a partnership between DKFZ and Klinikum rechts der Isar, 81675 Munich, Germany
- Bavarian Cancer Research Center (BZKF), 93053 Regensburg, Germany
| | - Georg Häcker
- Institute of Medical Microbiology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
| | - Justus Duyster
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center, University of Freiburg, 79106 Freiburg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg Germany
| | - Natalie Köhler
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
| | - Ernst Holler
- Department of Internal Medicine III, Haematology and Internal Oncology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - David Nachbaur
- Department of Internal Medicine V, Hematology and Oncology, Medical University Innsbruck, 6020 Innsbruck, Austria
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79110 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center, University of Freiburg, 79106 Freiburg, Germany
| | - Romana R Gerner
- Department of Medicine III, University Hospital rechts der Isar, TUM School of Medicine and Health, Technical University of Munich, 81675 Munich, Germany
- TUM School of Life Sciences Weihenstephan, ZIEL Institute for Food & Health, 85354 Freising-Weihenstephan, Germany
| | - Dominic Grün
- Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg, 97078 Würzburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
- German Cancer Consortium (DKTK), Partner site Freiburg, a partnership between DKFZ and Medical Center, University of Freiburg, 79106 Freiburg, Germany
- Comprehensive Cancer Center Freiburg (CCCF), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79106 Freiburg Germany
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21
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Del Pilar C, Garrido-Matilla L, Del Pozo-Filíu L, Lebrón-Galán R, Arias RF, Clemente D, Alonso JR, Weruaga E, Díaz D. Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration. J Neuroinflammation 2024; 21:49. [PMID: 38355633 PMCID: PMC10867997 DOI: 10.1186/s12974-023-03000-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 12/18/2023] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) constitute a recently discovered bone-marrow-derived cell type useful for dealing with neuroinflammatory disorders. However, these cells are only formed during inflammatory conditions from immature myeloid cells (IMCs) that acquire immunosuppressive activity, thus being commonly gathered from diseased animals. Then, to obtain a more clinically feasible source, we characterized IMCs directly derived from healthy bone marrow and proved their potential immunosuppressive activity under pathological conditions in vitro. We then explored their neuroprotective potential in a model of human cerebellar ataxia, the Purkinje Cell Degeneration (PCD) mouse, as it displays a well-defined neurodegenerative and neuroinflammatory process that can be also aggravated by invasive surgeries. METHODS IMCs were obtained from healthy bone marrow and co-cultured with activated T cells. The proliferation and apoptotic rate of the later were analyzed with Tag-it Violet. For in vivo studies, IMCs were transplanted by stereotactic surgery into the cerebellum of PCD mice. We also used sham-operated animals as controls of the surgical effects, as well as their untreated counterparts. Motor behavior of mice was assessed by rotarod test. The Purkinje cell density was measured by immunohistochemistry and cell death assessed with the TUNEL technique. We also analyzed the microglial phenotype by immunofluorescence and the expression pattern of inflammation-related genes by qPCR. Parametric tests were applied depending on the specific experiment: one or two way ANOVA and Student's T test. RESULTS IMCs were proven to effectively acquire immunosuppressive activity under pathological conditions in vitro, thus acting as MDSCs. Concerning in vivo studios, sham-operated PCD mice suffered detrimental effects in motor coordination, Purkinje cell survival and microglial activation. After intracranial administration of IMCs into the cerebellum of PCD mice, no special benefits were detected in the transplanted animals when compared to untreated mice. Nonetheless, this transplant almost completely prevented the impairments caused by the surgery in PCD mice, probably by the modulation of the inflammatory patterns. CONCLUSIONS Our work comprise two main translational findings: (1) IMCs can be directly used as they behave as MDSCs under pathological conditions, thus avoiding their gathering from diseased subjects; (2) IMCs are promising adjuvants when performing neurosurgery.
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Affiliation(s)
- Carlos Del Pilar
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain
| | - Lucía Garrido-Matilla
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Departamento de Psicobiología, Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Lucía Del Pozo-Filíu
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Translational Stroke Laboratory (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Rafael Lebrón-Galán
- Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45004, Toledo, Spain
- Hospital Universitario de Toledo, Avd. Río Guadiana, s/n, 45007, Toledo, Spain
| | - Raúl F Arias
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain
| | - Diego Clemente
- Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45004, Toledo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Av. Monforte de Lemos, 3-5, 28029, Madrid, Spain
| | - José Ramón Alonso
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain
| | - Eduardo Weruaga
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain.
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain.
| | - David Díaz
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain.
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain.
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22
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Oza K, Kang J, Patil D, Owen KL, Cui W, Khan K, Kaufman SS, Kroemer A. Current Advances in Graft-versus-host Disease After Intestinal Transplantation. Transplantation 2024; 108:399-408. [PMID: 37309025 DOI: 10.1097/tp.0000000000004703] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Graft-versus-host disease (GvHD) remains a potentially fatal complication following intestinal transplant (ITx). Over the past decade, advances in the understanding of the pathophysiology of this complex immunological phenomenon have led to the reassessment of the host systemic immune response and have created a gateway for novel preventive and therapeutic strategies. Although sufficient evidence dictates the use of corticosteroids as a first-line option, the treatment for refractory disease remains contentious and lacks a standardized therapeutic approach. Timely diagnosis remains crucial, and the advent of chimerism detection and immunological biomarkers have transformed the identification, prognostication, and potential for survival after GvHD in ITx. The objectives of the following review aim to discuss the clinical and diagnostic features, pathophysiology, advances in immune biomarkers, as well as therapeutic opportunities in the prevention and treatment of GvHD in ITx.
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Affiliation(s)
- Kesha Oza
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
- Department of General Surgery, MedStar Georgetown University Hospital, Washington, DC
| | - Jiman Kang
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC
| | - Digvijay Patil
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Kathryn L Owen
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Wanxing Cui
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
- Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC
| | - Khalid Khan
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Stuart S Kaufman
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
| | - Alexander Kroemer
- MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital and the Center for Translational Transplant Medicine, Georgetown University Medical Center, Washington, DC
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Fraternale A, Green KA, Schiavano GF, Bruschi M, Retini M, Magnani M, Green WR. Inhibition of myeloid-derived suppressor cell (MDSC) activity by redox-modulating agents restores T and B cell proliferative responses in murine AIDS. Int Immunopharmacol 2023; 124:110882. [PMID: 37659111 DOI: 10.1016/j.intimp.2023.110882] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 08/28/2023] [Accepted: 08/28/2023] [Indexed: 09/04/2023]
Abstract
The mechanisms by which myeloid-derived suppressor cells (MDSCs) mediate inhibition prominently include the production of reactive nitrogen species, in particular those generated by inducible nitric oxide synthase (iNOS), and reactive oxygen species. LP-BM5 murine retroviral infection results in a profound immunodeficiency, known as murine AIDS, as well as in increased numbers and activity of monocytic-type MDSCs (M-MDSCs) that suppress both T and B cell responses. While M-MDSCs suppress T cells ex vivo in a fully iNOS/NO-dependent manner, M-MDSC suppression of B cell responses is only partially due to iNOS/NO. This study preliminarily explored the role of two redox-modulating compounds in inhibiting the M-MDSC suppressive activity in LP-BM5 infection. The tested molecules were: I-152 consisting in a conjugate of N-acetyl-cysteine (NAC) and S-acetyl-cysteamine (SMEA) and C4-GSH that is the n-butanoyl glutathione (GSH) derivative. The results show that both molecules, tested in a concentration range between 3 and 20 mM, blocked the M-MDSC suppression of activated B and T cells ex vivo and restored their proliferative capacity in vivo. Ex vivo I-152 blockade of M-MDSC suppressiveness was more significant for T cell (about 70%) while M-MDSC blockade by C4-GSH was preferential for B cell responsiveness (about 60%), which was also confirmed by in vivo investigation. Beyond insights into redox-dependent suppressive effector mechanism(s) of M-MDSCs in LP-BM5 infection, these findings may ultimately be important to identify new immunotherapeutics against infectious diseases.
