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Heo BY, Koh JS, Choi SY, Pham TTD, Lee SW, Park JH, Jang Y, Lee MW, Lee SB, Seo W, Jo DY, Kwon J, Song IC. Comparison of Regulatory T-Cell Subpopulations in Antithymocytic Globulin Versus Post-Transplant Cyclophosphamide for Preventing Graft-Versus-Host Disease in Allogeneic Hematopoietic Stem Cell Transplantation-A Retrospective Study. Int J Mol Sci 2025; 26:2521. [PMID: 40141165 PMCID: PMC11941908 DOI: 10.3390/ijms26062521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 02/26/2025] [Accepted: 03/04/2025] [Indexed: 03/28/2025] Open
Abstract
Antithymocytic globulin (ATG) and post-transplant cyclophosphamide (PTCy) are frequently used regimens for graft-versus-host disease (GVHD) prophylaxis. However, there is a lack of data about the difference in regulatory T-cell (Treg) subpopulations between these two regimens. Peripheral blood samples were collected on day +21 following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), and the Treg subpopulations were analyzed using flow cytometry. The Treg populations were categorized into three distinct subgroups: naïve, effector, and non-suppressive. And we compared overall survival (OS), the cumulative incidence of acute and chronic GVHD, and the relapse rate between the ATG and PTCy groups. We enrolled 45 patients (28 in ATG, 17 in PTCy) in total. In the ATG group, 16 and 12 patients underwent human leukocyte antigen (HLA) matched-sibling donor and unrelated donor HSCT, respectively. In the PTCy group, 12 patients underwent haplo-identical HSCT, and 5 patients underwent HLA-matched unrelated donor HSCT. The cumulative incidence of Grade 2-4 acute GVHD was 18.3% in the ATG group compared to 38.1% in the PTCy group (p = 0.13), while severe chronic GVHD occurred in 19.4% of ATG patients and 41.7% of PTCy patients (p = 0.343). And OS and the relapse rate were not statistically different between the two groups. The conventional CD25+FOXP3+Treg count of CD4 + T cells was higher in the PTCy group than in the ATG group (p = 0.0020). The effector Treg subset was significantly higher in the PTCy group than in the ATG group (p = 0.0412). And the effector Treg cell count had an inverse correlation with the severity of acute GVHD (p = 0.0007). Effector Tregs may be used as a biomarker to predict the severity of acute GVHD after allo-HSCT.
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Affiliation(s)
- Bu-Yeon Heo
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (B.-Y.H.); (S.-Y.C.); (T.T.D.P.); (S.-W.L.)
- Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Jeong Suk Koh
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 34134, Republic of Korea; (J.S.K.); (M.-W.L.); (S.-B.L.); (W.S.); (D.-Y.J.)
| | - Su-Young Choi
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (B.-Y.H.); (S.-Y.C.); (T.T.D.P.); (S.-W.L.)
- Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Thi Thuy Duong Pham
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (B.-Y.H.); (S.-Y.C.); (T.T.D.P.); (S.-W.L.)
- Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
| | - Sang-Woo Lee
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (B.-Y.H.); (S.-Y.C.); (T.T.D.P.); (S.-W.L.)
| | - Jung-Hyun Park
- Translational Immunology Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (J.-H.P.); (Y.J.)
| | - Yunseon Jang
- Translational Immunology Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (J.-H.P.); (Y.J.)
| | - Myung-Won Lee
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 34134, Republic of Korea; (J.S.K.); (M.-W.L.); (S.-B.L.); (W.S.); (D.-Y.J.)
| | - Seul-Bi Lee
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 34134, Republic of Korea; (J.S.K.); (M.-W.L.); (S.-B.L.); (W.S.); (D.-Y.J.)
| | - Wonhyoung Seo
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 34134, Republic of Korea; (J.S.K.); (M.-W.L.); (S.-B.L.); (W.S.); (D.-Y.J.)
| | - Deog-Yeon Jo
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 34134, Republic of Korea; (J.S.K.); (M.-W.L.); (S.-B.L.); (W.S.); (D.-Y.J.)
| | - Jaeyul Kwon
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (B.-Y.H.); (S.-Y.C.); (T.T.D.P.); (S.-W.L.)
- Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Translational Immunology Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (J.-H.P.); (Y.J.)
| | - Ik-Chan Song
- Department of Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (B.-Y.H.); (S.-Y.C.); (T.T.D.P.); (S.-W.L.)
- Brain Korea 21 FOUR Project for Medical Science, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea
- Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 34134, Republic of Korea; (J.S.K.); (M.-W.L.); (S.-B.L.); (W.S.); (D.-Y.J.)
- Translational Immunology Institute, College of Medicine, Chungnam National University, Daejeon 35015, Republic of Korea; (J.-H.P.); (Y.J.)
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Dashwood A, Makuyana N, van der Kant R, Ghodsinia A, Hernandez AR, Lienart S, Burton O, Dooley J, Ali M, Kouser L, Naranjo F, Holt MG, Rousseau F, Schymkowitz J, Liston A. Directed disruption of IL2 aggregation and receptor binding sites produces designer biologics with enhanced specificity and improved production capacity. Comput Struct Biotechnol J 2025; 27:1112-1123. [PMID: 40190571 PMCID: PMC11968297 DOI: 10.1016/j.csbj.2025.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 02/28/2025] [Accepted: 03/01/2025] [Indexed: 04/09/2025] Open
Abstract
The pleotropic nature of interleukin-2 (IL2) has allowed it to be used as both a pro-inflammatory and anti-inflammatory therapeutic agent, through promotion of regulatory T cell (Treg) responses via the trimeric IL2RABG receptor or promotion of CD8 T cell responses via the dimeric IL2RBG receptor, respectively. However, the utility of IL2 as a treatment is limited by this same pleiotropy, and protein engineering to bias specificity towards either Treg or CD8 T cell lineage often requires a trade-off in protein production or total bioactivity. Here we use SolubiS and dTANGO, computational algorithm-based methods, to predict mutations within the IL2 structure to improve protein production yield in muteins with altered cellular selectivity, to generate combined muteins with elevated therapeutic potential. The design and testing process identified the V106R (murine) / V91R (human) mutation as a Treg-enhancing mutein, creating a cation repulsion to inhibit primary binding to IL2RB, with a post-IL2RA confirmational shift enabling secondary IL2RB binding, and hence allowing the trimeric receptor complex to form. In human IL2, additional N90R T131R aggregation-protecting mutations could improve protein yield of the V91R mutation. The approach also generated novel CD8 T cell-promoting mutations. Y59K created a cation-cation repulsion with IL2RA, while Q30W enhanced CD8 T cell activity through potential π-stacking enhancing binding to IL2RB, with the combination highly stimulatory for CD8 T cells. For human IL2, Y45K (homolog to murine Y59K) coupled with E62K prevented IL2RA binding, however it required the aggregation-protecting mutations of N90R T131R to rescue production. These muteins, designed with both cellular specificity and protein production features, have potential as both biological tools and therapeutics.
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Affiliation(s)
- Amy Dashwood
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
- Immunology Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Ntombizodwa Makuyana
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
- Immunology Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Rob van der Kant
- KU Leuven, Leuven, Belgium
- VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Arman Ghodsinia
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - Alvaro R. Hernandez
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
- Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Stephanie Lienart
- Immunology Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Oliver Burton
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
- Immunology Programme, The Babraham Institute, Cambridge, United Kingdom
| | - James Dooley
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
- Immunology Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Magda Ali
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
| | - Lubna Kouser
- Immunology Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Francisco Naranjo
- Immunology Programme, The Babraham Institute, Cambridge, United Kingdom
| | - Matthew G. Holt
- KU Leuven, Leuven, Belgium
- VIB Center for Brain and Disease Research, Leuven, Belgium
- Instituto de Investigação e Inovação em Saúde (i3S), University of Porto, Porto, Portugal
| | - Frederic Rousseau
- KU Leuven, Leuven, Belgium
- VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Joost Schymkowitz
- KU Leuven, Leuven, Belgium
- VIB Center for Brain and Disease Research, Leuven, Belgium
| | - Adrian Liston
- Department of Pathology, University of Cambridge, Cambridge, United Kingdom
- Immunology Programme, The Babraham Institute, Cambridge, United Kingdom
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Woodward CH, Solieva SO, Hwang D, De Paula VS, Fabilane CS, Young MC, Trent T, Teeley EC, Majumdar A, Spangler JB, Bowman GR, Sgourakis NG. Regulating IL-2 Immune Signaling Function Via A Core Allosteric Structural Network. J Mol Biol 2025; 437:168892. [PMID: 39662679 PMCID: PMC12077578 DOI: 10.1016/j.jmb.2024.168892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Revised: 11/16/2024] [Accepted: 12/02/2024] [Indexed: 12/13/2024]
Abstract
Human interleukin-2 (IL-2) is a crucial cytokine for T cell regulation, with therapeutic potential in cancer and autoimmune diseases. However, IL-2's pleiotropic effects across different immune cell types often lead to toxicity and limited efficacy. Previous efforts to enhance IL-2's therapeutic profile have focused on modifying its receptor binding sites. Yet, the underlying dynamics and intramolecular networks contributing to IL-2 receptor recognition remain unexplored. This study presents a detailed characterization of IL-2 dynamics compared to two engineered IL-2 mutants, "superkines" S15 and S1, which exhibit biased signaling towards effector T cells. Using NMR spectroscopy and molecular dynamics simulations, we demonstrate significant variations in core dynamic pathways and conformational exchange rates across these three IL-2 variants. We identify distinct allosteric networks and minor state conformations in the superkines, despite their structural similarity to wild-type IL-2. Furthermore, we rationally design a mutation (L56A) in the S1 superkine's core network, which partially reverts its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2. Our results reveal that IL-2 superkine core dynamics play a critical role in their enhanced receptor binding and function, suggesting that modulating IL-2 dynamics and core allostery represents an untapped approach for designing immunotherapies with improved immune cell selectivity profiles.
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Affiliation(s)
- Claire H Woodward
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Shahlo O Solieva
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Daniel Hwang
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Viviane S De Paula
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Charina S Fabilane
- Translational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Program in Molecular Biophysics, Johns Hopkins University, Baltimore, MD, USA
| | - Michael C Young
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Tony Trent
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Ella C Teeley
- Department of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Ananya Majumdar
- Biomolecular NMR Center, Johns Hopkins University, Baltimore, MD, USA
| | - Jamie B Spangler
- Translational Tissue Engineering Center, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Chemical & Biomolecular Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA; Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Gregory R Bowman
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Nikolaos G Sgourakis
- Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, PA, USA; Center for Computational and Genomic Medicine, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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Elliott J, Koldej R, Khot A, Ritchie D. Graft-Versus-Host Disease Mouse Models: A Clinical-Translational Perspective. Methods Mol Biol 2025; 2907:1-56. [PMID: 40100591 DOI: 10.1007/978-1-0716-4430-0_1] [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] [Indexed: 03/20/2025]
Abstract
A variety of graft-versus-host disease (GVHD) models have been developed in mice for the purpose of allowing laboratory investigation of the pathobiology, prevention, and treatment of GVHD in humans. While such models are crucial in advancing our knowledge in this field, there are some key limitations that need to be considered when translating laboratory discoveries into the clinical context. This chapter will discuss current clinical practices in transplantation and GVHD and the relative strengths and weaknesses of mouse models that attempt to replicate these states.
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Affiliation(s)
- Jessica Elliott
- ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia.
- Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
- Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia.
| | - Rachel Koldej
- ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia
- Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
| | - Amit Khot
- Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
| | - David Ritchie
- ACRF Translational Research Laboratory, Royal Melbourne Hospital, Melbourne, VIC, Australia
- Department of Clinical Haematology, Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Medicine Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
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Geramita E, Hou JZ, Shlomchik WD, Ito S. Maintenance strategies for relapse prevention and treatment. HEMATOLOGY. AMERICAN SOCIETY OF HEMATOLOGY. EDUCATION PROGRAM 2024; 2024:635-643. [PMID: 39644024 DOI: 10.1182/hematology.2024000589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/09/2024]
Abstract
Posttransplant relapse is the most significant challenge in allogeneic stem cell transplantation (alloSCT). Posttransplant interventions, in conjunction with optimal conditioning regimens and donor selection, are increasingly supported by evidence for their potential to prolong patient survival by promoting antileukemia or graft-versus-leukemia effects. Our review begins by highlighting the current evidence supporting maintenance therapy for relapse prevention in acute myeloid leukemia and acute lymphocytic leukemia. This includes a broad spectrum of strategies, such as targeted therapies, hypomethylating agents, venetoclax, and immunotherapies. We then shift our focus to the role of disease monitoring after alloSCT, emphasizing the potential importance of early detection of measurable residual disease and a drop in donor chimerism. We also provide an overview of salvage therapies for overt relapse, including targeted therapies, chemotherapies, immunotherapies, donor lymphocyte infusion, and selected agents under investigation in ongoing clinical trials. Finally, we review the evidence for a second alloSCT (HSCT2) and discuss factors that impact donor selection for HSCT2.
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Affiliation(s)
- Emily Geramita
- Hematology and Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Jing-Zhou Hou
- Hematology and Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Warren D Shlomchik
- Hematology and Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
| | - Sawa Ito
- Hematology and Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA
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Ehx G, Ritacco C, Baron F. Pathophysiology and preclinical relevance of experimental graft-versus-host disease in humanized mice. Biomark Res 2024; 12:139. [PMID: 39543777 PMCID: PMC11566168 DOI: 10.1186/s40364-024-00684-9] [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: 08/27/2024] [Accepted: 11/06/2024] [Indexed: 11/17/2024] Open
Abstract
Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantations (allo-HCT) used for the treatment of hematological malignancies and other blood-related disorders. Until recently, the discovery of actionable molecular targets to treat GVHD and their preclinical testing was almost exclusively based on modeling allo-HCT in mice by transplanting bone marrow and splenocytes from donor mice into MHC-mismatched recipient animals. However, due to fundamental differences between human and mouse immunology, the translation of these molecular targets into the clinic can be limited. Therefore, humanized mouse models of GVHD were developed to circumvent this limitation. In these models, following the transplantation of human peripheral blood mononuclear cells (PBMCs) into immunodeficient mice, T cells recognize and attack mouse organs, inducing GVHD. Thereby, humanized mice provide a platform for the evaluation of the effects of candidate therapies on GVHD mediated by human immune cells in vivo. Understanding the pathophysiology of this xenogeneic GVHD is therefore crucial for the design and interpretation of experiments performed with this model. In this article, we comprehensively review the cellular and molecular mechanisms governing GVHD in the most commonly used model of xenogeneic GVHD: PBMC-engrafted NOD/LtSz-PrkdcscidIL2rγtm1Wjl (NSG) mice. By re-analyzing public sequencing data, we also show that the clonal expansion and the transcriptional program of T cells in humanized mice closely reflect those in humans. Finally, we highlight the strengths and limitations of this model, as well as arguments in favor of its biological relevance for studying T-cell reactions against healthy tissues or cancer cells.
