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Klein BY, Ben-David I, Gofrit ON, Greenblatt CL. Repurposing peripheral immunocytes of Bacillus Calmette Guerin-vaccinated melanoma patients to reveal preventive Alzheimer's disease mechanisms, possibly via the unfolded protein response. J Alzheimers Dis Rep 2025; 9:25424823241309664. [PMID: 40034523 PMCID: PMC11864245 DOI: 10.1177/25424823241309664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 12/05/2024] [Indexed: 03/05/2025] Open
Abstract
Background Alzheimer's disease (AD) dysfunctional unfolded protein response (UPR) is revealed by amyloid-β aggregates. Normally, UPR reacts to endoplasmic reticulum stress by resolving misfolded/aggregated proteins, and UPR failure induces brain-cell apoptosis consistent with AD pathology. Peripheral blood mononuclear cells (PBMC) and immunocyte brain infiltrates are involved in AD pathogenesis, whose risk is lowered by the Bacillus Calmette Guerin (BCG) vaccine. Hypothetically, BCG prevents AD caused by UPR-driven apoptosis in PBMC brain infiltrates, corrected by BCG-vaccinated PBMC brain infiltrates. Objective To reveal whether BCG shifts the UPR towards cell survival. Method: PBMC proteins from 6 individuals were compared by immuno-electrophoresis before and after BCG hypervaccination. Cryopreserved PBMC provided an opportunity to analyze the BCG impact on the UPR, although their donor destiny to develop AD was unknown. UPR signaling responsive to BCG was recorded to examine if BCG can influence UPR signaling and thereby explain the previously demonstrated AD prevention by BCG. Results UPR signal levels were scored according to positive versus negative cell survival odds by the BCG impact on a dozen UPR signals. The balance between positive and negative scores of individuals emphasizes the impact of the BCG vaccine on the UPR. The antiapoptotic UPR signals under BCG show opposite trends to UPR signals in AD brains, reported by the literature. In conclusion, 3/6 individuals had superior PBMC survival chances under BCG. Conclusions These results suggest that the UPR is part of the mechanism responsible for reducing the risk of AD, as previously shown among BCG-treated bladder cancer patients.
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Affiliation(s)
- Benjamin Y Klein
- Department of Microbiology and Molecular Genetics Hebrew University Medical School, Hadassah University Medical School, Ein-Karem, Jerusalem, Israel
| | - Inna Ben-David
- Sharett Institute of Oncology, Hadassah University Medical School,
Ein-Karem, Jerusalem, Israel
| | - Ofer N Gofrit
- Department of Urology, Hadassah University Medical School, Ein-Karem, Jerusalem, Israel
| | - Charles L Greenblatt
- Department of Microbiology and Molecular Genetics Hebrew University Medical School, Hadassah University Medical School, Ein-Karem, Jerusalem, Israel
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2
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Liu Y, Li W, Lei L, Zhou Y, Huang M, Li Y, Zhang X, Jiang Y, Wu H, Zheng Z, Ma K, Tang C. Effects of PGK1 on immunoinfiltration by integrated single-cell and bulk RNA-sequencing analysis in sepsis. Front Immunol 2024; 15:1449975. [PMID: 39712033 PMCID: PMC11659135 DOI: 10.3389/fimmu.2024.1449975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2024] [Accepted: 11/20/2024] [Indexed: 12/24/2024] Open
Abstract
Background Sepsis, a life-threatening organ dysfunction caused by a dysregulated immune response to infection, remains a significant global health challenge. Phosphoglycerate kinase 1 (PGK1) has been implicated in regulating inflammation and immune cell infiltration in inflammatory conditions. However, the role of PGK1 in sepsis remains largely unexplored. Methods Four microarray datasets and a high throughput sequencing dataset were acquired from GEO database to reveal the PGK1 expression in patients of sepsis. Quantitative real-time PCR and western blotting was then used to validate the PGK1 level. Additionally, microarray and single-cell RNA sequencing data integration, including gene set enrichment analysis (GSEA), KEGG and GO functional enrichment analysis, immune infiltration analysis, and single-cell sequencing analysis, were performed to elucidate the role of PGK1 in sepsis. Results Our results revealed a significant upregulation of PGK1 in sepsis patients, with the area under the ROC curve (AUC) exceeding 0.9 across multiple datasets, indicating PGK1's strong potential as a diagnostic biomarker. Notably, PGK1 was enriched in key immune-related pathways, including the TNF signaling pathways, and leukocyte transendothelial migration, suggesting its involvement in immune regulation. Furthermore, PGK1 expression showed a positive correlation with the levels of inflammatory mediators CXCL1, CXCL16, and the chemokine receptor CCR1. In terms of immune cell infiltration, PGK1 was positively correlated with naive B cells, resting memory CD4 T cell, gamma delta T cells, M0 macrophages, eosinophils and negatively correlated with plasma cells, CD8 T cells, activated memory CD4 T cell, Tregs, activated dendritic cells. Conclusions This study concluded that PGK1 served as a novel diagnostic biomarker for sepsis, with potential implications for prognosis and immune regulation. The significant upregulation of PGK1 in sepsis patients and its association with immune-related pathways and cell types highlight its potential role in the pathogenesis of sepsis.