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Affiliation(s)
- Alessandra Fraternale
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy.
| | - Kathy A Green
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, NH, United States
| | | | - Michela Bruschi
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy
| | - Michele Retini
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy
| | - Mauro Magnani
- Department of Biomolecular Sciences, University of Urbino Carlo Bo, Urbino, PU, Italy
| | - William R Green
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, NH, United States
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24
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Peterlin P, Béné MC, Jullien M, Guillaume T, Bourgeois AL, Garnier A, Debord C, Eveillard M, Chevallier P. Assessment of monocytic-myeloid-derived suppressive cells (M-MDSC) before and after allogeneic hematopoietic stem cell transplantation in acute leukemia patients. EJHAEM 2023; 4:1089-1095. [PMID: 38024608 PMCID: PMC10660606 DOI: 10.1002/jha2.795] [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: 06/08/2023] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 12/01/2023]
Abstract
In this monocentric prospective study, the influence on long-term outcomes of peripheral blood levels of monocytic-myeloid-derived suppressive cells (M-MDSC) was investigated in 56 patients with acute leukemia (myeloid n = 47; lymphoid n = 9) before and after (Days+60/+90) allogeneic hematopoietic stem cell transplantation (Allo-HSCT). A risk of relapse was found to be associated with a level of pregraft M-MDSC above 1.4% by ROC curve analysis. In multivariate analysis, this threshold retained a strong statistical significance (HR: 5.94 [2.09-16.87], p = 0.001). Considering only the group of patients who were in complete remission prior to Allo-HSCT (n = 44), a significant prediction of relapse was found to be associated, in multivariate analysis, with a level of pregraft M-MDSC above 1.4% (HR: 55.01 [14.95-202.37], p < 0.001) together with pregraft-positive measurable -residual disease (MRD) (HR: 11.04 [1.89-64.67], p = 0.008). A poorer OS (HR: 6.05 [1.24-29.59], p = 0.026) and disease-free survival (HR: 6.52 [1.41-30.19], p = 0.016) were also associated with higher levels of pregraft M-MDSC. Remarkably, no relapse occurred in patients with pregraft-negative MRD and ≤1.4% of M-MDSC (vs. a 3-year relapse rate of 60% for others, p = 0.004). Patients developing grade 3-4 acute graft-versus-host-disease (GVHD, median occurrence: day+30 posttransplant) showed significantly higher levels of M-MDSC% at days +60 and +90, suggesting a possible amplification of these immunosuppressive cells as a reaction to GVHD. In conclusion, this prospective study demonstrates a negative impact of higher proportions of peripheral M-MDSC before Allo-HSCT in leukemic patients. This paves the way to potential therapeutic intervention to decrease M-MDSC levels before Allo-HSCT and thus perhaps the incidence of relapse in such patients.
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Affiliation(s)
| | - Marie C. Béné
- Department of Hematology BiologyNantes University HospitalNantesFrance
- INSERM UMR1232, CRCINA IRS‐UNUniversity of NantesNantesFrance
| | - Maxime Jullien
- Hematology DepartmentNantes University HospitalNantesFrance
| | - Thierry Guillaume
- Hematology DepartmentNantes University HospitalNantesFrance
- INSERM UMR1232, CRCINA IRS‐UNUniversity of NantesNantesFrance
| | | | - Alice Garnier
- Hematology DepartmentNantes University HospitalNantesFrance
| | - Camille Debord
- Department of Hematology BiologyNantes University HospitalNantesFrance
| | - Marion Eveillard
- Department of Hematology BiologyNantes University HospitalNantesFrance
| | - Patrice Chevallier
- Hematology DepartmentNantes University HospitalNantesFrance
- INSERM UMR1232, CRCINA IRS‐UNUniversity of NantesNantesFrance
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25
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Lee JY, Kim S, Sohn HJ, Kim CH, Kim TG, Lee HS. Local Myeloid-Derived Suppressor Cells Impair Progression of Experimental Autoimmune Uveitis by Alleviating Oxidative Stress and Inflammation. Invest Ophthalmol Vis Sci 2023; 64:39. [PMID: 37878302 PMCID: PMC10615146 DOI: 10.1167/iovs.64.13.39] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023] Open
Abstract
Purpose To evaluate the immune regulatory effect of human cord blood myeloid-derived suppressor cells (MDSCs) in experimental autoimmune uveitis (EAU) models. Methods MDSCs (1 × 106) or PBS were injected into established C57BL/6 EAU mice via the subconjunctival route on days 0 and 7. The severity of intraocular inflammation was evaluated for up to 3 weeks. Tissue injury and inflammation were analyzed using immunolabelled staining, real-time PCR, and ELISA. In addition, immune cells in draining lymph nodes (LNs) were quantified using flow cytometry. Results After 21 days, the clinical scores and histopathological grades of EAU were lower in the MDSCs group compared with the PBS group. Local administration of MDSCs suppressed the oxidative stress and the expression of TNF-α and IL-1β in the retinal tissues. In addition, it inhibited the activation of pathogenic T helper 1 (Th1) and Th17 cells in draining LNs. MDSCs increased the frequency of CD25+ Foxp3+ regulatory T cells and the mRNA expression of IL-10, as an immune modulator. Conclusions MDSCs suppressed inflammation and oxidative stress in the retina and inhibited pathogenic T cells in the LNs in EAU. Therefore, ocular administration of MDSCs has therapeutic potential for uveitis.
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Affiliation(s)
- Jae-Young Lee
- Department of Ophthalmology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sueon Kim
- ViGenCell Inc., Seoul, Republic of Korea
| | | | | | - Tai-Gyu Kim
- ViGenCell Inc., Seoul, Republic of Korea
- Catholic Hematopoietic Stem Cell Bank, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hyun Soo Lee
- Department of Ophthalmology, Eunpyeong St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, United States
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26
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Ostrand-Rosenberg S, Lamb TJ, Pawelec G. Here, There, and Everywhere: Myeloid-Derived Suppressor Cells in Immunology. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:1183-1197. [PMID: 37068300 PMCID: PMC10111205 DOI: 10.4049/jimmunol.2200914] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/06/2023] [Indexed: 04/19/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) were initially identified in humans and mice with cancer where they profoundly suppress T cell- and NK cell-mediated antitumor immunity. Inflammation is a central feature of many pathologies and normal physiological conditions and is the dominant driving force for the accumulation and function of MDSCs. Therefore, MDSCs are present in conditions where inflammation is present. Although MDSCs are detrimental in cancer and conditions where cellular immunity is desirable, they are beneficial in settings where cellular immunity is hyperactive. Because MDSCs can be generated ex vivo, they are being exploited as therapeutic agents to reduce damaging cellular immunity. In this review, we discuss the detrimental and beneficial roles of MDSCs in disease settings such as bacterial, viral, and parasitic infections, sepsis, obesity, trauma, stress, autoimmunity, transplantation and graft-versus-host disease, and normal physiological settings, including pregnancy and neonates as well as aging. The impact of MDSCs on vaccination is also discussed.