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Affiliation(s)
- Grégory Ehx
- Laboratory of Hematology, GIGA Institute, University of Liege, Liege, Belgium.
- Walloon Excellence in Life Sciences and Biotechnology (WELBIO) Department, WEL Research Institute, Wavre, Belgium.
| | - Caroline Ritacco
- Laboratory of Hematology, GIGA Institute, University of Liege, Liege, Belgium
| | - Frédéric Baron
- Laboratory of Hematology, GIGA Institute, University of Liege, Liege, Belgium
- Department of Medicine, Division of Hematology, CHU of Liege, University of Liege, Liege, Belgium
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Najaf Khosravi H, Razi S, Rezaei N. The role of interleukin-2 in graft-versus-host disease pathogenesis, prevention and therapy. Cytokine 2024; 183:156723. [PMID: 39173281 DOI: 10.1016/j.cyto.2024.156723] [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: 05/31/2024] [Revised: 07/22/2024] [Accepted: 08/01/2024] [Indexed: 08/24/2024]
Abstract
Graft-versus-host disease (GVHD) is a significant complication following allogeneic hematopoietic cell transplantation (allo-HCT), posing substantial risks to patient survival. In the late follow-up phase of transplanted patients, GVHD is also a major cause of morbidity and disability, mostly due to low response to first-line steroids and the lack of effective standard therapies in the second line. This review provides a description of GVHD pathogenesis, with a focus on the central role of Interleukin-2 (IL-2). IL-2 is one of the critical mediators in the complex pathogenesis of GVHD, contributing to the intricate balance between regulatory T cells (Tregs) and effector T cells (Teffs). Due to this pivotal role, several studies investigate the potential of IL-2 as a therapeutic option for GVHD management. We discuss the outcomes of low-dose IL-2 therapies and their impact on Treg proliferation and steroid dependency reduction. Additionally, the effects of combining IL-2 with other treatments, such as extracorporeal photopheresis (ECP) and Treg-enriched lymphocyte infusions, are highlighted. Novel approaches, including modified IL-2 complexes and IL-2 receptor blockade, are explored for their potential in selectively enhancing Treg function and limiting Teff activation. The evolving understanding of IL-2's pivotal role in immune regulation presents promising prospects for applying treatment and prevention strategies for GVHD.
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Affiliation(s)
- Hila Najaf Khosravi
- Royan Institute for Stem Cell Biology and Technology, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Stockholm, Sweden.
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Shi Y, Hao D, Qian H, Tao Z. Natural killer cell-based cancer immunotherapy: from basics to clinical trials. Exp Hematol Oncol 2024; 13:101. [PMID: 39415291 PMCID: PMC11484118 DOI: 10.1186/s40164-024-00561-z] [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: 06/19/2024] [Accepted: 09/07/2024] [Indexed: 10/18/2024] Open
Abstract
Cellular immunotherapy exploits the capacity of the human immune system in self-protection and surveillance to achieve the anti-tumor effects. Natural killer (NK) cells are lymphocytes of innate immune system and they display a unique inherent ability to identify and eliminate tumor cells. In this review, we first introduce the basic characteristics of NK cells in the physiological and pathological milieus, followed by a discussion of their effector function and immunosuppression in the tumor microenvironment. Clinical strategies and reports regarding NK cellular therapy are analyzed in the context of tumor treatment, especially against solid tumors. Given the widely studied T-cell therapy in the recent years, particularly the chimeric antigen receptor (CAR) T-cell therapy, we compare the technical features of NK- and T-cell based tumor therapies at the clinical front. Finally, the technical challenges and potential solutions for both T and NK cell-based immunotherapies in treating tumor malignancies are delineated. By overviewing its clinical applications, we envision the NK-cell based immunotherapy as an up-and-comer in cancer therapeutics.
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Affiliation(s)
- Yinghong Shi
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated With Jiangsu University, Changzhou, 213017, Jiangsu, China
- Jiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China
| | - Donglin Hao
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated With Jiangsu University, Changzhou, 213017, Jiangsu, China.
| | - Hui Qian
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated With Jiangsu University, Changzhou, 213017, Jiangsu, China.
- Jiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
| | - Zhimin Tao
- Wujin Institute of Molecular Diagnostics and Precision Cancer Medicine of Jiangsu University, Wujin Hospital Affiliated With Jiangsu University, Changzhou, 213017, Jiangsu, China.
- Jiangsu Province Key Laboratory of Medical Science and Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, China.
- Department of Emergency Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, Jiangsu, China.
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Woodward CH, Solieva SO, Hwang D, De Paula VS, Fabilane CS, Young MC, Trent T, Teeley EC, Majumdar A, Spangler JB, Bowman GR, Sgourakis NG. Regulating IL-2 immune signaling function via a core allosteric structural network. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.07.617024. [PMID: 39416199 PMCID: PMC11482754 DOI: 10.1101/2024.10.07.617024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
Human interleukin-2 (IL-2) is a crucial cytokine for T cell regulation, with therapeutic potential in cancer and autoimmune diseases. However, IL-2's pleiotropic effects across different immune cell types often lead to toxicity and limited efficacy. Previous efforts to enhance IL-2's therapeutic profile have focused on modifying its receptor binding sites. Yet, the underlying dynamics and intramolecular networks contributing to IL-2 receptor recognition remain unexplored. This study presents a detailed characterization of IL-2 dynamics compared to two engineered IL-2 mutants, "superkines" S15 and S1, which exhibit biased signaling towards effector T cells. Using NMR spectroscopy and molecular dynamics simulations, we demonstrate significant variations in core dynamic pathways and conformational exchange rates across these three IL-2 variants. We identify distinct allosteric networks and excited state conformations in the superkines, despite their structural similarity to wild-type IL-2. Furthermore, we rationally design a mutation (L56A) in the S1 superkine's core network, which partially reverts its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2. Our results reveal that IL-2 superkine core dynamics play a critical role in their enhanced receptor binding and function, suggesting that modulating IL-2 dynamics and core allostery represents an untapped approach for designing immunotherapies with improved immune cell selectivity profiles. Highlights NMR and molecular dynamics simulations revealed distinct conformational dynamics and allosteric networks in computationally re-designed IL-2 superkines compared to wild-type IL-2, despite their similar crystal structures.The superkines S1 and S15 exhibit altered sampling of excited state conformations at an intermediate timescale, with slower conformational exchange rates compared to wild-type IL-2.A rationally designed mutation (L56A) in the S1 superkine's core allosteric network partially reverted its dynamics, receptor binding affinity, and T cell signaling behavior towards that of wild-type IL-2.Our study demonstrates that IL-2 core dynamics play a critical role in receptor binding and signaling function, providing a foundation for engineering more selective IL-2-based immunotherapies.
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10
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Amini L, Kaeda J, Weber O, Reinke P. Low-dose Interleukin-2 Therapy: Fine-tuning Treg in Solid Organ Transplantation? Transplantation 2024; 108:1492-1508. [PMID: 38294829 PMCID: PMC11188637 DOI: 10.1097/tp.0000000000004866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 09/29/2023] [Accepted: 10/05/2023] [Indexed: 02/01/2024]
Abstract
Regulatory T cells (Treg), a subset of CD4 + T cells, are potent regulators of immune reactions, which have been shown to be a promising therapeutic alternative to toxic immunosuppressive drugs. Data support the utility of Treg in managing immunopathologies, including solid organ transplant rejection, graft-versus-host disease, and autoimmune disorders. Notably, reports suggest that interleukin-2 (IL-2) is critical to survival of Treg, which constitutively express high levels of CD25, that is, the IL-2 receptor α-chain, and are exquisitely sensitive to IL-2, even at very low concentrations in contrast to effector T cells, which only upregulate IL-2 receptor α-chain on activation. This has led to the notion of using low doses of exogenous IL-2 therapeutically to modulate the immune system, specifically Treg numbers and function. Here, we summarize developments of clinical experience with low-dose IL-2 (LD-IL-2) as a therapeutic agent. So far, no clinical data are available to support the therapeutic use of LD-IL-2 therapy in the solid organ transplant setting. For the latter, fine-tuning by biotechnological approaches may be needed because of the narrow therapeutic window and off-target effects of LD-IL-2 therapy and so to realize the therapeutic potential of this molecule.
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Affiliation(s)
- Leila Amini
- Berlin Center for Advanced Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health – Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Jaspal Kaeda
- Berlin Center for Advanced Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Olaf Weber
- Institute of Molecular Medicine and Experimental Immunology (IMMEI), University of Bonn, Bonn, Germany
| | - Petra Reinke
- Berlin Center for Advanced Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute of Health – Center for Regenerative Therapies, Charité-Universitätsmedizin Berlin, Berlin, Germany
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11
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Pacini CP, Soares MVD, Lacerda JF. The impact of regulatory T cells on the graft-versus-leukemia effect. Front Immunol 2024; 15:1339318. [PMID: 38711496 PMCID: PMC11070504 DOI: 10.3389/fimmu.2024.1339318] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 04/08/2024] [Indexed: 05/08/2024] Open
Abstract
Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is the only curative therapy for many hematologic malignancies, whereby the Graft-versus-Leukemia (GVL) effect plays a pivotal role in controlling relapse. However, the success of GVL is hindered by Graft-versus-Host Disease (GVHD), where donor T cells attack healthy tissues in the recipient. The ability of natural regulatory T cells (Treg) to suppress immune responses has been exploited as a therapeutical option against GVHD. Still, it is crucial to evaluate if the ability of Treg to suppress GVHD does not compromise the benefits of GVL. Initial studies in animal models suggest that Treg can attenuate GVHD while preserving GVL, but results vary according to tumor type. Human trials using Treg as GVHD prophylaxis or treatment show promising results, emphasizing the importance of infusion timing and Treg/Tcon ratios. In this review, we discuss strategies that can be used aiming to enhance GVL post-Treg infusion and the proposed mechanisms for the maintenance of the GVL effect upon the adoptive Treg transfer. In order to optimize the therapeutic outcomes of Treg administration in allo-HSCT, future efforts should focus on refining Treg sources for infusion and evaluating their specificity for antigens mediating GVHD while preserving GVL responses.
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Affiliation(s)
- Carolina P. Pacini
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Maria V. D. Soares
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - João F. Lacerda
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, ULS Santa Maria, Lisbon, Portugal
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12
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Radi H, Ferdosi-Shahandashti E, Kardar GA, Hafezi N. An Updated Review of Interleukin-2 Therapy in Cancer and Autoimmune Diseases. J Interferon Cytokine Res 2024; 44:143-157. [PMID: 38421721 DOI: 10.1089/jir.2023.0178] [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] [Indexed: 03/02/2024] Open
Abstract
Interleukin-2 (IL-2) is a cytokine that acts in dual and paradoxical ways in the immunotherapy of cancers and autoimmune diseases. Numerous clinical trial studies have shown that the use of different doses of this cytokine in various autoimmune diseases, transplantations, and cancers has resulted in therapeutic success. However, side effects of varying severity have been observed in patients. In recent years, to prevent these side effects, IL-2 has been engineered to bind more specifically to its receptors on the cell surface, decreasing IL-2 toxicities in patients. In this review article, we focus on some recent clinical trial studies and analyze them to determine the appropriate dose of IL-2 drug with the least toxicities. In addition, we discuss the engineering performed on IL-2, which shows that engineered IL-2 increases the specificity function of IL-2 and decreases its adverse effects.
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Affiliation(s)
- Hale Radi
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
| | - Elaheh Ferdosi-Shahandashti
- Biomedical and Microbial Advanced Technologies (BMAT) Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Gholam Ali Kardar
- National Institute for Genetic Engineering and Biotechnology, Tehran University of Medical Sciences, Tehran, Iran
| | - Nasim Hafezi
- Cellular and Molecular Biology Research Center, Babol University of Medical Sciences, Babol, Iran
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13
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Ogando-Rivas E, Castillo P, Yang C, Trivedi V, Zhang D, Pohl-Guimarães F, Liu R, Barpujari A, Candelario KM, Mendez-Gomez H, Sayour EJ, Mitchell DA. Expanded specific T cells to hypomutated regions of the SARS-CoV-2 using mRNA electroporated antigen-presenting cells. Mol Ther Methods Clin Dev 2024; 32:101192. [PMID: 38327807 PMCID: PMC10847775 DOI: 10.1016/j.omtm.2024.101192] [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: 04/10/2023] [Accepted: 01/18/2024] [Indexed: 02/09/2024]
Abstract
The COVID-19 pandemic has caused about seven million deaths worldwide. Preventative vaccines have been developed including Spike gp mRNA-based vaccines that provide protection to immunocompetent patients. However, patients with primary immunodeficiencies, patients with cancer, or hematopoietic stem cell transplant recipients are not able to mount robust immune responses against current vaccine approaches. We propose to target structural SARS-CoV-2 antigens (i.e., Spike gp, Membrane, Nucleocapsid, and Envelope) using circulating human antigen-presenting cells electroporated with full length SARS-CoV-2 structural protein-encoding mRNAs to activate and expand specific T cells. Based on the Th1-type cytokine and cytolytic enzyme secretion upon antigen rechallenge, we were able to generate SARS-CoV-2 specific T cells in up to 70% of unexposed unvaccinated healthy donors (HDs) after 3 subsequent stimulations and in 100% of recovered patients (RPs) after 2 stimulations. By means of SARS-CoV-2 specific TCRβ repertoire analysis, T cells specific to Spike gp-derived hypomutated regions were identified in HDs and RPs despite viral genomic evolution. Hence, we demonstrated that SARS-CoV-2 mRNA-loaded antigen-presenting cells are effective activating and expanding COVID19-specific T cells. This approach represents an alternative to patients who are not able to mount adaptive immune responses to current COVID-19 vaccines with potential protection across new variants that have conserved genetic regions.