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Affiliation(s)
- Yu Liu
- Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Weijie Li
- Centre for Infection and Immunity Studies, School of Medicine, The Sun Yat-sen University, Shenzhen, China
| | - Lei Lei
- Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yaoliang Zhou
- Emergency and Disaster Medical Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Mingcheng Huang
- Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yide Li
- Department of Critical Care Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xiaoying Zhang
- Health Management Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yingyu Jiang
- Department of Renal Rheumatology and Immunology, The People’s Hospital of Hezhou, Hezhou, China
| | - Haiqi Wu
- Centre for Infection and Immunity Studies, School of Medicine, The Sun Yat-sen University, Shenzhen, China
| | - Zhihua Zheng
- Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Kongyang Ma
- Centre for Infection and Immunity Studies, School of Medicine, The Sun Yat-sen University, Shenzhen, China
| | - Chun Tang
- Department of Nephrology, Center of Kidney and Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
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Wang Y, Ullah MA, Waltner OG, Bhise SS, Ensbey KS, Schmidt CR, Legg SR, Sekiguchi T, Nelson EL, Kuns RD, Nemychenkov NS, Atilla E, Yeh AC, Takahashi S, Boiko JR, Varelias A, Blazar BR, Koyama M, Minnie SA, Clouston AD, Furlan SN, Zhang P, Hill GR. Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD. J Clin Invest 2024; 134:e170125. [PMID: 38828727 PMCID: PMC11142741 DOI: 10.1172/jci170125] [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: 03/02/2023] [Accepted: 04/09/2024] [Indexed: 06/05/2024] Open
Abstract
Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.
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Affiliation(s)
- Yewei Wang
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Md Ashik Ullah
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Olivia G. Waltner
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Shruti S. Bhise
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Kathleen S. Ensbey
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Christine R. Schmidt
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Samuel R.W. Legg
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Tomoko Sekiguchi
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Ethan L. Nelson
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Rachel D. Kuns
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Nicole S. Nemychenkov
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Erden Atilla
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Albert C. Yeh
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Shuichiro Takahashi
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Julie R. Boiko
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Antiopi Varelias
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Bruce R. Blazar
- Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Motoko Koyama
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Simone A. Minnie
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | | | - Scott N. Furlan
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Pediatrics and
| | - Ping Zhang
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Geoffrey R. Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Division of Medical Oncology, University of Washington, Seattle, Washington, USA
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4
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Burk AC, Apostolova P. Metabolic instruction of the graft-versus-leukemia immunity. Front Immunol 2024; 15:1347492. [PMID: 38500877 PMCID: PMC10944922 DOI: 10.3389/fimmu.2024.1347492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/05/2024] [Indexed: 03/20/2024] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed to cure hematological malignancies, such as acute myeloid leukemia (AML), through the graft-versus-leukemia (GVL) effect. In this immunological process, donor immune cells eliminate residual cancer cells in the patient and exert tumor control through immunosurveillance. However, GVL failure and subsequent leukemia relapse are frequent and associated with a dismal prognosis. A better understanding of the mechanisms underlying AML immune evasion is essential for developing novel therapeutic strategies to boost the GVL effect. Cellular metabolism has emerged as an essential regulator of survival and cell fate for both cancer and immune cells. Leukemia and T cells utilize specific metabolic programs, including the orchestrated use of glucose, amino acids, and fatty acids, to support their growth and function. Besides regulating cell-intrinsic processes, metabolism shapes the extracellular environment and plays an important role in cell-cell communication. This review focuses on recent advances in the understanding of how metabolism might affect the anti-leukemia immune response. First, we provide a general overview of the mechanisms of immune escape after allo-HCT and an introduction to leukemia and T cell metabolism. Further, we discuss how leukemia and myeloid cell metabolism contribute to an altered microenvironment that impairs T cell function. Next, we review the literature linking metabolic processes in AML cells with their inhibitory checkpoint ligand expression. Finally, we focus on recent findings concerning the role of systemic metabolism in sustained GVL efficacy. While the majority of evidence in the field still stems from basic and preclinical studies, we discuss translational findings and propose further avenues for bridging the gap between bench and bedside.