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Affiliation(s)
- Suzanne Ostrand-Rosenberg
- Division of Microbiology and Immunology, Department of Pathology, University of Utah 84112, Salt Lake City, UT
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Tracey J. Lamb
- Division of Microbiology and Immunology, Department of Pathology, University of Utah 84112, Salt Lake City, UT
| | - Graham Pawelec
- Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany, and Health Sciences North Research Institute, Sudbury, ON, Canada
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27
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Műzes G, Sipos F. Autoimmunity and Carcinogenesis: Their Relationship under the Umbrella of Autophagy. Biomedicines 2023; 11:1130. [PMID: 37189748 PMCID: PMC10135912 DOI: 10.3390/biomedicines11041130] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 04/11/2023] Open
Abstract
The immune system and autophagy share a functional relationship. Both innate and adaptive immune responses involve autophagy and, depending on the disease's origin and pathophysiology, it may have a detrimental or positive role on autoimmune disorders. As a "double-edged sword" in tumors, autophagy can either facilitate or impede tumor growth. The autophagy regulatory network that influences tumor progression and treatment resistance is dependent on cell and tissue types and tumor stages. The connection between autoimmunity and carcinogenesis has not been sufficiently explored in past studies. As a crucial mechanism between the two phenomena, autophagy may play a substantial role, though the specifics remain unclear. Several autophagy modifiers have demonstrated beneficial effects in models of autoimmune disease, emphasizing their therapeutic potential as treatments for autoimmune disorders. The function of autophagy in the tumor microenvironment and immune cells is the subject of intensive study. The objective of this review is to investigate the role of autophagy in the simultaneous genesis of autoimmunity and malignancy, shedding light on both sides of the issue. We believe our work will assist in the organization of current understanding in the field and promote additional research on this urgent and crucial topic.
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Affiliation(s)
| | - Ferenc Sipos
- Immunology Division, Department of Internal Medicine and Hematology, Semmelweis University, 1088 Budapest, Hungary;
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28
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Wang S, Zhao X, Wu S, Cui D, Xu Z. Myeloid-derived suppressor cells: key immunosuppressive regulators and therapeutic targets in hematological malignancies. Biomark Res 2023; 11:34. [PMID: 36978204 PMCID: PMC10049909 DOI: 10.1186/s40364-023-00475-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
The immunosuppressive tumor microenvironment (TME) supports the development of tumors and limits tumor immunotherapy, including hematological malignancies. Hematological malignancies remain a major public health issue with high morbidity and mortality worldwide. As an important component of immunosuppressive regulators, the phenotypic characteristics and prognostic value of myeloid-derived suppressor cells (MDSCs) have received much attention. A variety of MDSC-targeting therapeutic approaches have produced encouraging outcomes. However, the use of various MDSC-targeted treatment strategies in hematologic malignancies is still difficult due to the heterogeneity of hematologic malignancies and the complexity of the immune system. In this review, we summarize the biological functions of MDSCs and further provide a summary of the phenotypes and suppressive mechanisms of MDSC populations expanded in various types of hematological malignancy contexts. Moreover, we discussed the clinical correlation between MDSCs and the diagnosis of malignant hematological disease, as well as the drugs targeting MDSCs, and focused on summarizing the therapeutic strategies in combination with other immunotherapies, such as various immune checkpoint inhibitors (ICIs), that are under active investigation. We highlight the new direction of targeting MDSCs to improve the therapeutic efficacy of tumors.
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Affiliation(s)
- Shifen Wang
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xingyun Zhao
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Siwen Wu
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Zhenshu Xu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
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29
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Kim S, Lim S, Kim B, Ritchey J, Vij K, Prior J, Marsala L, Stoner A, Gao F, Achilefu S, Cooper ML, DiPersio JF, Choi J. S100A9 upregulated by IFNGR signaling blockade functions as a novel GVHD suppressor without compromising GVL in mice. Blood 2023; 141:945-950. [PMID: 36477272 PMCID: PMC10023737 DOI: 10.1182/blood.2021012687] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 11/03/2022] [Accepted: 11/23/2022] [Indexed: 12/12/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GVHD) and malignant relapse limit its therapeutic success. We previously demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction in GVHD while preserving graft-versus-leukemia (GVL) effects. However, the underlying molecular mechanisms remain inconclusive. In this study, we found that S100A9 is a novel GVHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1-/- and S100a9-overexpressing T cells significantly reduced GVHD without compromising GVL, altering donor T-cell trafficking to GVHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improved GVHD in our mouse model of xenogeneic human peripheral blood mononuclear cell transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab reduced human T-cell trafficking to the GVHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GVHD suppressor without compromising GVL.
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Affiliation(s)
- Sena Kim
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Sora Lim
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Boram Kim
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Julie Ritchey
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Kiran Vij
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Julie Prior
- Molecular Imaging Center in the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Lynne Marsala
- Molecular Imaging Center in the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Alyssa Stoner
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Feng Gao
- Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO
| | - Samuel Achilefu
- Molecular Imaging Center in the Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO
| | - Matthew L. Cooper
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - John F. DiPersio
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
| | - Jaebok Choi
- Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO
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30
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Differential Expression Genes of the Head Kidney and Spleen in Streptococcus iniae-Infected East Asian Fourfinger Threadfin Fish ( Eleutheronema tetradactylum). Int J Mol Sci 2023; 24:ijms24043832. [PMID: 36835242 PMCID: PMC9958670 DOI: 10.3390/ijms24043832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 02/03/2023] [Accepted: 02/10/2023] [Indexed: 02/17/2023] Open
Abstract
Streptococcus iniae is a Gram-positive bacterium and is considered a harmful aquaculture pathogen worldwide. In this study, S. iniae strains were isolated from East Asian fourfinger threadfin fish (Eleutheronema tetradactylum) reared on a farm in Taiwan. A transcriptome analysis of the head kidney and spleen was performed in the fourfinger threadfin fish 1 day after infection using the Illumina HiSeq™ 4000 platform for RNA-seq to demonstrate the host immune mechanism against S. iniae. A total of 7333 genes based on the KEGG database were obtained after the de novo assembly of transcripts and functional annotations. Differentially expressed genes (DEGs) (2-fold difference) were calculated by comparing the S. iniae infection and phosphate-buffered saline control group gene expression levels in each tissue sample. We identified 1584 and 1981 differentially expressed genes in the head kidney and spleen, respectively. Based on Venn diagrams, 769 DEGs were commonly identified in both the head kidney and spleen, and 815 and 1212 DEGs were specific to the head kidney and spleen, respectively. The head-kidney-specific DEGs were enriched in ribosome biogenesis. The spleen-specific and common DEGs were found to be significantly enriched in immune-related pathways such as phagosome, Th1, and Th2 cell differentiation; complement and coagulation cascades; hematopoietic cell lineage; antigen processing and presentation; and cytokine-cytokine receptor interactions, based on the KEGG database. These pathways contribute to immune responses against S. iniae infection. Inflammatory cytokines (IL-1β, IL-6, IL-11, IL-12, IL-35, and TNF) and chemokines (CXCL8 and CXCL13) were upregulated in the head kidney and spleen. Neutrophil-related genes, including phagosomes, were upregulated post-infection in the spleen. Our results could offer a strategy for the treatment and prevention of S. iniae infection in fourfinger threadfin fish.