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Affiliation(s)
- Elizabeth Ogando-Rivas
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Paul Castillo
- UF Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Changlin Yang
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Vrunda Trivedi
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Dingpeng Zhang
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Fernanda Pohl-Guimarães
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Ruixuan Liu
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Arnav Barpujari
- UF Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Kate M. Candelario
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Hector Mendez-Gomez
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
| | - Elias J. Sayour
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
- UF Division of Pediatric Hematology Oncology, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Duane A. Mitchell
- UF Brain Tumor Immunotherapy Program, Preston A. Wells Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA
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14
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Albarrán Fernández V, Ballestín Martínez P, Stoltenborg Granhøj J, Borch TH, Donia M, Marie Svane I. Biomarkers for response to TIL therapy: a comprehensive review. J Immunother Cancer 2024; 12:e008640. [PMID: 38485186 PMCID: PMC10941183 DOI: 10.1136/jitc-2023-008640] [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] [Accepted: 02/05/2024] [Indexed: 03/17/2024] Open
Abstract
Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) has demonstrated durable clinical responses in patients with metastatic melanoma, substantiated by recent positive results of the first phase III trial on TIL therapy. Being a demanding and logistically complex treatment, extensive preclinical and clinical effort is required to optimize patient selection by identifying predictive biomarkers of response. This review aims to comprehensively summarize the current evidence regarding the potential impact of tumor-related factors (such as mutational burden, neoantigen load, immune infiltration, status of oncogenic driver genes, and epigenetic modifications), patient characteristics (including disease burden and location, baseline cytokines and lactate dehydrogenase serum levels, human leucocyte antigen haplotype, or prior exposure to immune checkpoint inhibitors and other anticancer therapies), phenotypic features of the transferred T cells (mainly the total cell count, CD8:CD4 ratio, ex vivo culture time, expression of exhaustion markers, costimulatory signals, antitumor reactivity, and scope of target tumor-associated antigens), and other treatment-related factors (such as lymphodepleting chemotherapy and postinfusion administration of interleukin-2).
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Affiliation(s)
- Víctor Albarrán Fernández
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
- Ramón y Cajal University Hospital, Department of Medical Oncology, Madrid, Spain
| | - Pablo Ballestín Martínez
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
- Clínico San Carlos University Hospital, Department of Medical Oncology, Madrid, Spain
| | - Joachim Stoltenborg Granhøj
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Troels Holz Borch
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Marco Donia
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
| | - Inge Marie Svane
- National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, Herlev, Denmark
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15
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Thiolat A, Pilon C, Caudana P, Moatti A, To NH, Sedlik C, Leclerc M, Maury S, Piaggio E, Cohen JL. Treg-targeted IL-2/anti-IL-2 complex controls graft- versus-host disease and supports anti-tumor effect in allogeneic hematopoietic stem cell transplantation. Haematologica 2024; 109:129-142. [PMID: 37706355 PMCID: PMC10772500 DOI: 10.3324/haematol.2022.282653] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 09/07/2023] [Indexed: 09/15/2023] Open
Abstract
Modulating an immune response in opposite directions represents the holy grail in allogeneic hematopoietic stem cell transplantation (allo-HSCT) to avoid insufficient reactivity of donor T cells and hematologic malignancy relapse while controlling the potential development of graft-versus-host disease (GVHD), in which donor T cells attack the recipient's tissues. IL-2/anti-IL-2 complexes (IL-2Cx) represent a therapeutic option to selectively accentuate or dampen the immune response. In dedicated experimental models of allo-HSCT, including also human cells injected in immunodeficient NSG mice, we evaluated side-by-side the therapeutic effect of two IL-2Cx designed either to boost regulatory T cells (Treg) or alternatively to activate effector T cells (Teff), on GVHD occurrence and tumor relapse. We also evaluated the effect of the complexes on the phenotype and function of immune cells in vivo. Unexpectedly, both pro-Treg and pro-Teff IL-2Cx prevented GVHD development. They both induced Treg expansion and reduced CD8+ T-cell numbers, compared to untreated mice. However, only mice treated with the pro-Treg IL-2Cx, showed a dramatic reduction of exhausted CD8+ T cells, consistent with a potent anti-tumor effect. When evaluated on human cells, pro-Treg IL-2Cx also preferentially induced Treg expansion in vitro and in vivo, while allowing the development of a potent anti-tumor effect in NSG mice. Our results demonstrate the clinical relevance of using a pro-Treg, but not a pro-Teff IL2Cx to modulate alloreactivity after HSCT, while promoting a graft-versus-leukemia effect.
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Affiliation(s)
- Allan Thiolat
- Univ Paris Est Créteil, INSERM U955, IMRB, F-94010 Créteil
| | - Caroline Pilon
- Univ Paris Est Créteil, INSERM U955, IMRB, F-94010 Créteil, France; AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Fédération hospitalo-Universitaire TRUE, F-94010 Créteil
| | - Pamela Caudana
- INSERM U932, PSL Research University, Institute Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris
| | - Audrey Moatti
- Univ Paris Est Créteil, INSERM U955, IMRB, F-94010 Créteil
| | - Nhu Hanh To
- Univ Paris Est Créteil, INSERM U955, IMRB, F-94010 Créteil
| | - Christine Sedlik
- INSERM U932, PSL Research University, Institute Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris
| | - Mathieu Leclerc
- Univ Paris Est Créteil, INSERM U955, IMRB, F-94010 Créteil, France; AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Service d'Hématologie Clinique, F-94010 Créteil
| | - Sébastien Maury
- Univ Paris Est Créteil, INSERM U955, IMRB, F-94010 Créteil, France; AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Fédération hospitalo-Universitaire TRUE, F-94010 Créteil, France; AP-HP, Groupe Hospitalo-Universitaire Chenevier Mondor, Service d'Hématologie Clinique, F-94010 Créteil
| | - Eliane Piaggio
- INSERM U932, PSL Research University, Institute Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris
| | - José L Cohen
- Univ Paris Est Créteil, INSERM U955, IMRB, F-94010 Créteil, France; AP-HP, Groupe hospitalo-universitaire Chenevier Mondor, Centre d'Investigation Clinique Biothérapie, Fédération hospitalo-Universitaire TRUE, F-94010 Créteil.
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16
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Baron KJ, Turnquist HR. Clinical Manufacturing of Regulatory T Cell Products For Adoptive Cell Therapy and Strategies to Improve Therapeutic Efficacy. Organogenesis 2023; 19:2164159. [PMID: 36681905 PMCID: PMC9870008 DOI: 10.1080/15476278.2022.2164159] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Based on successes in preclinical animal transplant models, adoptive cell therapy (ACT) with regulatory T cells (Tregs) is a promising modality to induce allograft tolerance or reduce the use of immunosuppressive drugs to prevent rejection. Extensive work has been done in optimizing the best approach to manufacture Treg cell products for testing in transplant recipients. Collectively, clinical evaluations have demonstrated that large numbers of Tregs can be expanded ex vivo and infused safely. However, these trials have failed to induce robust drug-free tolerance and/or significantly reduce the level of immunosuppression needed to prevent solid organ transplant (SOTx) rejection. Improving Treg therapy effectiveness may require increasing Treg persistence or orchestrating Treg migration to secondary lymphatic tissues or places of inflammation. In this review, we describe current clinical Treg manufacturing methods used for clinical trials. We also highlight current strategies being implemented to improve delivered Treg ACT persistence and migration in preclinical studies.
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Affiliation(s)
- Kassandra J. Baron
- Departments of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Department of Infectious Disease and Microbiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania, USA
| | - Hēth R. Turnquist
- Departments of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA,McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA,CONTACT Hēth R. Turnquist Departments of Surgery, University of Pittsburgh School of Medicine, Thomas E. Starzl Transplantation Institute 200 Lothrop Street, BST W1542, PittsburghPA 15213, USA
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Christofi P, Pantazi C, Psatha N, Sakellari I, Yannaki E, Papadopoulou A. Promises and Pitfalls of Next-Generation Treg Adoptive Immunotherapy. Cancers (Basel) 2023; 15:5877. [PMID: 38136421 PMCID: PMC10742252 DOI: 10.3390/cancers15245877] [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: 11/18/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 12/24/2023] Open
Abstract
Regulatory T cells (Tregs) are fundamental to maintaining immune homeostasis by inhibiting immune responses to self-antigens and preventing the excessive activation of the immune system. Their functions extend beyond immune surveillance and subpopulations of tissue-resident Treg cells can also facilitate tissue repair and homeostasis. The unique ability to regulate aberrant immune responses has generated the concept of harnessing Tregs as a new cellular immunotherapy approach for reshaping undesired immune reactions in autoimmune diseases and allo-responses in transplantation to ultimately re-establish tolerance. However, a number of issues limit the broad clinical applicability of Treg adoptive immunotherapy, including the lack of antigen specificity, heterogeneity within the Treg population, poor persistence, functional Treg impairment in disease states, and in vivo plasticity that results in the loss of suppressive function. Although the early-phase clinical trials of Treg cell therapy have shown the feasibility and tolerability of the approach in several conditions, its efficacy has remained questionable. Leveraging the smart tools and platforms that have been successfully developed for primary T cell engineering in cancer, the field has now shifted towards "next-generation" adoptive Treg immunotherapy, where genetically modified Treg products with improved characteristics are being generated, as regards antigen specificity, function, persistence, and immunogenicity. Here, we review the state of the art on Treg adoptive immunotherapy and progress beyond it, while critically evaluating the hurdles and opportunities towards the materialization of Tregs as a living drug therapy for various inflammation states and the broad clinical translation of Treg therapeutics.
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Affiliation(s)
- Panayiota Christofi
- Gene and Cell Therapy Center, Hematopoietic Cell Transplantation Unit, Hematology Department, George Papanikolaou Hospital, 57010 Thessaloniki, Greece; (P.C.); (C.P.); (I.S.); (E.Y.)
- University General Hospital of Patras, 26504 Rio, Greece
| | - Chrysoula Pantazi
- Gene and Cell Therapy Center, Hematopoietic Cell Transplantation Unit, Hematology Department, George Papanikolaou Hospital, 57010 Thessaloniki, Greece; (P.C.); (C.P.); (I.S.); (E.Y.)
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Institute of Applied Biosciences (INAB), Centre for Research and Technology Hellas (CERTH), 57001 Thessaloniki, Greece
| | - Nikoleta Psatha
- Department of Genetics, Development and Molecular Biology, School of Biology, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Ioanna Sakellari
- Gene and Cell Therapy Center, Hematopoietic Cell Transplantation Unit, Hematology Department, George Papanikolaou Hospital, 57010 Thessaloniki, Greece; (P.C.); (C.P.); (I.S.); (E.Y.)
| | - Evangelia Yannaki
- Gene and Cell Therapy Center, Hematopoietic Cell Transplantation Unit, Hematology Department, George Papanikolaou Hospital, 57010 Thessaloniki, Greece; (P.C.); (C.P.); (I.S.); (E.Y.)
- Department of Medicine, University of Washington, Seattle, WA 98195-7710, USA
| | - Anastasia Papadopoulou
- Gene and Cell Therapy Center, Hematopoietic Cell Transplantation Unit, Hematology Department, George Papanikolaou Hospital, 57010 Thessaloniki, Greece; (P.C.); (C.P.); (I.S.); (E.Y.)
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18
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Konecny AJ, Shows DM, Lord JD. Colonic mucosal associated invariant T cells in Crohn's disease have a diverse and non-public T cell receptor beta chain repertoire. PLoS One 2023; 18:e0285918. [PMID: 37922286 PMCID: PMC10624325 DOI: 10.1371/journal.pone.0285918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Accepted: 10/13/2023] [Indexed: 11/05/2023] Open
Abstract
OBJECTIVES Mucosal-Associated Invariant T (MAIT) cells are T cells with a semi-invariant T cell receptor (TCR), recognizing riboflavin precursors presented by a non-polymorphic MR1 molecule. As these precursors are produced by the gut microbiome, we characterized the frequency, phenotype and clonality of MAIT cells in human colons with and without Crohn's disease (CD). METHODS The transcriptome of MAIT cells sorted from blood and intestinal lamina propria cells from colectomy recipients were compared with other CD8+ T cells. Colon biopsies from an additional ten CD patients and ten healthy controls (HC) were analyzed by flow cytometry. TCR genes were sequenced from individual MAIT cells from these biopsies and compared with those of MAIT cells from autologous blood. RESULTS MAIT cells in the blood and colon showed a transcriptome distinct from other CD8 T cells, with more expression of the IL-23 receptor. MAIT cells were enriched in the colons of CD patients, with less NKG2D in inflamed versus uninflamed segments. Regardless of disease, most MAIT cells expressed integrin α4β7 in the colon but not in the blood, where they were enriched for α4β7 expression. TCR sequencing revealed heterogeneity in the colon and blood, with few public sequences associated with cohorts. CONCLUSION MAIT cells are enriched in the colons of CD patients and disproportionately express molecules (IL-23R, integrin α4β7) targeted by CD therapeutics, to suggest a pathogenic role for them in CD. Public TCR sequences were neither common nor sufficiently restricted to a cohort to suggest protective or pathogenic antigen-specificities.
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Affiliation(s)
- Andrew J. Konecny
- Benaroya Research Institute, Translational Research Program, Seattle, WA, United States of America
- Department of Immunology, University of Washington, Seattle, WA, United States of America
| | - Donna M. Shows
- Benaroya Research Institute, Translational Research Program, Seattle, WA, United States of America
| | - James D. Lord
- Benaroya Research Institute, Translational Research Program, Seattle, WA, United States of America
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19
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Buxbaum NP, Socié G, Hill GR, MacDonald KPA, Tkachev V, Teshima T, Lee SJ, Ritz J, Sarantopoulos S, Luznik L, Zeng D, Paczesny S, Martin PJ, Pavletic SZ, Schultz KR, Blazar BR. Chronic GvHD NIH Consensus Project Biology Task Force: evolving path to personalized treatment of chronic GvHD. Blood Adv 2023; 7:4886-4902. [PMID: 36322878 PMCID: PMC10463203 DOI: 10.1182/bloodadvances.2022007611] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 10/26/2022] [Accepted: 10/26/2022] [Indexed: 01/26/2023] Open
Abstract
Chronic graft-versus-host disease (cGvHD) remains a prominent barrier to allogeneic hematopoietic stem cell transplantion as the leading cause of nonrelapse mortality and significant morbidity. Tremendous progress has been achieved in both the understanding of pathophysiology and the development of new therapies for cGvHD. Although our field has historically approached treatment from an empiric position, research performed at the bedside and bench has elucidated some of the complex pathophysiology of cGvHD. From the clinical perspective, there is significant variability of disease manifestations between individual patients, pointing to diverse biological underpinnings. Capitalizing on progress made to date, the field is now focused on establishing personalized approaches to treatment. The intent of this article is to concisely review recent knowledge gained and formulate a path toward patient-specific cGvHD therapy.
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Affiliation(s)
- Nataliya P. Buxbaum
- Department of Pediatrics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Gerard Socié
- Hematology-Transplantation, Assistance Publique-Hopitaux de Paris & University of Paris – INSERM UMR 676, Hospital Saint Louis, Paris, France
| | - Geoffrey R. Hill
- Division of Medical Oncology, The University of Washington, Seattle, WA
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Kelli P. A. MacDonald
- Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Victor Tkachev
- Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Stephanie J. Lee
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Jerome Ritz
- Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
| | - Stefanie Sarantopoulos
- Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Duke Cancer Institute, Durham, NC
| | - Leo Luznik
- Division of Hematologic Malignancies, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, Hematologic Maligancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Sophie Paczesny
- Department of Microbiology and Immunology and Cancer Immunology Program, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
| | - Paul J. Martin
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Steven Z. Pavletic
- Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Kirk R. Schultz
- Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Bruce R. Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneappolis, MN
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20
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Larson JH, Jin S, Loschi M, Bolivar Wagers S, Thangavelu G, Zaiken MC, McDonald-Hyman C, Saha A, Aguilar EG, Koehn B, Osborn MJ, Panoskaltsis-Mortari A, Macdonald KPA, Hill GR, Murphy WJ, Serody JS, Maillard I, Kean LS, Kim SV, Littman DR, Blazar BR. Enforced gut homing of murine regulatory T cells reduces early graft-versus-host disease severity. Am J Transplant 2023; 23:1102-1115. [PMID: 36878433 PMCID: PMC10475494 DOI: 10.1016/j.ajt.2023.01.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 01/31/2023] [Indexed: 03/07/2023]
Abstract
Damage to the gastrointestinal tract following allogeneic hematopoietic stem cell transplantation is a significant contributor to the severity and perpetuation of graft-versus-host disease. In preclinical models and clinical trials, we showed that infusing high numbers of regulatory T cells reduces graft-versus-host disease incidence. Despite no change in in vitro suppressive function, transfer of ex vivo expanded regulatory T cells transduced to overexpress G protein-coupled receptor 15 or C-C motif chemokine receptor 9, specific homing receptors for colon or small intestine, respectively, lessened graft-versus-host disease severity in mice. Increased regulatory T cell frequency and retention within the gastrointestinal tissues of mice that received gut homing T cells correlated with lower inflammation and gut damage early post-transplant, decreased graft-versus-host disease severity, and prolonged survival compared with those receiving control transduced regulatory T cells. These data provide evidence that enforced targeting of ex vivo expanded regulatory T cells to the gastrointestinal tract diminishes gut injury and is associated with decreased graft-versus-host disease severity.
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Affiliation(s)
- Jemma H Larson
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sujeong Jin
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Michael Loschi
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Sara Bolivar Wagers
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Govindarajan Thangavelu
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Michael C Zaiken
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Cameron McDonald-Hyman
- Division of Hematology/Oncology/Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota, USA
| | - Asim Saha
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Ethan G Aguilar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Brent Koehn
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Mark J Osborn
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Angela Panoskaltsis-Mortari
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
| | - Kelli P A Macdonald
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Immunology Department, Brisbane, Queensland, Australia
| | - Geoffrey R Hill
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA; Division of Medical Oncology, University of Washington, Seattle, Washington, USA
| | - William J Murphy
- Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA; Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis School of Medicine, Sacramento, California, USA
| | - Jonathan S Serody
- Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Computational Medicine Program, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Ivan Maillard
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Leslie S Kean
- Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
| | - Sangwon V Kim
- Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA
| | - Dan R Littman
- Molecular Pathogenesis Program, The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, USA
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA.
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21
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Wang Y, Tang X, Zhu Y, Yang XX, Liu B. Role of interleukins in acute myeloid leukemia. Leuk Lymphoma 2023; 64:1400-1413. [PMID: 37259867 DOI: 10.1080/10428194.2023.2218508] [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: 04/27/2023] [Accepted: 05/21/2023] [Indexed: 06/02/2023]
Abstract
Acute myeloid leukemia (AML) is a hematological malignancy with strong heterogeneity. Immune disorders are a feature of various malignancies, including AML. Interleukins (ILs) and other cytokines participate in a series of biological processes of immune disorders in the microenvironment, and serve as a bridge for communication between various cellular components in the immune system. The role of ILs in AML is complex and pleiotropic. It can not only play an anti-AML role by enhancing anti-leukemia immunity and directly inducing AML cell apoptosis, but also promote the growth, proliferation and drug resistance of AML. These properties of ILs can be used to explore their potential efficacy in disease monitoring, prognosis assessment, and development of new treatment strategies for AML. This review aims to clarify some of the complex roles of ILs in AML and their clinical applications.
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Affiliation(s)
- Yin Wang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Xiao Tang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Yu Zhu
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Xiao-Xiao Yang
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Bei Liu
- The First Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Hematology, The First Affiliated Hospital of Lanzhou University, Lanzhou, China
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22
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Pang Y, Holtzman NG. Immunopathogenic mechanisms and modulatory approaches to graft-versus-host disease prevention in acute myeloid leukaemia. Best Pract Res Clin Haematol 2023; 36:101475. [PMID: 37353287 PMCID: PMC10291443 DOI: 10.1016/j.beha.2023.101475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Revised: 05/03/2023] [Accepted: 05/03/2023] [Indexed: 06/25/2023]
Abstract
Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only potential cure for intermediate to high-risk acute myeloid leukaemia (AML). The therapeutic effect of HSCT is largely dependent on the powerful donor-derived immune response against recipient leukaemia cells, known as graft-versus-leukaemia effect (GvL). However, the donor-derived immune system can also cause acute or chronic damage to normal recipient organs and tissues, in a process known as graft-versus-host disease (GvHD). GvHD is a leading cause of non-relapse mortality in HSCT recipients. There are many similarities and cross talk between the immune pathways of GvL and GvHD. Studies have demonstrated that both processes require the presence of mismatched alloantigens between the donor and recipient, and activation of immune responses centered around donor T-cells, which can be further modulated by various recipient or donor factors. Dissecting GvL from GvHD to achieve more effective GvHD prevention and enhanced GvL has been the holy grail of HSCT research. In this review, we focused on the key factors that contribute to the immune responses of GvL and GvHD, the effect on GvL with different GvHD prophylactic strategies, and the potential impact of various AML relapse prevention therapy or treatments on GvHD.
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Affiliation(s)
- Yifan Pang
- Department of Haematologic Oncology and Blood Disorders, Levine Cancer Institute, Charlotte, NC, USA.
| | - Noa G Holtzman
- Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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23
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Felices M, Wesley E, Bendzick LE, Kodal B, Hopps R, Grzywacz B, Hinderlie P, Miller JS, Geller MA. Reverse Translation Identifies the Synergistic Role of Immune Checkpoint Blockade and IL15 to Enhance Immunotherapy of Ovarian Cancer. Cancer Immunol Res 2023; 11:674-686. [PMID: 36807510 PMCID: PMC10155036 DOI: 10.1158/2326-6066.cir-22-0600] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 12/02/2022] [Accepted: 02/14/2023] [Indexed: 02/22/2023]
Abstract
Immune checkpoint blockade (ICB) has changed the standard of care for many patients with cancer, yet no ICB is approved for ovarian cancer. We hypothesized that maintenance therapy with an IL15 "superagonist" (N-803) and ICB in combination could induce potent immune activation in ovarian cancer. Using flow cytometry, cytometry by time of flight analysis, and cytotoxicity assays, we analyzed patient samples from women with advanced epithelial ovarian cancer treated with N-803 for indications of PD-1/PD-L1 upregulation with this treatment. In addition, ICB and N-803 were evaluated in preclinical studies to determine the functional impact of combination therapy on natural killer (NK) cells in vitro and in vivo. We observed that N-803 stimulated initial NK-cell expansion in patient samples; however, proliferation was not sustained beyond 2 weeks despite continued treatment. This result was reverse translated back to the laboratory to determine the functional relevance of this finding. The addition of ICB with an antibody-dependent cellular cytotoxicity IgG1 antibody against PD-L1 (avelumab) or an IgG4 antibody against PD-1 (pembrolizumab) enhanced N-803 induced NK-cell function in vitro. Using models of human ovarian cancer and NK-cell adoptive transfer in mice, we showed enhanced antitumor control with N-803 and ICB, as well as a combination effect that enhanced NK-cell persistence and expansion in vivo. This work suggests that PD-1/PD-L1 blockade combined with IL15 signaling may overcome resistance to cytokine therapy in ovarian cancer.
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Affiliation(s)
- Martin Felices
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Erin Wesley
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Laura E. Bendzick
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Behiye Kodal
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Rachel Hopps
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota
| | - Bartosz Grzywacz
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota
| | - Peter Hinderlie
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Jeffrey S. Miller
- Department of Medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Melissa A. Geller
- Department of Obstetrics, Gynecology, and Women's Health, University of Minnesota, Minneapolis, Minnesota
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24
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Fiyouzi T, Pelaez-Prestel HF, Reyes-Manzanas R, Lafuente EM, Reche PA. Enhancing Regulatory T Cells to Treat Inflammatory and Autoimmune Diseases. Int J Mol Sci 2023; 24:ijms24097797. [PMID: 37175505 PMCID: PMC10177847 DOI: 10.3390/ijms24097797] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 04/19/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
Regulatory T cells (Tregs) control immune responses and are essential to maintain immune homeostasis and self-tolerance. Hence, it is no coincidence that autoimmune and chronic inflammatory disorders are associated with defects in Tregs. These diseases have currently no cure and are treated with palliative drugs such as immunosuppressant and immunomodulatory agents. Thereby, there is a great interest in developing medical interventions against these diseases based on enhancing Treg cell function and numbers. Here, we give an overview of Treg cell ontogeny and function, paying particular attention to mucosal Tregs. We review some notable approaches to enhance immunomodulation by Tregs with therapeutic purposes including adoptive Treg cell transfer therapy and discuss relevant clinical trials for inflammatory bowel disease. We next introduce ways to expand mucosal Tregs in vivo using microbiota and dietary products that have been the focus of clinical trials in various autoimmune and chronic-inflammatory diseases.
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Affiliation(s)
- Tara Fiyouzi
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| | - Hector F Pelaez-Prestel
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| | - Raquel Reyes-Manzanas
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| | - Esther M Lafuente
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
| | - Pedro A Reche
- Laboratory of Immunomedicine, Faculty of Medicine, University Complutense of Madrid, Ave Complutense S/N, 28040 Madrid, Spain
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25
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Giardino G, Romano R, Lougaris V, Castagnoli R, Cillo F, Leonardi L, La Torre F, Soresina A, Federici S, Cancrini C, Pacillo L, Toriello E, Cinicola BL, Corrente S, Volpi S, Marseglia GL, Pignata C, Cardinale F. Immune tolerance breakdown in inborn errors of immunity: Paving the way to novel therapeutic approaches. Clin Immunol 2023; 251:109302. [PMID: 36967025 DOI: 10.1016/j.clim.2023.109302] [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: 10/07/2022] [Revised: 03/06/2023] [Accepted: 03/22/2023] [Indexed: 05/12/2023]
Abstract
Up to 25% of the patients with inborn errors of immunity (IEI) also exhibit immunodysregulatory features. The association of immune dysregulation and immunodeficiency may be explained by different mechanisms. The understanding of mechanisms underlying immune dysregulation in IEI has paved the way for the development of targeted treatments. In this review article, we will summarize the mechanisms of immune tolerance breakdown and the targeted therapeutic approaches to immune dysregulation in IEI.