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Shen M, Fan X, Shen Y, Wang X, Wu R, Wang Y, Huang C, Zhao S, Zheng Y, Men R, Luo X, Yang L. Myeloid-derived suppressor cells ameliorate liver mitochondrial damage to protect against autoimmune hepatitis by releasing small extracellular vesicles. Int Immunopharmacol 2023; 114:109540. [PMID: 36516541 DOI: 10.1016/j.intimp.2022.109540] [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: 07/25/2022] [Revised: 11/22/2022] [Accepted: 12/01/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Autoimmune hepatitis (AIH) is an inflammatory liver disease that is associated with impaired self-tolerance. Myeloid-derived supprfessor cells (MDSCs) have been considered to exert counterregulatory effects on AIH. However, the specific mechanism underlying these effects is unclear. Herein, we investigated the efficacy and safety of MDSCs in protecting against AIH and explored the underlying mechanism. METHODS Circulating and liver MDSC expression levels in 71 AIH patients and 47 healthy control (HC) individuals were detected by flow cytometry and immunohistochemistry. The adoptive transfer of induced bone marrow-derived MDSCs (BM MDSCs) to AIH mice was used to explore the function of MDSCs. Hepatic injury and mitochondrial damage were evaluated by transaminase levels, histopathology, immunohistochemistry, transmission electron microscopy and western blotting. MDSCs were pretreated with the small extracellular vesicle (sEV) generation inhibitor GW4869 to explore the mechanism. Importantly, sEVs derived from MDSCs and MDSCs-GW4869 were injected into model mice to monitor mitochondrial function and biogenesis. RESULTS Circulating and liver MDSCs were expanded in AIH patients and mouse model. Furthermore, the follow-up data of AIH patients showed that immunosuppressive therapy further promoted the expansion of MDSCs. More importantly, the adoptive transfer of BM MDSCs to AIH mice effectively ameliorated liver injury and regulated the imbalance of the immune microenvironment. Additionally, BM MDSCs reduced liver mitochondrial damage and improved mitochondrial biogenesis. Mechanistically, sEVs derived from BM MDSCs showed the same biological effects as cells, and blocking sEV production weakened the function of BM MDSCs. Finally, multiple long-term administrations of BM MDSCs were proven to be safe in general. CONCLUSION In conclusion, MDSCs ameliorate liver mitochondrial damage to protect against autoimmune hepatitis by releasing small extracellular vesicles.
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Affiliation(s)
- Mengyi Shen
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoli Fan
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yi Shen
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoze Wang
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ruiqi Wu
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yi Wang
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chen Huang
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Shenglan Zhao
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yanyi Zheng
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Ruoting Men
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xuefeng Luo
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Li Yang
- Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, Frontiers Science Center for Disease-related Molecular Network, Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Sieow JL, Penny HL, Gun SY, Tan LQ, Duan K, Yeong JPS, Pang A, Lim D, Toh HC, Lim TKH, Engleman E, Rotzschke O, Ng LG, Chen J, Tan SM, Wong SC. Conditional Knockout of Hypoxia-Inducible Factor 1-Alpha in Tumor-Infiltrating Neutrophils Protects against Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2023; 24:ijms24010753. [PMID: 36614196 PMCID: PMC9821271 DOI: 10.3390/ijms24010753] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 12/21/2022] [Accepted: 12/24/2022] [Indexed: 01/04/2023] Open
Abstract
Large numbers of neutrophils infiltrate tumors and comprise a notable component of the inflammatory tumor microenvironment. While it is established that tumor cells exhibit the Warburg effect for energy production, the contribution of the neutrophil metabolic state to tumorigenesis is unknown. Here, we investigated whether neutrophil infiltration and metabolic status promotes tumor progression in an orthotopic mouse model of pancreatic ductal adenocarcinoma (PDAC). We observed a large increase in the proportion of neutrophils in the blood and tumor upon orthotopic transplantation. Intriguingly, these tumor-infiltrating neutrophils up-regulated glycolytic factors and hypoxia-inducible factor 1-alpha (HIF-1α) expression compared to neutrophils from the bone marrow and blood of the same mouse. This enhanced glycolytic signature was also observed in human PDAC tissue samples. Strikingly, neutrophil-specific deletion of HIF-1α (HIF-1αΔNφ) significantly reduced tumor burden and improved overall survival in orthotopic transplanted mice, by converting the pro-tumorigenic neutrophil phenotype to an anti-tumorigenic phenotype. This outcome was associated with elevated reactive oxygen species production and activated natural killer cells and CD8+ cytotoxic T cells compared to littermate control mice. These data suggest a role for HIF-1α in neutrophil metabolism, which could be exploited as a target for metabolic modulation in cancer.
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Affiliation(s)
- Je Lin Sieow
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| | - Hweixian Leong Penny
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Sin Yee Gun
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Ling Qiao Tan
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Kaibo Duan
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Joe Poh Sheng Yeong
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
- Department of Anatomical Pathology, Singapore General Hospital, Singapore 169856, Singapore
| | - Angela Pang
- Department of Haematology-Oncology, National University Cancer Institute, Singapore 119228, Singapore
| | - Diana Lim
- Department of Pathology, National University Health System, Singapore 119074, Singapore
| | - Han Chong Toh
- Department of Oncology, National Cancer Centre, Singapore 169610, Singapore
| | - Tony Kiat Hon Lim
- Department of Anatomical Pathology, Singapore General Hospital, Singapore 169856, Singapore
| | - Edgar Engleman
- Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Olaf Rotzschke
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Lai Guan Ng
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Jinmiao Chen
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
| | - Suet Mien Tan
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
| | - Siew Cheng Wong
- Singapore Immunology Network, Agency for Science, Technology and Research (A*STAR), Singapore 138648, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore
- Correspondence: ; Tel.: +65-64070030
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Modified method for differentiation of myeloid-derived suppressor cells in vitro enhances immunosuppressive ability via glutathione metabolism. Biochem Biophys Rep 2022; 33:101416. [PMID: 36605123 PMCID: PMC9807831 DOI: 10.1016/j.bbrep.2022.101416] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 12/29/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs), which accumulate in tumor bearers, are known to suppress anti-tumor immunity and thus promote tumor progression. MDSCs are considered a major cause of resistance against immune checkpoint inhibitors in patients with cancer. Therefore, MDSCs are potential targets in cancer immunotherapy. In this study, we modified an in vitro method of MDSC differentiation. Upon stimulating bone marrow (BM) cells with granulocyte-macrophage colony-stimulating factor in vitro, we obtained both lymphocyte antigen 6G positive (Ly-6G+) and negative (Ly-6G-) MDSCs (collectively, hereafter referred to as conventional MDSCs), which were non-immunosuppressive and immunosuppressive, respectively. We then found that MDSCs differentiated from Ly-6G- BM (hereafter called 6G- BM-MDSC) suppressed T-cell proliferation more strongly than conventional MDSCs, whereas the cells differentiated from Ly-6G+ BM (hereafter called 6G+ BM-MDSC) were non-immunosuppressive. In line with this, conventional MDSCs or 6G- BM-MDSC, but not 6G+ BM-MDSC, promoted tumor progression in tumor-bearing mice. Moreover, we identified that activated glutathione metabolism was responsible for the enhanced immunosuppressive ability of 6G- BM-MDSC. Finally, we showed that Ly-6G+ cells in 6G- BM-MDSC, which exhibited weak immunosuppression, expressed higher levels of Cybb mRNA, an immunosuppressive gene of MDSCs, than 6G+ BM-MDSC. Together, these data suggest that the depletion of Ly-6G+ cells from the BM cells leads to differentiation of immunosuppressive Ly-6G+ MDSCs. In summary, we propose a better method for MDSC differentiation in vitro. Moreover, our findings contribute to the understanding of MDSC subpopulations and provide a basis for further research on MDSCs.