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Affiliation(s)
- Giuliana Giardino
- Pediatric Section, Department of Translational Medical Sciences, Federico II University, Naples, Italy.
| | - Roberta Romano
- Pediatric Section, Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Vassilios Lougaris
- Department of Clinical and Experimental Sciences, Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, University of Brescia and ASST-Spedali Civili di Brescia, Brescia, Italy
| | - Riccardo Castagnoli
- Department of Pediatrics, Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Francesca Cillo
- Pediatric Section, Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Lucia Leonardi
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - Francesco La Torre
- Department of Pediatrics, Giovanni XXIII Pediatric Hospital, University of Bari, Bari, Italy
| | - Annarosa Soresina
- Unit of Pediatric Immunology, Pediatrics Clinic, University of Brescia, ASST Spedali Civili Brescia, Brescia, Italy
| | - Silvia Federici
- Division of Rheumatology, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Caterina Cancrini
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Research Unit of Primary Immunodeficiencies, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Lucia Pacillo
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy; Research Unit of Primary Immunodeficiencies, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
| | - Elisabetta Toriello
- Pediatric Section, Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Bianca Laura Cinicola
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | | | - Stefano Volpi
- Center for Autoinflammatory Diseases and Immunodeficiency, IRCCS Istituto Giannina Gaslini, Università degli Studi di Genova, Genoa, Italy
| | - Gian Luigi Marseglia
- Department of Pediatrics, Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Claudio Pignata
- Pediatric Section, Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Fabio Cardinale
- Department of Pediatrics, Giovanni XXIII Pediatric Hospital, University of Bari, Bari, Italy
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26
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Dhawan M, Rabaan AA, Alwarthan S, Alhajri M, Halwani MA, Alshengeti A, Najim MA, Alwashmi ASS, Alshehri AA, Alshamrani SA, AlShehail BM, Garout M, Al-Abdulhadi S, Al-Ahmed SH, Thakur N, Verma G. Regulatory T Cells (Tregs) and COVID-19: Unveiling the Mechanisms, and Therapeutic Potentialities with a Special Focus on Long COVID. Vaccines (Basel) 2023; 11:vaccines11030699. [PMID: 36992283 DOI: 10.3390/vaccines11030699] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/16/2023] [Accepted: 03/17/2023] [Indexed: 03/31/2023] Open
Abstract
The COVID-19 pandemic has caused havoc all around the world. The causative agent of COVID-19 is the novel form of the coronavirus (CoV) named SARS-CoV-2, which results in immune system disruption, increased inflammation, and acute respiratory distress syndrome (ARDS). T cells have been important components of the immune system, which decide the fate of the COVID-19 disease. Recent studies have reported an important subset of T cells known as regulatory T cells (Tregs), which possess immunosuppressive and immunoregulatory properties and play a crucial role in the prognosis of COVID-19 disease. Recent studies have shown that COVID-19 patients have considerably fewer Tregs than the general population. Such a decrement may have an impact on COVID-19 patients in a number of ways, including diminishing the effect of inflammatory inhibition, creating an inequality in the Treg/Th17 percentage, and raising the chance of respiratory failure. Having fewer Tregs may enhance the likelihood of long COVID development in addition to contributing to the disease's poor prognosis. Additionally, tissue-resident Tregs provide tissue repair in addition to immunosuppressive and immunoregulatory activities, which may aid in the recovery of COVID-19 patients. The severity of the illness is also linked to abnormalities in the Tregs' phenotype, such as reduced expression of FoxP3 and other immunosuppressive cytokines, including IL-10 and TGF-beta. Hence, in this review, we summarize the immunosuppressive mechanisms and their possible roles in the prognosis of COVID-19 disease. Furthermore, the perturbations in Tregs have been associated with disease severity. The roles of Tregs are also explained in the long COVID. This review also discusses the potential therapeutic roles of Tregs in the management of patients with COVID-19.
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Affiliation(s)
- Manish Dhawan
- Department of Microbiology, Punjab Agricultural University, Ludhiana 141004, India
- Trafford College, Altrincham, Manchester WA14 5PQ, UK
| | - Ali A Rabaan
- Molecular Diagnostic Laboratory, Johns Hopkins Aramco Healthcare, Dhahran 31311, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Public Health and Nutrition, The University of Haripur, Haripur 22610, Pakistan
| | - Sara Alwarthan
- Department of Internal Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia
| | - Mashael Alhajri
- Department of Internal Medicine, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 34212, Saudi Arabia
| | - Muhammad A Halwani
- Department of Medical Microbiology, Faculty of Medicine, Al Baha University, Al Baha 4781, Saudi Arabia
| | - Amer Alshengeti
- Department of Pediatrics, College of Medicine, Taibah University, Al-Madinah 41491, Saudi Arabia
- Department of Infection Prevention and Control, Prince Mohammad Bin Abdulaziz Hospital, National Guard Health Affairs, Al-Madinah 41491, Saudi Arabia
| | - Mustafa A Najim
- Department of Medical Laboratories Technology, College of Applied Medical Sciences, Taibah University, Al-Madinah 41411, Saudi Arabia
| | - Ameen S S Alwashmi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Ahmad A Alshehri
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia
| | - Saleh A Alshamrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Najran University, Najran 61441, Saudi Arabia
| | - Bashayer M AlShehail
- Pharmacy Practice Department, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Mohammed Garout
- Department of Community Medicine and Health Care for Pilgrims, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia
| | - Saleh Al-Abdulhadi
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Prince Sattam Bin Abdulaziz University, Riyadh 11942, Saudi Arabia
- Dr. Saleh Office for Medical Genetic and Genetic Counseling Services, The House of Expertise, Prince Sattam Bin Abdulaziz University, Dammam 32411, Saudi Arabia
| | - Shamsah H Al-Ahmed
- Specialty Paediatric Medicine, Qatif Central Hospital, Qatif 32654, Saudi Arabia
| | - Nanamika Thakur
- University Institute of Biotechnology, Department of Biotechnology, Chandigarh University, Mohali 140413, India
| | - Geetika Verma
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, India
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27
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Harris F, Berdugo YA, Tree T. IL-2-based approaches to Treg enhancement. Clin Exp Immunol 2023; 211:149-163. [PMID: 36399073 PMCID: PMC10019135 DOI: 10.1093/cei/uxac105] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 09/12/2022] [Accepted: 11/17/2022] [Indexed: 11/19/2022] Open
Abstract
Immune homeostasis is heavily dependent on the action of regulatory T cells (Tregs) which act to suppress the activation of many immune cell types including autoreactive conventional T cells. A body of evidence has shown that Tregs are intrinsically defective in many common autoimmune diseases, and gene polymorphisms which increase the susceptibility of autoimmune disease development have implicated the interleukin-2 (IL-2) signaling pathway as a key dysregulated mechanism. IL-2 is essential for Treg function and survival, and Tregs are highly sensitive to low levels of this cytokine in their environment. This review will revisit the rationale behind using low-dose IL-2 as a therapy to treat autoimmune diseases and evaluate the outcomes of trials to date. Furthermore, novel engineered IL-2 therapies with increased Treg specificity have shown promise in pre-clinical studies and human clinical trials for some agents have begun. Future studies will determine whether low-dose IL-2 or engineered IL-2 therapies can change the course of autoimmune and inflammatory diseases in patients.
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Affiliation(s)
- Ffion Harris
- Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College, London, UK
| | - Yoana Arroyo Berdugo
- Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College, London, UK
| | - Timothy Tree
- Department of Immunobiology, Faculty of Life Sciences and Medicine, King’s College, London, UK
- National Institute of Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust, King’s College London, London, UK
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28
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Laukova M, Glatman Zaretsky A. Regulatory T cells as a therapeutic approach for inflammatory bowel disease. Eur J Immunol 2023; 53:e2250007. [PMID: 36562391 PMCID: PMC10107179 DOI: 10.1002/eji.202250007] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/20/2022] [Accepted: 12/22/2022] [Indexed: 12/24/2022]
Abstract
Foxp3+ T regulatory (Treg) cells suppress inflammation and are essential for maintaining tissue homeostasis. A growing appreciation of tissue-specific Treg functions has built interest in leveraging the endogenous suppressive mechanisms of these cells into cellular therapeutics in organ-specific diseases. Notably, Treg cells play a critical role in maintaining the intestinal environment. As a barrier site, the gut requires Treg cells to mediate interactions with the microbiota, support barrier integrity, and regulate the immune system. Without fully functional Treg cells, intestinal inflammation and microbial dysbiosis ensue. Thus, there is a particular interest in developing Treg cellular therapies for intestinal inflammatory disease, such as inflammatory bowel disease (IBD). This article reviews some of the critical pathways that are dysregulated in IBD, Treg cell mechanisms of suppression, and the efforts and approaches in the field to develop these cells as a cellular therapy for IBD.
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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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30
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Shaikh H, Pezoldt J, Mokhtari Z, Gamboa Vargas J, Le DD, Peña Mosca J, Arellano Viera E, Kern MA, Graf C, Beyersdorf N, Lutz MB, Riedel A, Büttner-Herold M, Zernecke A, Einsele H, Saliba AE, Ludewig B, Huehn J, Beilhack A. Fibroblastic reticular cells mitigate acute GvHD via MHCII-dependent maintenance of regulatory T cells. JCI Insight 2022; 7:154250. [PMID: 36227687 DOI: 10.1172/jci.insight.154250] [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: 08/23/2021] [Accepted: 10/07/2022] [Indexed: 12/15/2022] Open
Abstract
Acute graft versus host disease (aGvHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation (allo-HCT) inflicted by alloreactive T cells primed in secondary lymphoid organs (SLOs) and subsequent damage to aGvHD target tissues. In recent years, Treg transfer and/or expansion has emerged as a promising therapy to modulate aGvHD. However, cellular niches essential for fostering Tregs to prevent aGvHD have not been explored. Here, we tested whether and to what extent MHC class II (MHCII) expressed on Ccl19+ fibroblastic reticular cells (FRCs) shape the donor CD4+ T cell response during aGvHD. Animals lacking MHCII expression on Ccl19-Cre-expressing FRCs (MHCIIΔCcl19) showed aberrant CD4+ T cell activation in the effector phase, resulting in exacerbated aGvHD that was associated with significantly reduced expansion of Foxp3+ Tregs and invariant NK T (iNKT) cells. Skewed Treg maintenance in MHCIIΔCcl19 mice resulted in loss of protection from aGvHD provided by adoptively transferred donor Tregs. In contrast, although FRCs upregulated costimulatory surface receptors, and although they degraded and processed exogenous antigens after myeloablative irradiation, FRCs were dispensable to activate alloreactive CD4+ T cells in 2 mouse models of aGvHD. In summary, these data reveal an immunoprotective, MHCII-mediated function of FRC niches in secondary lymphoid organs (SLOs) after allo-HCT and highlight a framework of cellular and molecular interactions that regulate CD4+ T cell alloimmunity.
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Affiliation(s)
- Haroon Shaikh
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
| | - Joern Pezoldt
- Laboratory of Systems Biology and Genetics, Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.,Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany
| | - Zeinab Mokhtari
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Juan Gamboa Vargas
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
| | - Duc-Dung Le
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Josefina Peña Mosca
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
| | - Estibaliz Arellano Viera
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Michael Ag Kern
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
| | - Caroline Graf
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Niklas Beyersdorf
- Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.,Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany
| | - Manfred B Lutz
- Graduate School of Life Sciences, Würzburg University, Würzburg, Germany.,Institute for Virology and Immunobiology, Würzburg University, Würzburg, Germany
| | - Angela Riedel
- Mildred Scheel Early Career Centre, University Hospital of Würzburg, Würzburg, Germany
| | - Maike Büttner-Herold
- Department of Nephropathology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Alma Zernecke
- Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
| | - Hermann Einsele
- Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany
| | - Antoine-Emmanuel Saliba
- Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection (HZI), Würzburg, Germany
| | - Burkhard Ludewig
- Institute of Immunobiology, Kantonsspital St. Gallen, St. Gallen, Switzerland.,Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Jochen Huehn
- Department of Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.,Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Andreas Beilhack
- Interdisciplinary Center for Clinical Research (IZKF), Experimental Stem Cell Transplantation Laboratory, and.,Department of Internal Medicine II, Würzburg University Hospital, Würzburg, Germany.,Graduate School of Life Sciences, Würzburg University, Würzburg, Germany
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Nguyen R, Zhang X, Sun M, Abbas S, Seibert C, Kelly MC, Shern JF, Thiele CJ. Anti-GD2 Antibodies Conjugated to IL15 and IL21 Mediate Potent Antitumor Cytotoxicity against Neuroblastoma. Clin Cancer Res 2022; 28:3785-3796. [PMID: 35802683 PMCID: PMC9444978 DOI: 10.1158/1078-0432.ccr-22-0717] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 05/18/2022] [Accepted: 07/06/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE Half of the patients with high-risk neuroblastoma who receive GD2-targeted mAb do not achieve long-term remissions. Recently, the antibody hu14.18 has been linked to IL2 (hu14.18-IL2) to enhance its efficacy and shown promising preclinical and clinical activity. We developed two new immunocytokines (IC) by linking two other γc cytokines, IL15 and IL21, to hu14.18. The purpose of this study was to compare hu14.18-IL15 and -IL21 with hu14.18-IL2 in their ability to induce antibody-dependent cell-mediated cytotoxicity (ADCC) against neuroblastoma. EXPERIMENTAL DESIGN We assessed ADCC of hu14.18-IL15 and -IL2 (human cytokines, cross-reactive to mouse) against GD2low and GD2high neuroblastoma cell lines in vitro. T-cell-deficient mice with orthotopic patient-derived xenografts (PDX) and immunocompetent mice with transplantable orthotopic neuroblastoma were used to test all three ICs, including hu14.18-IL21 (murine IL21, not cross-reactive to human). Mechanistic studies were performed using single-cell RNA-sequencing (scRNA-seq). RESULTS hu14.18-IL15 and hu14.18-IL2 mediated equivalent in vitro ADCC by human NK cells. When combined with chemotherapy, all three ICs similarly controlled the growth of PDXs in nude mice with murine NK effector cells. However, hu14.18-IL15 and -IL21 outperformed hu14.18-IL2 in immunocompetent mice with syngeneic neuroblastoma, inducing complete tumor regressions and extending survival. scRNA-seq data revealed an increase in CD8+ T cells and M1 tumor-associated macrophages and decreased regulatory T cells and myeloid-derived suppressor cells in the tumor microenvironment. CONCLUSIONS Hu14.18-IL15 and Hu14.18-IL21 exhibit robust preclinical activity, warranting further consideration for clinical testing in patients with GD2-expressing neuroblastoma.
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Affiliation(s)
- Rosa Nguyen
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Corresponding author: Rosa Nguyen, Pediatric Oncology Branch, 10 Center Drive, Building 10, Room 1W-5816, Bethesda, MD, USA; phone: 443-902-3243; fax: 301-451-7052;
| | - Xiyuan Zhang
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Ming Sun
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Shahroze Abbas
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Charlie Seibert
- Center for Cancer Research Single Cell Analysis Facility CCR, Cancer Research Technology Program, Frederick National Laboratory, Bethesda, MD, USA
| | - Michael C. Kelly
- Center for Cancer Research Single Cell Analysis Facility CCR, Cancer Research Technology Program, Frederick National Laboratory, Bethesda, MD, USA
| | - Jack F. Shern
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Carol J. Thiele
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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32
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Naoun AA, Raphael I, Forsthuber TG. Immunoregulation via Cell Density and Quorum Sensing-like Mechanisms: An Underexplored Emerging Field with Potential Translational Implications. Cells 2022; 11:cells11152442. [PMID: 35954285 PMCID: PMC9368058 DOI: 10.3390/cells11152442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/27/2022] [Accepted: 08/01/2022] [Indexed: 11/16/2022] Open
Abstract
Quorum sensing (QS) was historically described as a mechanism by which bacteria detect and optimize their population density via gene regulation based on dynamic environmental cues. Recently, it was proposed that QS or similar mechanisms may have broader applications across different species and cell types. Indeed, emerging evidence shows that the mammalian immune system can also elicit coordinated responses on a population level to regulate cell density and function, thus suggesting that QS-like mechanisms may also be a beneficial trait of the immune system. In this review, we explore and discuss potential QS-like mechanisms deployed by the immune system to coordinate cellular-level responses, such as T cell responses mediated via the common gamma chain (γc) receptor cytokines and the aryl hydrocarbon receptors (AhRs). We present evidence regarding a novel role of QS as a multifunctional mechanism coordinating CD4+ and CD8+ T cell behavior during steady state and in response to infection, inflammatory diseases, and cancer. Successful clinical therapies such as adoptive cell transfer for cancer treatment may be re-evaluated to harness the effects of the QS mechanism(s) and enhance treatment responsiveness. Moreover, we discuss how signaling threshold perturbations through QS-like mediators may result in disturbances of the complex crosstalk between immune cell populations, undesired T cell responses, and induction of autoimmune pathology. Finally, we discuss the potential therapeutic role of modulating immune-system-related QS as a promising avenue to treat human diseases.
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Affiliation(s)
- Adrian A. Naoun
- Department of Molecular Microbiology and Immunology, University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Itay Raphael
- Department of Neurological Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15217, USA
- Correspondence: (I.R.); (T.G.F.)
| | - Thomas G. Forsthuber
- Department of Molecular Microbiology and Immunology, University of Texas at San Antonio, San Antonio, TX 78249, USA
- Correspondence: (I.R.); (T.G.F.)
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33
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Hippen KL, Hefazi M, Larson JH, Blazar BR. Emerging translational strategies and challenges for enhancing regulatory T cell therapy for graft-versus-host disease. Front Immunol 2022; 13:926550. [PMID: 35967386 PMCID: PMC9366169 DOI: 10.3389/fimmu.2022.926550] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 06/27/2022] [Indexed: 02/03/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for many types of cancer. Genetic disparities between donor and host can result in immune-mediated attack of host tissues, known as graft versus host disease (GVHD), a major cause of morbidity and mortality following HSCT. Regulatory CD4+ T cells (Tregs) are a rare cell type crucial for immune system homeostasis, limiting the activation and differentiation of effector T cells (Teff) that are self-reactive or stimulated by foreign antigen exposure. Adoptive cell therapy (ACT) with Treg has demonstrated, first in murine models and now in patients, that prophylactic Treg infusion can also suppress GVHD. While clinical trials have demonstrated Treg reduce severe GVHD occurrence, several impediments remain, including Treg variability and practical need for individualized Treg production for each patient. Additionally, there are challenges in the use of in vitro expansion techniques and in achieving in vivo Treg persistence in context of both immune suppressive drugs and in lymphoreplete patients being treated for GVHD. This review will focus on 3 main translational approaches taken to improve the efficacy of tTreg ACT in GVHD prophylaxis and development of treatment options, following HSCT: genetic modification, manipulating TCR and cytokine signaling, and Treg production protocols. In vitro expansion for Treg ACT presents a multitude of approaches for gene modification to improve efficacy, including: antigen specificity, tissue targeting, deletion of negative regulators/exhaustion markers, resistance to immunosuppressive drugs common in GVHD treatment. Such expansion is particularly important in patients without significant lymphopenia that can drive Treg expansion, enabling a favorable Treg:Teff ratio in vivo. Several potential therapeutics have also been identified that enhance tTreg stability or persistence/expansion following ACT that target specific pathways, including: DNA/histone methylation status, TCR/co-stimulation signaling, and IL-2/STAT5 signaling. Finally, this review will discuss improvements in Treg production related to tissue source, Treg subsets, therapeutic approaches to increase Treg suppression and stability during tTreg expansion, and potential for storing large numbers of Treg from a single production run to be used as an off-the-shelf infusion product capable of treating multiple recipients.
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Affiliation(s)
- Keli L. Hippen
- University of Minnesota Cancer Center and the Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, Minneapolis, MN, United States
| | - Mehrdad Hefazi
- Division of Hematology, Mayo Clinic, Rochester, MN, United States
| | - Jemma H. Larson
- University of Minnesota Cancer Center and the Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, Minneapolis, MN, United States
| | - Bruce R. Blazar
- University of Minnesota Cancer Center and the Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, Minneapolis, MN, United States
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34
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Yuan Y, Kolios AGA, Liu Y, Zhang B, Li H, Tsokos GC, Zhang X. Therapeutic potential of interleukin-2 in autoimmune diseases. Trends Mol Med 2022; 28:596-612. [PMID: 35624009 DOI: 10.1016/j.molmed.2022.04.010] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 04/25/2022] [Accepted: 04/25/2022] [Indexed: 12/27/2022]
Abstract
Autoimmune diseases are characterized by dysregulation and aberrant activation of cells in the immune system. Therefore, restoration of the immune balance represents a promising therapeutic target in autoimmune diseases. Interleukin-2 (IL-2) can promote the expansion and differentiation of different immune cell subsets dose-dependently. At high doses, IL-2 can promote the differentiation and expansion of effector and memory T cells, whereas at low doses, IL-2 can promote the differentiation, survival, and function of regulatory T (Treg) cells, a CD4+ T cell subset that is essential for the maintenance of immune homeostasis and immune tolerance. Therefore, IL-2 exerts immunostimulatory and immunosuppressive effects in autoimmune diseases. The immunoregulatory role of low-dose IL-2 has sparked excitement for the therapeutic exploration of modulating the IL-2-Treg axis in the context of autoimmune diseases. In this review, we discuss recent advances in the therapeutic potential of IL-2 or IL-2-derived molecules in the treatment of autoimmune diseases.
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Affiliation(s)
- Yeshuang Yuan
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Antonios G A Kolios
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Dermatology, University Hospital Zurich, Zurich, Switzerland
| | - Yudong Liu
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Bo Zhang
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China
| | - Hao Li
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - George C Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | - Xuan Zhang
- Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
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35
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Zeng Q, Xiang B, Liu Z. Autologous hematopoietic stem cell transplantation followed by interleukin-2 for adult acute myeloid leukemia patients with favorable or intermediate risk after complete remission. Ann Hematol 2022; 101:1711-1718. [PMID: 35570208 DOI: 10.1007/s00277-022-04863-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 05/08/2022] [Indexed: 02/08/2023]
Abstract
High-dose chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) is generally the optimal option for patients with acute myeloid leukemia (AML). However, for favorable- and intermediate-risk patients, the regimen remains less understood due to graft versus host disease (GVHD) and increased non-relapsed mortality (NRM) caused by allo-HSCT. Additionally, the benefit of maintenance therapy has not yet been conclusively proven. Here, we conducted a retrospective study on the long-term outcome of AML patients with favorable or intermediate risk who underwent autologous hematopoietic stem cell transplantation (auto-HSCT) followed by interleukin-2 (IL-2) subcutaneous injection as maintenance therapy. A total of 49 patients from 2007 to 2019 were included in our study. They all received a daunorubicin + cytarabine regimen as induction chemotherapy followed by four to six cycles of consolidation therapy with medium- or high-dose cytarabine. Once patients achieved complete remission (CR1), they started receiving auto-HSCT followed by IL-2 injections. The results showed that no patients stopped receiving IL-2 injections on account of adverse side effects, and the 5-year overall survival (OS) and leukemia-free survival (LFS) rates were 85.6 ± 5.0% and 78.5 ± 6.1%, respectively. The multivariate analysis also suggested that age, gender, initial white blood cell (WBC) count, AML subtype, cytogenetic risk, and conditioning regimen did not affect the prognosis. In conclusion, auto-HSCT followed by IL-2 injection is an effective treatment that can improve the prognosis of AML for patients with favorable or intermediate risk.
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Affiliation(s)
- Qiang Zeng
- Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Bing Xiang
- Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Zhigang Liu
- Department of Hematology and Institute of Hematology, West China Hospital, Sichuan University, 610041, Chengdu, China.
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Using stroma-anchoring cytokines to augment ADCC: a phase 1 trial of F16IL2 and BI 836858 for posttransplant AML relapse. Blood Adv 2022; 6:3684-3696. [PMID: 35468621 DOI: 10.1182/bloodadvances.2021006909] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 04/14/2022] [Indexed: 11/20/2022] Open
Abstract
Natural killer (NK) cells are key effectors in cancer immunosurveillance and posttransplant immunity, but deficiency of environmental signals and insufficient tumor recognition may limit their activity. We hypothesized that the antibody-mediated anchoring of interleukin-2 (IL-2) to a spliced isoform of the extracellular matrix (ECM) glycoprotein tenascin-C would potentiate NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) against leukemic blasts. In this novel-novel combination, dose-escalation phase 1 trial, we enrolled patients with posttransplant acute myeloid leukemia (AML) relapse to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of the antibody-cytokine fusion F16IL2 (10-20x106 IU IV, days 1, 8, 15, and 22 of 28-day cycles) in combination with the anti-CD33 antibody BI 836858 (10-40 mg IV, 2 days after each F16IL2 infusion). Among 15 patients (median [range] age, 50 [20-68] years) treated across 4 dose levels (DL), 6 (40%) had received 2 or 3 prior transplantations. The most frequent adverse events were pyrexia, chills and infusion-related reactions, which were manageable, transient and of grade ≤ 2. One dose-limiting toxicity occurred at each of DL 3 (pulmonary edema) and 4 (GVHD). Three objective responses were observed among 7 patients treated at the 2 higher DL, whereas no responses occurred at the 2 starting DL. Combination therapy stimulated the expansion and activation of NK cells, including those expressing the FcγRIIIA/CD16 receptor. ECM-targeted IL-2 combined with anti-CD33 immunotherapy represents an innovative approach associated with acceptable safety and encouraging biologic and clinical activity in posttransplant AML relapse. This trial was registered at EudraCT (2015-004763-37).
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37
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Cremoni M, Massa F, Sicard A. Overcoming barriers to widespread use of CAR-Treg therapy in organ transplant recipients. HLA 2022; 99:565-572. [PMID: 35233971 DOI: 10.1111/tan.14591] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 02/27/2022] [Indexed: 11/30/2022]
Abstract
Preventing allograft rejection has been the main challenge of transplantation medicine since the discovery of immune responses against foreign HLA molecules in the mid-20th century. Prevention of rejection currently relies on immunosuppressive drugs, which lack antigen specificity and therefore increase the risk for infections and cancers. Adoptive cell therapy with donor-reactive regulatory T cells (Tregs) has progressively emerged as a promising approach to reduce the need for pan-immunosuppressive drugs and minimize morbidity and mortality in solid-organ transplant recipients. Chimeric antigen receptor (CAR) technology has recently been used successfully to generate Tregs specific for donor HLA molecules and overcome the limitations of Tregs enrichment protocols based on repetitive stimulations with alloantigens. While this novel approach opens new possibilities to make Tregs therapy more feasible, it also creates additional challenges. It is essential to determine which source of therapeutic Tregs, CAR constructs, target alloantigens, safety strategies, patients and immunosuppressive regimens are optimal for the success of CAR Treg therapy. Here, we discuss unmet needs and strategies to bring donor-specific CAR Treg therapy to the clinic and make it as accessible as possible.
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Affiliation(s)
- Marion Cremoni
- Department of Nephrology, Dialysis, Transplantation, Nice University Hospital, Nice, France.,Clinical Research Unit, University Côte d'Azur (UR2CA), Nice, France
| | - Filippo Massa
- Department of Nephrology, Dialysis, Transplantation, Nice University Hospital, Nice, France.,Laboratory of Molecular Physio Medicine (LP2M), University Côte d'Azur, Nice, France
| | - Antoine Sicard
- Department of Nephrology, Dialysis, Transplantation, Nice University Hospital, Nice, France.,Laboratory of Molecular Physio Medicine (LP2M), University Côte d'Azur, Nice, France
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38
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Campe J, Ullrich E. T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy? Front Immunol 2022; 12:806529. [PMID: 35069590 PMCID: PMC8766661 DOI: 10.3389/fimmu.2021.806529] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
Allogenic hematopoietic stem cell transplantation (allo-HSCT) represents a potent and potentially curative treatment for many hematopoietic malignancies and hematologic disorders in adults and children. The donor-derived immunity, elicited by the stem cell transplant, can prevent disease relapse but is also responsible for the induction of graft-versus-host disease (GVHD). The pathophysiology of acute GVHD is not completely understood yet. In general, acute GVHD is driven by the inflammatory and cytotoxic effect of alloreactive donor T cells. Since several experimental approaches indicate that CD4 T cells play an important role in initiation and progression of acute GVHD, the contribution of the different CD4 T helper (Th) cell subtypes in the pathomechanism and regulation of the disease is a central point of current research. Th lineages derive from naïve CD4 T cell progenitors and lineage commitment is initiated by the surrounding cytokine milieu and subsequent changes in the transcription factor (TF) profile. Each T cell subtype has its own effector characteristics, immunologic function, and lineage specific cytokine profile, leading to the association with different immune responses and diseases. Acute GVHD is thought to be mainly driven by the Th1/Th17 axis, whereas Treg cells are attributed to attenuate GVHD effects. As the differentiation of each Th subset highly depends on the specific composition of activating and repressing TFs, these present a potent target to alter the Th cell landscape towards a GVHD-ameliorating direction, e.g. by inhibiting Th1 and Th17 differentiation. The finding, that targeting of Th1 and Th17 differentiation appears more effective for GVHD-prevention than a strategy to inhibit Th1 and Th17 cytokines supports this concept. In this review, we shed light on the current advances of potent TF inhibitors to alter Th cell differentiation and consecutively attenuate GVHD. We will focus especially on preclinical studies and outcomes of TF inhibition in murine GVHD models. Finally, we will point out the possible impact of a Th cell subset-specific immune modulation in context of GVHD.