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Key Words
- Ab, antibody
- BM, bone marrow
- BM-MDSC
- CTLA-4, cytotoxic T-lymphocyte-associated protein 4
- Cybb, Cytochrome b-245 beta polypeptide
- FBS, fetal bovine serum
- GM-CSF, granulocyte-macrophage colony-stimulating factor
- Glutathione metabolism
- ICI, immune checkpoint inhibitor
- Immunosuppression
- Ly-6G
- Ly-6G, lymphocyte antigen 6G
- M-MDSCs, monocytic MDSCs
- MDSCs, myeloid-derived suppressor cells
- Myeloid-derived suppressor cell
- PBS, phosphate-buffered saline
- PD-1, programmed cell death 1
- PD-L1, programmed cell death 1 ligand 1
- PMN-MDSCs, polymorphonuclear MDSCs
- ROS, reactive oxygen species
- Rb1, retinoblastoma 1
- Tumor progression
- iNOS, inducible nitric oxide synthase
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Ghobadinezhad F, Ebrahimi N, Mozaffari F, Moradi N, Beiranvand S, Pournazari M, Rezaei-Tazangi F, Khorram R, Afshinpour M, Robino RA, Aref AR, Ferreira LMR. The emerging role of regulatory cell-based therapy in autoimmune disease. Front Immunol 2022; 13:1075813. [PMID: 36591309 PMCID: PMC9795194 DOI: 10.3389/fimmu.2022.1075813] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 11/28/2022] [Indexed: 12/23/2022] Open
Abstract
Autoimmune disease, caused by unwanted immune responses to self-antigens, affects millions of people each year and poses a great social and economic burden to individuals and communities. In the course of autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, and multiple sclerosis, disturbances in the balance between the immune response against harmful agents and tolerance towards self-antigens lead to an immune response against self-tissues. In recent years, various regulatory immune cells have been identified. Disruptions in the quality, quantity, and function of these cells have been implicated in autoimmune disease development. Therefore, targeting or engineering these cells is a promising therapeutic for different autoimmune diseases. Regulatory T cells, regulatory B cells, regulatory dendritic cells, myeloid suppressor cells, and some subsets of innate lymphoid cells are arising as important players among this class of cells. Here, we review the roles of each suppressive cell type in the immune system during homeostasis and in the development of autoimmunity. Moreover, we discuss the current and future therapeutic potential of each one of these cell types for autoimmune diseases.
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Affiliation(s)
- Farbod Ghobadinezhad
- Student Research Committee, Kermanshah University of Medical Sciences, Kermanshah, Iran,Universal Scientific Education and Research Network (USERN) Office, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Nasim Ebrahimi
- Division of Genetics, Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Fatemeh Mozaffari
- Department of Nutrition, School of Medicine, Zabol University of Medical Sciences, Zabol, Iran
| | - Neda Moradi
- Division of Biotechnology, Department of Cell and Molecular Biology and Microbiology, Nourdanesh Institute of Higher Education, University of Meymeh, Isfahan, Iran
| | - Sheida Beiranvand
- Department of Biology, Faculty of Basic Sciences, Islamic Azad University, Shahrekord, Iran
| | - Mehran Pournazari
- Clinical Research Development Center, Imam Reza Hospital, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Maral Afshinpour
- Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, United States
| | - Rob A. Robino
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States,Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States,Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States,Xsphera Biosciences, Boston, MA, United States,*Correspondence: Leonardo M. R. Ferreira, ; Amir Reza Aref,
| | - Leonardo M. R. Ferreira
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, United States,Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, United States,Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States,*Correspondence: Leonardo M. R. Ferreira, ; Amir Reza Aref,
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Ding Y, Wang Z, Zhou F, Chen C, Qin Y. Associating resistance to immune checkpoint inhibitors with immunological escape in colorectal cancer. Front Oncol 2022; 12:987302. [PMID: 36248998 PMCID: PMC9561929 DOI: 10.3389/fonc.2022.987302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 09/13/2022] [Indexed: 11/13/2022] Open
Abstract
Colorectal cancer is a common malignant tumor that ranks third in incidence and second in mortality worldwide, and surgery in conjunction with chemotherapy and radiotherapy remains the most common treatment option. As a result of radiotherapy’s severe side effects and dismal survival rates, it is anticipated that more alternatives may emerge. Immunotherapy, a breakthrough treatment, has made significant strides in colorectal cancer over the past few years, overcoming specialized therapy, which has more selectivity and a higher survival prognosis than chemoradiotherapy. Among these, immune checkpoint inhibitor therapy has emerged as the primary immunotherapy for colorectal cancer nowadays. Nonetheless, as the use of immune checkpoint inhibitor has expanded, resistance has arisen inevitably. Immune escape is the primary cause of non-response and resistance to immune checkpoint inhibitors. That is the development of primary and secondary drug resistance. In this article, we cover the immune therapy-related colorectal cancer staging, the specific immune checkpoint inhibitors treatment mechanism, and the tumor microenvironment and immune escape routes of immunosuppressive cells that may be associated with immune checkpoint inhibitors resistance reversal. The objective is to provide better therapeutic concepts for clinical results and to increase the number of individuals who can benefit from colorectal cancer immunotherapy.
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Affiliation(s)
- Yi Ding
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zehua Wang
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Fengmei Zhou
- Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China
| | - Chen Chen
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yanru Qin
- Department of Oncology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- *Correspondence: Yanru Qin,
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Ma S, Qin L, Wang X, Wang W, Li J, Wang H, Li H, Cai X, Yang Y, Qu M. The expression of VISTA on CD4+ T cells associate with poor prognosis and immune status in non-small cell lung cancer patients. Bosn J Basic Med Sci 2022; 22:707-715. [PMID: 35122478 PMCID: PMC9519165 DOI: 10.17305/bjbms.2021.6531] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 01/19/2022] [Indexed: 11/16/2022] Open
Abstract
Besides the two main histologic types of papillary thyroid carcinoma (PTC), the classical PTC (CL-PTC) and the follicular variant PTC (FV-PTC), several other variants are described. The encapsulated FV-PTC variant was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its similarities to benign lesions. Specific molecular signatures, however, are still unavailable. It is well known that improper DNA repair of dysfunctional telomeres may cause telomere-related genome instability. The mechanisms involved in the damaged telomere repair processing may lead to detrimental outcomes, altering the three-dimensional (3D) nuclear telomere and genome organization in cancer cells. This pilot study aimed to evaluate whether a specific 3D nuclear telomere architecture might characterize NIFTP, potentially distinguishing it from other PTC histologic variants. Our findings demonstrate that 3D telomere profiles of CL-PTC and FV-PTC were different from NIFTP and that NIFTP more closely resembles follicular thyroid adenoma (FTA). NIFTP has longer telomeres than CL-PTC and FV-PTC samples, and the telomere length of NIFTP overlaps with that of the FTA histotype. In contrast, there was no association between BRAF expression and telomere length in all tested samples. These preliminary findings reinforce the view that NIFTP is closer to non-malignant thyroid nodules and confirm that PTC features short telomeres.
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Affiliation(s)
- Shengyao Ma
- School of Pharmacy, School of Life Science and Technology, Weifang Medical University, Weifang, China
- Translational Medical Center, Weifang Second People’s Hospital, The Second Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Liya Qin
- School of Pharmacy, School of Life Science and Technology, Weifang Medical University, Weifang, China
- Translational Medical Center, Weifang Second People’s Hospital, The Second Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xinling Wang
- Translational Medical Center, Weifang Second People’s Hospital, The Second Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Weiyu Wang
- Translational Medical Center, Weifang Second People’s Hospital, The Second Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Jinfeng Li
- Cancer Research Institute of The Fifth Medical Center, The General Hospital of the PLA, Beijing, China
| | - Huaijie Wang
- Translational Medical Center, Weifang Second People’s Hospital, The Second Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Hanyue Li
- School of Pharmacy, School of Life Science and Technology, Weifang Medical University, Weifang, China
- Translational Medical Center, Weifang Second People’s Hospital, The Second Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaoshan Cai
- Translational Medical Center, Weifang Second People’s Hospital, The Second Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yang Yang
- School of Public Health, Qingdao University, Qingdao, China
| | - Meihua Qu
- Translational Medical Center, Weifang Second People’s Hospital, The Second Affiliated Hospital of Weifang Medical University, Weifang, China
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Immune landscape after allo-HSCT: TIGIT- and CD161-expressing CD4 T cells are associated with subsequent leukemia relapse. Blood 2022; 140:1305-1321. [PMID: 35820057 DOI: 10.1182/blood.2022015522] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Accepted: 06/27/2022] [Indexed: 11/20/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective treatment for selected patients with acute myeloid leukemia (AML) and relies on a "graft-versus-leukemia" effect (GVL) where donor T lymphocytes mediate control of malignant cell growth. However, relapse remains the major cause of death after allo-HSCT. In various malignancies, several immunoregulatory mechanisms have been shown to restrain antitumor immunity, including ligand-mediated engagement of inhibitory receptors (IRs) on effector cells, and induction of immunosuppressive cell subsets, such as regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). Relapse after HSCT remains a major therapeutic challenge, but immunoregulatory mechanisms involved in restraining the GVL effect must be better deciphered in humans. We used mass cytometry to comprehensively characterize circulating leukocytes in 2 cohorts of patients after allo-HSCT. We first longitudinally assessed various immunoregulatory parameters highlighting specific trends, such as opposite dynamics between MDSCs and Tregs. More generally, the immune landscape was stable from months 3 to 6, whereas many variations occurred from months 6 to 12 after HSCT. Comparison with healthy individuals revealed that profound alterations in the immune equilibrium persisted 1 year after HSCT. Importantly, we found that high levels of TIGIT and CD161 expression on CD4 T cells at month 3 after HSCT were distinct features significantly associated with subsequent AML relapse in a second cross-sectional cohort. Altogether, these data provide global insights into the reconstitution of the immunoregulatory landscape after HSCT and highlight non-canonical IRs associated with relapse, which could open the path to new prognostic tools or therapeutic targets to restore subverted anti-AML immunity.