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Affiliation(s)
- Julia Campe
- Experimental Immunology, Children's University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.,Children's University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany
| | - Evelyn Ullrich
- Experimental Immunology, Children's University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.,Children's University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany.,Frankfurt Cancer Institute, Goethe University Frankfurt, Frankfurt am Main, Germany.,German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung (DKTK)), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany
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39
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Landwehr-Kenzel S, Zobel A, Schmitt-Knosalla I, Forke A, Hoffmann H, Schmueck-Henneresse M, Klopfleisch R, Volk HD, Reinke P. Cyclosporine A but Not Corticosteroids Support Efficacy of Ex Vivo Expanded, Adoptively Transferred Human Tregs in GvHD. Front Immunol 2021; 12:716629. [PMID: 34707604 PMCID: PMC8543016 DOI: 10.3389/fimmu.2021.716629] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Accepted: 09/02/2021] [Indexed: 11/13/2022] Open
Abstract
Reshaping the immune balance by adoptive transfer of regulatory T-cells (Tregs) has emerged as a promising strategy to combat undesired immune reactions, including in Graft-versus-Host Disease (GvHD), which is the most lethal non-relapse complication of allogeneic hematopoietic stem cell transplantation. Currently however, little is known about the potentially inhibitory in vivo effects of conventional immunosuppressive drugs, which are routinely used to treat GvHD, on adoptively transferred Tregs. Here we demonstrate drug-specific effects of the conventional immunosuppressive drugs Cyclosporine A, Mycophenolate mofetil and methylprednisolone on adoptively transferred Tregs in a humanized NOD/SCID/IL2Rgamma-/- GvHD mouse model. The clinical course of GvHD and postmortem organ histology, including cellular organ infiltration, showed that co-administration of Cyclosporine A and Tregs is highly beneficial as it enhanced Treg accumulation at inflammatory sites like lung and liver. Similarly, co-administration of Mycophenolate mofetil and Tregs improved clinical signs of GvHD. In contrast, co-administration of methylprednisolone and Tregs resulted in reduced Treg recruitment to inflammatory sites and the fast deterioration of some animals. Consequently, when clinical trials investigating safety and efficacy of adjunctive Treg therapy in GvHD are designed, we suggest co-administering Cyclosporine A, whereas high doses of glucocorticosteroids should be avoided.
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Affiliation(s)
- Sybille Landwehr-Kenzel
- Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anne Zobel
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Isabela Schmitt-Knosalla
- Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Anne Forke
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Henrike Hoffmann
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Michael Schmueck-Henneresse
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Robert Klopfleisch
- Department of Veterinary Medicine, Institute of Veterinary Pathology, Freie Universität Berlin, Berlin, Germany
| | - Hans-Dieter Volk
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Medical Immunology, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Petra Reinke
- Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, BIH-Center for Regenerative Therapies (BCRT), Berlin, Germany
- Berlin Center for Advanced Therapies (BeCAT), Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
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40
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Hefazi M, Bolivar-Wagers S, Blazar BR. Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges. Int J Mol Sci 2021; 22:9676. [PMID: 34575843 PMCID: PMC8469916 DOI: 10.3390/ijms22189676] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/03/2021] [Accepted: 09/04/2021] [Indexed: 12/14/2022] Open
Abstract
Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation using regulatory T cells (Tregs) offers an exciting option to prevent and/or treat GVHD as these cells naturally function to maintain immune homeostasis, can induce tolerance following HSCT, and have a tissue reparative function. Studies to date have established a clinical safety profile for polyclonal Tregs. Functional enhancement through genetic engineering offers the possibility of improved potency, specificity, and persistence. In this review, we provide the most up to date preclinical and clinical data on Treg cell therapy with a particular focus on GVHD. We discuss the different Treg subtypes and highlight the pharmacological and genetic approaches under investigation to enhance the application of Tregs in allo-HSCT. Lastly, we discuss the remaining challenges for optimal clinical translation and provide insights as to future directions of the field.
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Affiliation(s)
- Mehrdad Hefazi
- Division of Hematology, Mayo Clinic, Rochester, MN 55905, USA;
| | - Sara Bolivar-Wagers
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA;
| | - Bruce R. Blazar
- Division of Blood and Marrow Transplant & Cellular Therapy, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55454, USA;
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Giovannelli I, Bayatti N, Brown A, Wang D, Mickunas M, Camu W, Veyrune JL, Payan C, Garlanda C, Locati M, Juntas-Morales R, Pageot N, Malaspina A, Andreasson U, Suehs C, Saker S, Masseguin C, de Vos J, Zetterberg H, Al-Chalabi A, Leigh PN, Tree T, Bensimon G, Heath PR, Shaw PJ, Kirby J. Amyotrophic lateral sclerosis transcriptomics reveals immunological effects of low-dose interleukin-2. Brain Commun 2021; 3:fcab141. [PMID: 34409288 PMCID: PMC8364666 DOI: 10.1093/braincomms/fcab141] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 04/29/2021] [Accepted: 05/04/2021] [Indexed: 11/30/2022] Open
Abstract
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease causing upper and lower motor neuron loss and currently no effective disease-modifying treatment is available. A pathological feature of this disease is neuroinflammation, a mechanism which involves both CNS-resident and peripheral immune system cells. Regulatory T-cells are immune-suppressive agents known to be dramatically and progressively decreased in patients with amyotrophic lateral sclerosis. Low-dose interleukin-2 promotes regulatory T-cell expansion and was proposed as an immune-modulatory strategy for this disease. A randomized placebo-controlled pilot phase-II clinical trial called Immuno-Modulation in Amyotrophic Lateral Sclerosis was carried out to test safety and activity of low-dose interleukin-2 in 36 amyotrophic lateral sclerosis patients (NCT02059759). Participants were randomized to 1MIU, 2MIU-low-dose interleukin-2 or placebo and underwent one injection daily for 5 days every 28 days for three cycles. In this report, we describe the results of microarray gene expression profiling of trial participants' leukocyte population. We identified a dose-dependent increase in regulatory T-cell markers at the end of the treatment period. Longitudinal analysis revealed an alteration and inhibition of inflammatory pathways occurring promptly at the end of the first treatment cycle. These responses are less pronounced following the end of the third treatment cycle, although an activation of immune-regulatory pathways, involving regulatory T-cells and T helper 2 cells, was evident only after the last cycle. This indicates a cumulative effect of repeated low-dose interleukin-2 administration on regulatory T-cells. Our analysis suggested the existence of inter-individual variation amongst trial participants and we therefore classified patients into low, moderate and high-regulatory T-cell-responders. NanoString profiling revealed substantial baseline differences between participant immunological transcript expression profiles with the least responsive patients showing a more inflammatory-prone phenotype at the beginning of the trial. Finally, we identified two genes in which pre-treatment expression levels correlated with the magnitude of drug responsiveness. Therefore, we proposed a two-biomarker based regression model able to predict patient regulatory T-cell-response to low-dose interleukin-2. These findings and the application of this methodology could be particularly relevant for future precision medicine approaches to treat amyotrophic lateral sclerosis.
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Affiliation(s)
- Ilaria Giovannelli
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
| | - Nadhim Bayatti
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
| | - Abigail Brown
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
| | - Dennis Wang
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK.,Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
| | - Marius Mickunas
- Department of Computer Science, University of Sheffield, Sheffield S1 4DP, UK
| | - William Camu
- Department of Immunobiology, Faculty of Life Science and Medicine, King's College London, London SE1 9RT, UK
| | - Jean-Luc Veyrune
- Clinique du Motoneurone, CHU Gui de Chaliac, University of Montpellier, Montpellier 34295, France
| | - Christine Payan
- Department of Cell and Tissue Engineering, University of Montpellier, CHU Montpellier, Montpellier 34000, France.,Department of Biostatistics, Clinical Epidemiology, Public Health and Innovation in Methodology (BESPIM), Nîmes University Hospital, Nîmes 30029, France
| | - Cecilia Garlanda
- Department of Pharmacology, AP-HP Sorbonne University, Pitié-Salpêtrière Hospital, F-75013 Paris, 75013 France.,Humanitas Clinical & Research Center-IRCCS, Milan 20089, Italy
| | - Massimo Locati
- Humanitas University, Pieve Emanuele, Milan 20090, Italy.,Department of Medical Biotechnologies and Translational Medicine, University Milan, Milan 20133, Italy
| | - Raul Juntas-Morales
- Department of Immunobiology, Faculty of Life Science and Medicine, King's College London, London SE1 9RT, UK
| | - Nicolas Pageot
- Department of Immunobiology, Faculty of Life Science and Medicine, King's College London, London SE1 9RT, UK
| | - Andrea Malaspina
- Department of Neuroimmunology, Barts and the London School of Medicine and Dentistry, Neuroscience and Trauma Centre, Institute of Cell and Molecular Medicine, London E1 2AT, UK
| | - Ulf Andreasson
- Department of Psychiatry & Neurochemistry, University of Gothenburg, Mölndal 41345, Sweden
| | - Carey Suehs
- Department of Biostatistics, Clinical Epidemiology, Public Health and Innovation in Methodology (BESPIM), Nîmes University Hospital, Nîmes 30029, France.,Department of Medical Information, University of Montpellier, CHU Montpellier, Montpellier, France.,Department of Respiratory Diseases, University of Montpellier, CHU Montpellier, Montpellier 34090, France
| | - Safa Saker
- DNA and Cell Bank, Genethon, Evry 91000, France
| | - Christophe Masseguin
- Delegation for Clinical Research and Innovation, Nîmes University Hospital, Nîmes 30029, France
| | - John de Vos
- Clinique du Motoneurone, CHU Gui de Chaliac, University of Montpellier, Montpellier 34295, France
| | - Henrik Zetterberg
- Department of Psychiatry & Neurochemistry, University of Gothenburg, Mölndal 41345, Sweden.,Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal 43180, Sweden.,Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.,UK Dementia Research Institute at UCL, London WC1E 6BT, UK
| | - Ammar Al-Chalabi
- Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London SE5 9RX, UK.,Department of Neurology, King's College Hospital, London SE5 9RS, UK
| | - P Nigel Leigh
- Brighton and Sussex Medical School, The Trafford Centre for Biomedical Research, Falmer, Brighton BN1 9RY, UK
| | - Timothy Tree
- Department of Computer Science, University of Sheffield, Sheffield S1 4DP, UK.,NIHR Biomedical Research Centre, Guy's and St Thomas' NHS Foundation Trust and King's College London, London SE1 9RT, UK
| | - Gilbert Bensimon
- Department of Cell and Tissue Engineering, University of Montpellier, CHU Montpellier, Montpellier 34000, France.,Department of Biostatistics, Clinical Epidemiology, Public Health and Innovation in Methodology (BESPIM), Nîmes University Hospital, Nîmes 30029, France.,Department of Pharmacology, Sorbonne University Médecine, F-75013 Paris 75013, France
| | - Paul R Heath
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
| | - Pamela J Shaw
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
| | - Janine Kirby
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield S10 2HQ, UK
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CD4+ T-cell reconstitution predicts survival outcomes after acute graft-versus-host-disease: a dual-center validation. Blood 2021; 137:848-855. [PMID: 33150379 DOI: 10.1182/blood.2020007905] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Accepted: 10/04/2020] [Indexed: 11/20/2022] Open
Abstract
Acute graft-versus-host-Disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). We previously showed that early CD4+ T-cell immune reconstitution (IR; CD4+ IR) predicts survival after HCT. Here, we studied the relation between CD4+ IR and survival in patients developing aGVHD. Pediatric patients undergoing first allogeneic HCT at University Medical Center Utrecht (UMC)/Princess Máxima Center (PMC) or Memorial Sloan Kettering Cancer Center (MSK) were included. Primary outcomes were nonrelapse mortality (NRM) and overall survival (OS), stratified for aGVHD and CD4+ IR, defined as ≥50 CD4+ T cells per μL within 100 days after HCT or before aGVHD onset. Multivariate and time-to-event Cox proportional hazards models were applied, and 591 patients (UMC/PMC, n = 276; MSK, n = 315) were included. NRM in patients with grade 3 to 4 aGVHD with or without CD4+ IR within 100 days after HCT was 30% vs 80% (P = .02) at UMC/PMC and 5% vs 67% (P = .02) at MSK. This was associated with lower OS without CD4+ IR (UMC/PMC, 61% vs 20%; P = .04; MSK, 75% vs 33%; P = .12). Inadequate CD4+ IR before aGVHD onset was associated with significantly higher NRM (74% vs 12%; P < .001) and inferior OS (24% vs 78%; P < .001). In this retrospective analysis, we demonstrate that early CD4+ IR, a simple and robust marker predictive of outcomes after HCT, is associated with survival after moderate to severe aGVHD. This association must be confirmed prospectively but suggests strategies to improve T-cell recovery after HCT may influence survival in patients developing aGVHD.
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43
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Guo WW, Su XH, Wang MY, Han MZ, Feng XM, Jiang EL. Regulatory T Cells in GVHD Therapy. Front Immunol 2021; 12:697854. [PMID: 34220860 PMCID: PMC8250864 DOI: 10.3389/fimmu.2021.697854] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/02/2021] [Indexed: 12/25/2022] Open
Abstract
Graft versus host disease (GVHD) is a common complication and the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Pharmacological immunosuppression used in GVHD prophylaxis and treatment lacks specificity and can increase the likelihood of infection and relapse. Regulatory T lymphocytes (Tregs) play a vital role in restraining excessive immune responses and inducing peripheral immune tolerance. In particular, clinical trials have demonstrated that Tregs can prevent and treat GVHD, without increasing the risk of relapse and infection. Hence, adoptive transfer of Tregs to control GVHD using their immunosuppressive properties represents a promising therapeutic approach. To optimally apply Tregs for control of GVHD, a thorough understanding of their biology is necessary. In this review, we describe the biological characteristics of Tregs, including how the stability of FOXP3 expression can be maintained. We will also discuss the mechanisms underlying Tregs-mediated modulation of GVHD and approaches to effectively increase Tregs’ numbers. Finally, we will examine the developing trends in the use of Tregs for clinical therapy.