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Tayuwijaya K, Raharja SL, Rosana M, Nurhayati RW. Prognostic Factors Contributing to the Survival of Hematopoietic Stem Cell Transplantation in the General Population with Leukemia: a Systematic Review. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2022. [DOI: 10.1007/s40883-022-00269-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Monocytic myeloid-derived suppressive cells mitigate over-adipogenesis of bone marrow microenvironment in aplastic anemia by inhibiting CD8 + T cells. Cell Death Dis 2022; 13:620. [PMID: 35851002 PMCID: PMC9293984 DOI: 10.1038/s41419-022-05080-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 07/04/2022] [Accepted: 07/06/2022] [Indexed: 01/21/2023]
Abstract
Aplastic anemia (AA) is a blood disorder resulted from over-activated T-cell related hematopoietic failure, with the characterization of hypocellularity and enhanced adipogenic differentiation of mesenchymal stroma cells (MSCs) in bone marrow (BM). However, little is known about the relationship between immune imbalance and polarized adipogenic abnormity of BM microenvironment in this disease entity. In the present study, we differentiated BM-MSCs into osteoblastic or adipogenic lineages to mimic the osteo-adipogenic differentiation. Activated CD8+ T cells and interferon-γ (IFN-γ) were found to stimulate adipogenesis of BM-MSCs either in vitro or in vivo of AA mouse model. Interestingly, myeloid-derived suppressive cells (MDSCs), one of the immune-regulating populations, were decreased within BM of AA mice. We found that it was not CD11b+Ly6G+Ly6C- granulocytic-MDSCs (gMDSCs) but CD11b+Ly6G-Ly6C+ monocytic-MDSCs (mMDSCs) inhibiting both T cell proliferation and IFN-γ production via inducible nitric oxide synthetase (iNOS) pathway. Single-cell RNA-sequencing (scRNA-seq) of AA- and mMDSCs-treated murine BM cells revealed that mMDSCs transfusion could reconstitute BM hematopoietic progenitors by inhibiting T cells population and signature cytokines and decreasing immature Adipo-Cxcl12-abundant reticular cells within BM. Multi-injection of mMDSCs into AA mice reduced intra-BM T cells infiltration and suppressed BM adipogenesis, which subsequently restored the intra-BM immune balance and eventually prevented pancytopenia and hypo-hematopoiesis. In conclusion, adoptive transfusion of mMDSCs might be a novel immune-regulating strategy to treat AA, accounting for not only restoring the intra-BM immune balance but also improving stroma's multi-differentiating microenvironment.
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Stem Cells in the Tumor Immune Microenvironment -Part of the Cure or Part of the Disease? Ontogeny and Dichotomy of Stem and Immune Cells has Led to better Understanding. Stem Cell Rev Rep 2022; 18:2549-2565. [PMID: 35841518 DOI: 10.1007/s12015-022-10428-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/11/2022] [Indexed: 10/17/2022]
Abstract
Stem cells are at the basis of tissue homeostasis, hematopoiesis and various regenerative processes. Epigenetic changes in their somatically imprinted genes, prolonged exposure to mutagens/carcinogens or alteration of their niche can lead to the development of an enabling environment for tumor growth and progression. The involvement of stem cells in both health and disease becomes even more compelling with ontogeny as embryonic and extraembryonic stem cells which persist into adulthood in well established and specific niche may have distinct implications in tumorigenesis. Immune surveillance plays an important role in this interplay since the response of immune cells toward the oncogenic process can range from reactivity to placidity and even complicity, being orchestrated by intercellular molecular dialogues with the other key players of the tumor microenvironment. With the current understanding that every developing and adult tissue contains inherent stem and progenitor cells, in this manuscript we review the most relevant interactions carried out between the stem cells, tumor cells and immune cells in a bottom-up incursion through the tumor microenvironment beginning from the perivascular niche and going through the tumoral parenchyma and the related stroma. With the exploitation of various factors that influence the behavior of immune effectors toward stem cells and other resting cells in their niche, new therapeutic strategies to tackle the polarization of immune effectors toward a more immunogenic phenotype may arise.
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Sakowska J, Arcimowicz Ł, Jankowiak M, Papak I, Markiewicz A, Dziubek K, Kurkowiak M, Kote S, Kaźmierczak-Siedlecka K, Połom K, Marek-Trzonkowska N, Trzonkowski P. Autoimmunity and Cancer-Two Sides of the Same Coin. Front Immunol 2022; 13:793234. [PMID: 35634292 PMCID: PMC9140757 DOI: 10.3389/fimmu.2022.793234] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 04/12/2022] [Indexed: 02/06/2023] Open
Abstract
Autoimmune disease results from the immune response against self-antigens, while cancer develops when the immune system does not respond to malignant cells. Thus, for years, autoimmunity and cancer have been considered as two separate fields of research that do not have a lot in common. However, the discovery of immune checkpoints and the development of anti-cancer drugs targeting PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways proved that studying autoimmune diseases can be extremely helpful in the development of novel anti-cancer drugs. Therefore, autoimmunity and cancer seem to be just two sides of the same coin. In the current review, we broadly discuss how various regulatory cell populations, effector molecules, genetic predisposition, and environmental factors contribute to the loss of self-tolerance in autoimmunity or tolerance induction to cancer. With the current paper, we also aim to convince the readers that the pathways involved in cancer and autoimmune disease development consist of similar molecular players working in opposite directions. Therefore, a deep understanding of the two sides of immune tolerance is crucial for the proper designing of novel and selective immunotherapies.
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Affiliation(s)
- Justyna Sakowska
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | - Łukasz Arcimowicz
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Martyna Jankowiak
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
| | - Ines Papak
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Aleksandra Markiewicz
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
| | - Katarzyna Dziubek
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Małgorzata Kurkowiak
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | - Sachin Kote
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
| | | | - Karol Połom
- Department of Surgical Oncology, Medical University of Gdańsk, Gdańsk, Poland
| | - Natalia Marek-Trzonkowska
- International Centre for Cancer Vaccine Science, University of Gdańsk, Gdańsk, Poland
- Laboratory of Immunoregulation and Cellular Therapies, Department of Family Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Piotr Trzonkowski
- Department of Medical Immunology, Medical University of Gdańsk, Gdańsk, Poland
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Song Q, Nasri U, Zeng D. Steroid-Refractory Gut Graft-Versus-Host Disease: What We Have Learned From Basic Immunology and Experimental Mouse Model. Front Immunol 2022; 13:844271. [PMID: 35251043 PMCID: PMC8894323 DOI: 10.3389/fimmu.2022.844271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Accepted: 01/26/2022] [Indexed: 11/23/2022] Open
Abstract
Intestinal graft-versus-host disease (Gut-GVHD) is one of the major causes of mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). While systemic glucocorticoids (GCs) comprise the first-line treatment option, the response rate for GCs varies from 30% to 50%. The prognosis for patients with steroid-refractory acute Gut-GVHD (SR-Gut-aGVHD) remains dismal. The mechanisms underlying steroid resistance are unclear, and apart from ruxolitinib, there are no approved treatments for SR-Gut-aGVHD. In this review, we provide an overview of the current biological understanding of experimental SR-Gut-aGVHD pathogenesis, the advanced technology that can be applied to the human SR-Gut-aGVHD studies, and the potential novel therapeutic options for patients with SR-Gut-aGVHD.
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Affiliation(s)
- Qingxiao Song
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, United States
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, China
- *Correspondence: Qingxiao Song,
| | - Ubaydah Nasri
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, United States
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, United States
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA, United States
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Park SJ, Nam DE, Seong HC, Hahn YS. New Discovery of Myeloid-Derived Suppressor Cell's Tale on Viral Infection and COVID-19. Front Immunol 2022; 13:842535. [PMID: 35185933 PMCID: PMC8850309 DOI: 10.3389/fimmu.2022.842535] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 01/17/2022] [Indexed: 01/08/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are generated under biological stress such as cancer, inflammatory tissue damage, and viral infection. In recent years, with occurrence of global infectious diseases, new discovery on MDSCs functions has been significantly expanded during viral infection and COVID-19. For a successful viral infection, pathogens viruses develop immune evasion strategies to avoid immune recognition. Numerous viruses induce the differentiation and expansion of MDSCs in order to suppress host immune responses including natural killer cells, antigen presenting cells, and T-cells. Moreover, MDSCs play an important role in regulation of immunopathogenesis by balancing viral infection and tissue damage. In this review article, we describe the overview of immunomodulation and genetic regulation of MDSCs during viral infection in the animal model and human studies. In addition, we include up-to-date review of role of MDSCs in SARS-CoV-2 infection and COVID-19. Finally, we discuss potential therapeutics targeting MDSCs.
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Affiliation(s)
- Soo-Jeung Park
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
| | - Da-eun Nam
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
| | - Hae Chang Seong
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
| | - Young S. Hahn
- Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, VA, United States
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, United States
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Provan D, Semple JW. Recent advances in the mechanisms and treatment of immune thrombocytopenia. EBioMedicine 2022; 76:103820. [PMID: 35074629 PMCID: PMC8792416 DOI: 10.1016/j.ebiom.2022.103820] [Citation(s) in RCA: 76] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 11/30/2021] [Accepted: 01/07/2022] [Indexed: 01/09/2023] Open
Abstract
Primary immune thrombocytopenia is an autoimmune disease associated with a reduced peripheral blood platelet count. The phenotype is variable with some patients suffering no bleeding whilst others have severe bleeding which may be fatal. Variability in clinical behaviour and treatment responses reflects its complex underlying pathophysiology. Historically the management has relied heavily on immune suppression. Recent studies have shown that the older empirical immune suppressants fail to alter the natural history of the disease and are associated with a poor quality of life for patients. Newer treatments, such as the thrombopoietin receptor agonists, have transformed ITP care. They have high efficacy, are well tolerated and improve patients’ quality of life. A greater understanding of the underlying pathophysiology of this disorder has helped develop a number of new targeted therapies. These include inhibitors of the neonatal Fc receptor inhibitors, Bruton tyrosine kinase and complement pathway. Here we discuss the mechanisms underlying ITP and the new approach to ITP care.
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Affiliation(s)
- Drew Provan
- Centre for Immunology, Blizard Institute, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, London UK.
| | - John W Semple
- Division of Hematology and Transfusion Medicine, Lund University, Lund, Sweden; Clinical Immunology and Transfusion Medicine, Office of Medical Services, Region Skåne, Lund, Sweden; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
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Detection of Circulating and Tissue Myeloid-Derived Suppressor Cells (MDSC) by Flow Cytometry. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2422:247-261. [PMID: 34859411 DOI: 10.1007/978-1-0716-1948-3_17] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Flow cytometry allows the multiparameter analysis of heterogeneous cell populations and is an essential tool for detecting and characterizing different cell populations from peripheral blood and dissociated tissues. Myeloid-derived suppressor cells (MDSC) are a heterogeneous and plastic group of myeloid precursors with immune-suppressive capacity, which are a characteristic feature of chronic inflammation, such as cancer. The optimal measurement of MDSC levels could be used as a biomarker for clinicians for prognosis and/or management and for researchers to track and understand the role of MDSC in different pathological diseases.The criteria for defining MDSC include phenotypic surface markers, but ideally should also include the functional immunosuppressive effect on T cells, and, if possible, assessing the main biochemical and molecular features. Two major functional mechanisms to suppress T cell responses are the production of arginase-1 and reactive oxygen species (ROS) molecules. Here is presented a nine-parameter seven-color flow cytometric assay to identify and quantify MDSC from both peripheral blood mononuclear cells (PBMC) and dissociated tissue (e.g., tumor) by using fluorescence-tagged antibodies against surface markers. Also, the intracellular levels of arginase-1 and superoxide (O2-) content were performed to potentially distinguish their functional status.
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46
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Resolution of Inflammation in Acute Graft-Versus-Host-Disease: Advances and Perspectives. Biomolecules 2022; 12:biom12010075. [PMID: 35053223 PMCID: PMC8773806 DOI: 10.3390/biom12010075] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/21/2021] [Accepted: 12/29/2021] [Indexed: 02/04/2023] Open
Abstract
Inflammation is an essential reaction of the immune system to infections and sterile tissue injury. However, uncontrolled or unresolved inflammation can cause tissue damage and contribute to the pathogenesis of various inflammatory diseases. Resolution of inflammation is driven by endogenous molecules, known as pro-resolving mediators, that contribute to dampening inflammatory responses, promoting the resolution of inflammation and the recovery of tissue homeostasis. These mediators have been shown to be useful to decrease inflammatory responses and tissue damage in various models of inflammatory diseases. Graft-versus-host disease (GVHD) is a major unwanted reaction following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is characterized by an exacerbated inflammatory response provoked by antigen disparities between transplant recipient and donor. There is no fully effective treatment or prophylaxis for GVHD. This review explores the effects of several pro-resolving mediators and discusses their potential use as novel therapies in the context of GVHD.
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Michniacki TF, Choi SW, Peltier DC. Immune Suppression in Allogeneic Hematopoietic Stem Cell Transplantation. Handb Exp Pharmacol 2022; 272:209-243. [PMID: 34628553 PMCID: PMC9055779 DOI: 10.1007/164_2021_544] [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] [Indexed: 01/03/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for high-risk hematologic disorders. There are multiple immune-mediated complications following allo-HSCT that are prevented and/or treated by immunosuppressive agents. Principal among these immune-mediated complications is acute graft-versus-host disease (aGVHD), which occurs when the new donor immune system targets host tissue antigens. The immunobiology of aGVHD is complex and involves all aspects of the immune system. Due to the risk of aGVHD, immunosuppressive aGVHD prophylaxis is required for nearly all allogeneic HSCT recipients. Despite prophylaxis, aGVHD remains a major cause of nonrelapse mortality. Here, we discuss the clinical features of aGVHD, the immunobiology of aGVHD, the immunosuppressive therapies used to prevent and treat aGVHD, how to mitigate the side effects of these immunosuppressive therapies, and what additional immune-mediated post-allo-HSCT complications are also treated with immunosuppression.