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Affiliation(s)
- Wen-Wen Guo
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Xiu-Hua Su
- School of Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Ming-Yang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Ming-Zhe Han
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Xiao-Ming Feng
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - Er-Lie Jiang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
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44
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Immunomodulatory Therapies for the Treatment of Graft-versus-host Disease. Hemasphere 2021; 5:e581. [PMID: 34095764 PMCID: PMC8171375 DOI: 10.1097/hs9.0000000000000581] [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: 03/13/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies, and its therapeutic success is based on the graft-versus-leukemia (GvL) effect. Severe acute and chronic graft-versus-host disease (GvHD) are life-threatening complications after allo-HCT. To date, most of the approved treatment strategies for GvHD rely on broadly immunosuppressive regimens, which limit the beneficial GvL effect by reducing the cytotoxicity of anti-leukemia donor T-cells. Therefore, novel therapeutic strategies that rely on immunomodulatory rather than only immunosuppressive effects could help to improve patient outcomes. Treatments should suppress severe GvHD while preserving anti-leukemia immunity. New treatment strategies include the blockade of T-cell activation via inhibition of dipeptidyl peptidase 4 and cluster of differentiation 28-mediated co-stimulation, reduction of proinflammatory interleukin (IL)-2, IL-6 and tumor necrosis factor-α signaling, as well as kinase inhibition. Janus kinase (JAK)1/2 inhibition acts directly on T-cells, but also renders antigen presenting cells more tolerogenic and blocks dendritic cell-mediated T-cell activation and proliferation. Extracorporeal photopheresis, hypomethylating agent application, and low-dose IL-2 are powerful approaches to render the immune response more tolerogenic by regulatory T-cell induction. The transfer of immunomodulatory and immunosuppressive cell populations, including mesenchymal stromal cells and regulatory T-cells, showed promising results in GvHD treatment. Novel experimental procedures are based on metabolic reprogramming of donor T-cells by reducing glycolysis, which is crucial for cytotoxic T-cell proliferation and activity.
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45
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Adhikary SR, Cuthbertson P, Nicholson L, Bird KM, Sligar C, Hu M, O'Connell PJ, Sluyter R, Alexander SI, Watson D. Post-transplant cyclophosphamide limits reactive donor T cells and delays the development of graft-versus-host disease in a humanized mouse model. Immunology 2021; 164:332-347. [PMID: 34021907 DOI: 10.1111/imm.13374] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 05/03/2021] [Accepted: 05/09/2021] [Indexed: 12/27/2022] Open
Abstract
Graft-versus-host disease (GVHD) is a major complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) that develops when donor T cells in the graft become reactive against the host. Post-transplant cyclophosphamide (PTCy) is increasingly used in mismatched allo-HSCT, but how PTCy impacts donor T cells and reduces GVHD is unclear. This study aimed to determine the effect of PTCy on reactive human donor T cells and GVHD development in a preclinical humanized mouse model. Immunodeficient NOD-scid-IL2Rγnull mice were injected intraperitoneally (i.p.) with 20 × 106 human peripheral blood mononuclear cells stained with carboxyfluorescein succinimidyl ester (CFSE) (day 0). Mice were subsequently injected (i.p.) with PTCy (33 mg kg-1 ) (PTCy-mice) or saline (saline-mice) (days 3 and 4). Mice were assessed for T-cell depletion on day 6 and monitored for GVHD for up to 10 weeks. Flow cytometric analysis of livers at day 6 revealed lower proportions of reactive (CFSElow ) human (h) CD3+ T cells in PTCy-mice compared with saline-mice. Over 10 weeks, PTCy-mice showed reduced weight loss and clinical GVHD, with prolonged survival and reduced histological liver GVHD compared with saline-mice. PTCy-mice also demonstrated increased splenic hCD4+ :hCD8+ T-cell ratios and reduced splenic Tregs (hCD4+ hCD25+ hCD127lo ) compared with saline-mice. This study demonstrates that PTCy reduces GVHD in a preclinical humanized mouse model. This corresponded to depletion of reactive human donor T cells, but fewer human Tregs.
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Affiliation(s)
- Sam R Adhikary
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.,Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
| | - Peter Cuthbertson
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.,Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
| | - Leigh Nicholson
- Westmead Institute for Medical Research, Westmead, NSW, Australia
| | - Katrina M Bird
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.,Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
| | - Chloe Sligar
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.,Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
| | - Min Hu
- Westmead Institute for Medical Research, Westmead, NSW, Australia.,Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
| | | | - Ronald Sluyter
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.,Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
| | | | - Debbie Watson
- Illawarra Health and Medical Research Institute, Wollongong, NSW, Australia.,Molecular Horizons and School of Chemistry and Molecular Bioscience, University of Wollongong, Wollongong, NSW, Australia
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Papillion A, Ballesteros-Tato A. The Potential of Harnessing IL-2-Mediated Immunosuppression to Prevent Pathogenic B Cell Responses. Front Immunol 2021; 12:667342. [PMID: 33986755 PMCID: PMC8112607 DOI: 10.3389/fimmu.2021.667342] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 04/06/2021] [Indexed: 11/18/2022] Open
Abstract
Immunosuppressive drugs can partially control Antibody (Ab)-dependent pathology. However, these therapeutic regimens must be maintained for the patient's lifetime, which is often associated with severe side effects. As research advances, our understanding of the cellular and molecular mechanisms underlying the development and maintenance of auto-reactive B cell responses has significantly advanced. As a result, novel immunotherapies aimed to restore immune tolerance and prevent disease progression in autoimmune patients are underway. In this regard, encouraging results from clinical and preclinical studies demonstrate that subcutaneous administration of low-doses of recombinant Interleukin-2 (r-IL2) has potent immunosuppressive effects in patients with autoimmune pathologies. Although the exact mechanism by which IL-2 induces immunosuppression remains unclear, the clinical benefits of the current IL-2-based immunotherapies are attributed to its effect on bolstering T regulatory (Treg) cells, which are known to suppress overactive immune responses. In addition to Tregs, however, rIL-2 also directly prevent the T follicular helper cells (Tfh), T helper 17 cells (Th17), and Double Negative (DN) T cell responses, which play critical roles in the development of autoimmune disorders and have the ability to help pathogenic B cells. Here we discuss the broader effects of rIL-2 immunotherapy and the potential of combining rIL-2 with other cytokine-based therapies to more efficiently target Tfh cells, Th17, and DN T cells and subsequently inhibit auto-antibody (ab) production in autoimmune patients.
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Affiliation(s)
| | - André Ballesteros-Tato
- Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States
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47
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Wang Y, Zheng J, Islam MS, Yang Y, Hu Y, Chen X. The role of CD4 +FoxP3 + regulatory T cells in the immunopathogenesis of COVID-19: implications for treatment. Int J Biol Sci 2021; 17:1507-1520. [PMID: 33907514 PMCID: PMC8071774 DOI: 10.7150/ijbs.59534] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/15/2021] [Indexed: 01/08/2023] Open
Abstract
The severe cases of Coronavirus Disease 2019 (COVID-19) frequently exhibit excessive inflammatory responses, acute respiratory distress syndrome (ARDS), coagulopathy, and organ damage. The most striking immunopathology of advanced COVID-19 is cytokine release syndrome or "cytokine storm" that is attributable to the deficiencies in immune regulatory mechanisms. CD4+FoxP3+ regulatory T cells (Tregs) are central regulators of immune responses and play an indispensable role in the maintenance of immune homeostasis. Tregs are likely involved in the attenuation of antiviral defense at the early stage of infection and ameliorating inflammation-induced organ injury at the late stage of COVID-19. In this article, we review and summarize the current understanding of the change of Tregs in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and discuss the potential role of Tregs in the immunopathology of COVID-19. The emerging concept of Treg-targeted therapies, including both adoptive Treg transfer and low dose of IL-2 treatment, is introduced. Furthermore, the potential Treg-boosting effect of therapeutic agents used in the treatment of COVID-19, including dexamethasone, vitamin D, tocilizumab and sarilumab, chloroquine, hydroxychloroquine, azithromycin, adalimumab and tetrandrine, is discussed. The problems in the current study of Treg cells in COVID-19 and future perspectives are also addressed.
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Affiliation(s)
| | | | | | | | | | - Xin Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau SAR 999078, China
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48
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Williams KM, Inamoto Y, Im A, Hamilton B, Koreth J, Arora M, Pusic I, Mays JW, Carpenter PA, Luznik L, Reddy P, Ritz J, Greinix H, Paczesny S, Blazar BR, Pidala J, Cutler C, Wolff D, Schultz KR, Pavletic SZ, Lee SJ, Martin PJ, Socie G, Sarantopoulos S. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report. Transplant Cell Ther 2021; 27:452-466. [PMID: 33877965 DOI: 10.1016/j.jtct.2021.02.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023]
Abstract
Preventing chronic graft-versus-host disease (GVHD) remains challenging because the unique cellular and molecular pathways that incite chronic GVHD are poorly understood. One major point of intervention for potential prevention of chronic GVHD occurs at the time of transplantation when acute donor anti-recipient immune responses first set the events in motion that result in chronic GVHD. After transplantation, additional insults causing tissue injury can incite aberrant immune responses and loss of tolerance, further contributing to chronic GVHD. Points of intervention are actively being identified so that chronic GVHD initiation pathways can be targeted without affecting immune function. The major objective in the field is to continue basic studies and to translate what is learned about etiopathology to develop targeted prevention strategies that decrease the risk of morbid chronic GVHD without increasing the risks of cancer relapse or infection. Development of strategies to predict the risk of developing debilitating or deadly chronic GVHD is a high research priority. This working group recommends further interrogation into the mechanisms underpinning chronic GVHD development, and we highlight considerations for future trial design in prevention trials.
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Affiliation(s)
- Kirsten M Williams
- Division of Blood and Marrow Transplantation, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
| | - Yoshihiro Inamoto
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Annie Im
- Division of Hematology Oncology, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Betty Hamilton
- Blood and Marrow Transplant Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
| | - John Koreth
- Dana-Farber Cancer Institute, Division of Hematologic Malignancies, Harvard Medical School, Boston, Massachusetts
| | - Mukta Arora
- Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Iskra Pusic
- BMT and Leukemia Section, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri
| | - Jacqueline W Mays
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Paul A Carpenter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Leo Luznik
- Division of Hematologic Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Pavan Reddy
- Divsion of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, Michigan
| | - Jerome Ritz
- Dana-Farber Cancer Institute, Division of Hematologic Malignancies, Harvard Medical School, Boston, Massachusetts
| | - Hildegard Greinix
- Clinical Division of Hematology, Medical University of Graz, Graz, Austria
| | - Sophie Paczesny
- Department of Microbiology and Immunology and Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina
| | - Bruce R Blazar
- Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Joseph Pidala
- Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Corey Cutler
- Dana-Farber Cancer Institute, Division of Hematologic Malignancies, Harvard Medical School, Boston, Massachusetts
| | - Daniel Wolff
- Department of Internal Medicine III, University Hospital of Regensburg, Regensburg, Germany
| | - Kirk R Schultz
- Pediatric Oncology, Hematology, and Bone Marrow Transplant, BC Children's Hospital, Vancouver, British Columbia, Canada
| | - Steven Z Pavletic
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephanie J Lee
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Paul J Martin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Gerard Socie
- Hematology Transplantation, Saint Louis Hospital, AP-HP, and University of Paris, INSERM U976, Paris, France.
| | - Stefanie Sarantopoulos
- Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Durham, North Carolina.
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49
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Immunopathology and biology-based treatment of steroid-refractory graft-versus-host disease. Blood 2021; 136:429-440. [PMID: 32526035 DOI: 10.1182/blood.2019000953] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 01/24/2020] [Indexed: 12/12/2022] Open
Abstract
Acute graft-versus-host disease (GVHD) is 1 of the major life-threating complications after allogeneic cell transplantation. Although steroids remain first-line treatment, roughly one-half of patients will develop steroid-refractory GVHD (SR-GVHD), which portends an extremely poor prognosis. Many agents that have shown encouraging response rates in early phase 1/2 trials for prevention and treatment have been unsuccessful in demonstrating a survival advantage when applied in the setting of SR-GVHD. The discovery of novel treatments has been further complicated by the absence of clinically informative animal models that address what may reflect a distinct pathophysiology. Nonetheless, the combined knowledge of established bone marrow transplantation models and recent human trials in SR-GVHD patients are beginning to illuminate novel mechanisms for inhibiting T-cell signaling and promoting tissue tolerance that provide an increased understanding of the underlying biology of SR-GVHD. Here, we discuss recent findings of newly appreciated cellular and molecular mechanisms and provide novel translational opportunities for advancing the effectiveness of treatment in SR-GVHD.
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Naserian S, Leclerc M, Shamdani S, Uzan G. Current Preventions and Treatments of aGVHD: From Pharmacological Prophylaxis to Innovative Therapies. Front Immunol 2020; 11:607030. [PMID: 33391276 PMCID: PMC7773902 DOI: 10.3389/fimmu.2020.607030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 11/16/2020] [Indexed: 12/16/2022] Open
Abstract
Graft versus host disease (GVHD) is one of the main causes of mortality and the reason for up to 50% of morbidity after hematopoietic stem cell transplantations (HSCT) which is the treatment of choice for many blood malignancies. Thanks to years of research and exploration, we have acquired a profound understanding of the pathophysiology and immunopathology of these disorders. This led to the proposition and development of many therapeutic approaches during the last decades, some of them with very promising results. In this review, we have focused on the recent GVHD treatments from classical chemical and pharmacological prophylaxis to more innovative treatments including gene therapy and cell therapy, most commonly based on the application of a variety of immunomodulatory cells. Furthermore, we have discussed the advantages and potentials of cell-free therapy as a newly emerging approach to treat GVHD. Among them, we have particularly focused on the implication of the TNFα-TNFR2 axis as a new immune checkpoint signaling pathway controlling different aspects of many immunoregulatory cells.
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Affiliation(s)
- Sina Naserian
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Paris-Saclay University, Villejuif, France
- CellMedEx, Saint Maur Des Fossés, France
| | - Mathieu Leclerc
- Service d’Hématologie Clinique et de Thérapie Cellulaire, Hôpital Henri Mondor, Créteil, France
- INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, France
- Faculté de Médecine de Créteil, Université Paris-Est, Créteil, France
| | - Sara Shamdani
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Paris-Saclay University, Villejuif, France
- CellMedEx, Saint Maur Des Fossés, France
| | - Georges Uzan
- INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France
- Paris-Saclay University, Villejuif, France
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