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Affiliation(s)
- Thomas F Michniacki
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA
| | - Sung Won Choi
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Daniel C Peltier
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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Li X, Li Y, Yu Q, Xu L, Fu S, Wei C, Wang L, Luo Y, Shi J, Qian P, Huang H, Lin Y. mTOR Signaling Regulates the Development and Therapeutic Efficacy of PMN-MDSCs in Acute GVHD. Front Cell Dev Biol 2021; 9:741911. [PMID: 35004668 PMCID: PMC8733691 DOI: 10.3389/fcell.2021.741911] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 11/19/2021] [Indexed: 12/13/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) represent a population of heterogeneous myeloid cells, which are characterized by their remarkable ability to suppress T cells and natural killer cells. MDSCs have been proven to play a positive role in protecting acute graft-versus-host disease (aGVHD). Here, we aimed to describe the mechanism behind how mTOR signaling regulates MDSCs' generation and explore its prophylactic and therapeutic potential in aGVHD. Reducing mTOR expression retains myeloid cells with immature characteristics and promotes polymorphonuclear MDSC (PMN-MDSC) immunosuppressive function through STAT3-C/EBPβ pathway. Prophylactic transfusion of mTORKO PMN-MDSCs could alleviate aGVHD while maintaining the graft-versus-leukemia (GVL) effect, which could downregulate the Th1/Th2 ratio, decrease serum proinflammatory cytokines, and increase the proportion of regulatory T cells (Tregs) in aGVHD models at the early stage after transplantation. Moreover, transfusion therapy could promote the reconstruction and function of donor-derived PMN-MDSCs. Not only the percentage and the absolute number of donor-derived PMN-MDSCs significantly increased but also the immunosuppressive ability was much more robust compared to other groups. Altogether, these findings indicated that mTOR is an intrinsic regulator for PMN-MDSCs' differentiation and immunosuppressive function. Together, mTORKO PMN-MDSC transfusion can play a protective role in alleviating cytokine storm at the initial stage and promoting the quantitative and functional recoveries of donor-derived PMN-MDSCs in aGVHD.
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Affiliation(s)
- Xiaoqing Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yixue Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Qinru Yu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Lin Xu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Shan Fu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Cong Wei
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Limengmeng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yi Luo
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Jimin Shi
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Pengxu Qian
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yu Lin
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
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Third-party type 2 innate lymphoid cells prevent and treat GI tract GvHD. Blood Adv 2021; 5:4578-4589. [PMID: 34619767 PMCID: PMC8759141 DOI: 10.1182/bloodadvances.2020001514] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 09/02/2021] [Indexed: 01/01/2023] Open
Abstract
Weekly infusions of third-party ILC2s prevent, and to a lesser extent, treat GVHD via production of IL-13 and amphiregulin. ILC2-derived IL-13 targets both host cells and the donor hematopoietic cells. Acute graft-versus-host disease (aGVHD), mediated by the recognition of host major histocompatibility complex/peptide polymorphisms by donor T cells, remains a significant complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). aGVHD most commonly involves the gastrointestinal tract, liver, and skin; symptomatic aGVHD is treated with corticosteroids. Steroid-nonresponsive aGVHD is a significant problem for patients undergoing allo-HSCT, with <15% of these patients alive 1 year after diagnosis. Previously, we found that the infusion of donor innate lymphoid type 2 (ILC2) cells could prevent and treat aGVHD of the lower gastrointestinal tract with no effect on the graft-versus-leukemia response. This approach for clinical translation is cumbersome, as it would require the generation of donor-derived ILC2 cells for each recipient. Thus, the ability to use third-party ILC2 cells would provide an “off-the-shelf” reagent that could be used to treat and/or prevent aGVHD. Here, we show that third-party ILC2 cells enhance the survival of allo-HSCT recipients. Treatment required at least 4 weekly infusions of ILC2 cells. Mechanistically, we show that ILC2 cell function was completely lost if the cells could not express both interleukin-13 (IL-13) and amphiregulin. Finally, we show that the activity of IL-13 has a greater dependence on the expression of the IL-13R on host rather than donor bone marrow cells. The ability to generate third-party ILC2 cells offers a new avenue for the prevention of aGVHD.
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50
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Scheurer J, Kitt K, Huber HJ, Fundel-Clemens K, Pflanz S, Debatin KM, Strauss G. Graft-Versus-Host Disease Prevention by In Vitro-Generated Myeloid-Derived Suppressor Cells Is Exclusively Mediated by the CD11b+CD11c+ MDSC Subpopulation. Front Immunol 2021; 12:754316. [PMID: 34721430 PMCID: PMC8551363 DOI: 10.3389/fimmu.2021.754316] [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: 08/06/2021] [Accepted: 09/21/2021] [Indexed: 01/09/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells that dampen overwhelming adaptive immune responses through multiple mechanisms and are recognized as an attractive novel immune intervention therapy for counteracting the destructive effects of graft-
versus
-host disease (GVHD) developing after allogeneic bone marrow transplantation (BMT). MDSCs can be produced in great numbers for cellular therapy, but they present a mixture of subsets whose functions in GVHD prevention are undefined. Here, we generated MDSCs in vitro from murine BM cells in the presence of GM-CSF and defined the integrin CD11c as a marker to subdivide MDSCs into two functional subgroups: CD11b+CD11c+ and CD11b+CD11c− MDSCs. Isolated CD11b+CD11c+ and CD11b+CD11c− MDSCs both inhibited alloantigen-stimulated T-cell proliferation in vitro, although CD11b+CD11c+ MDSCs were more efficient and expressed higher levels of different immunosuppressive molecules. Likewise, expression of surface markers such as MHC class II, CD80, CD86, or PD-L1 further delineated both subsets. Most importantly, only the adoptive transfer of CD11b+CD11c+ MDSCs into a single MHC class I-disparate allogeneic BMT model prevented GVHD development and strongly decreased disease-induced mortality, while CD11b+CD11c− MDSCs were totally ineffective. Surprisingly, allogeneic T-cell homing and expansion in lymphatic and GVHD target organs were not affected by cotransplanted CD11b+CD11c+ MDSCs indicating a clear contradiction between in vitro and in vivo functions of MDSCs. However, CD11b+CD11c+ MDSCs shifted immune responses towards type 2 immunity reflected by increased Th2-specific cytokine expression of allogeneic T cells. Induction of type 2 immunity was mandatory for GVHD prevention, since CD11b+CD11c+ MDSCs were ineffective if recipients were reconstituted with STAT6-deficient T cells unable to differentiate into Th2 cells. Most importantly, the beneficial graft-
versus
-tumor (GVT) effect was maintained in the presence of CD11b+CD11c+ MDSCs since syngeneic tumor cells were efficiently eradicated. Strong differences in the transcriptomic landscape of both subpopulations underlined their functional differences. Defining CD11b+CD11c+ MDSCs as the subset of in vitro-generated MDSCs able to inhibit GVHD development might help to increase efficiency of MDSC therapy and to further delineate relevant target molecules and signaling pathways responsible for GVHD prevention.
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Affiliation(s)
- Jasmin Scheurer
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Kerstin Kitt
- Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma Co KG, Biberach an der Riss, Germany
| | - Heinrich J Huber
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma Co KG, Biberach an der Riss, Germany.,Drug Discovery Services, Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG, Vienna, Austria
| | - Katrin Fundel-Clemens
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma Co KG, Biberach an der Riss, Germany
| | - Stefan Pflanz
- Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma Co KG, Biberach an der Riss, Germany
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Gudrun Strauss
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
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