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Affiliation(s)
- Ann-Cathrin Burk
- German Cancer Consortium (DKTK), partner site Freiburg, a partnership between DKFZ and Medical Center - University of Freiburg, Freiburg, Germany
- Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Petya Apostolova
- Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
- Division of Hematology, University Hospital Basel, Basel, Switzerland
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Nakano H, Sato K, Izawa J, Takayama N, Hayakawa H, Ikeda T, Kawaguchi SI, Mashima K, Umino K, Morita K, Ito R, Ohno N, Tominaga K, Endo H, Kanda Y. Fatty Acids Play a Critical Role in Mitochondrial Oxidative Phosphorylation in Effector T Cells in Graft-versus-Host Disease. Immunohorizons 2024; 8:228-241. [PMID: 38441482 PMCID: PMC10985061 DOI: 10.4049/immunohorizons.2300115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 03/07/2024] Open
Abstract
Although the role of aerobic glycolysis in activated T cells has been well characterized, whether and how fatty acids (FAs) contribute to donor T cell function in allogeneic hematopoietic stem cell transplantation is unclear. Using xenogeneic graft-versus-host disease (GVHD) models, this study demonstrated that exogenous FAs serve as a crucial source of mitochondrial respiration in donor T cells in humans. By comparing human T cells isolated from wild-type NOD/Shi-scid-IL2rγnull (NOG) mice with those from MHC class I/II-deficient NOG mice, we found that donor T cells increased extracellular FA uptake, the extent of which correlates with their proliferation, and continued to increase FA uptake during effector differentiation. Gene expression analysis showed the upregulation of a wide range of lipid metabolism-related genes, including lipid hydrolysis, mitochondrial FA transport, and FA oxidation. Extracellular flux analysis demonstrated that mitochondrial FA transport was required to fully achieve the mitochondrial maximal respiration rate and spare respiratory capacity, whereas the substantial disruption of glucose supply by either glucose deprivation or mitochondrial pyruvate transport blockade did not impair oxidative phosphorylation. Taken together, FA-driven mitochondrial respiration is a hallmark that differentiates TCR-dependent T cell activation from TCR-independent immune response after hematopoietic stem cell transplant.
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Affiliation(s)
- Hirofumi Nakano
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Kazuya Sato
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Junko Izawa
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Norihito Takayama
- Core Center of Research Apparatus, Jichi Medical University, Tochigi, Japan
| | - Hiroko Hayakawa
- Core Center of Research Apparatus, Jichi Medical University, Tochigi, Japan
| | - Takashi Ikeda
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Shin-Ichiro Kawaguchi
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Kiyomi Mashima
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Kento Umino
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Kaoru Morita
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Ryoji Ito
- Central Institute for Experimental Animals, Kawasaki, Kanagawa, Japan
| | - Nobuhiko Ohno
- Division of Histology and Cell Biology, Department of Anatomy, Jichi Medical University, Tochigi, Japan
| | - Kaoru Tominaga
- Department of Biochemistry, Jichi Medical University, Tochigi, Japan
| | - Hitoshi Endo
- Department of Biochemistry, Jichi Medical University, Tochigi, Japan
| | - Yoshinobu Kanda
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
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6
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Güzel N, Rink L, Fischer HJ. Zinc Modulates Glutamine Metabolism in T Cells. Mol Nutr Food Res 2023; 67:e2300155. [PMID: 37658486 DOI: 10.1002/mnfr.202300155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 07/27/2023] [Indexed: 09/03/2023]
Abstract
SCOPE Zinc and glutamine are well known to be essential for the function and polarization of immune cells. TH 17 cells are more frequently induced during zinc deficiency and cover their energy requirement mainly through glutaminolysis. A dysregulation of TH 17 cells can contribute to the development of autoimmune diseases. Both inhibition of glutaminolysis and zinc supplementation suppress experimental autoimmune encephalomyelitis in mice. Therefore, the aim of this study is to investigate whether zinc modulates glutaminolysis in T cells. METHODS AND RESULTS CD3/CD28 stimulation and mixed lymphocytes culture are used as in vitro models for T cell activation. Then, the glutaminolysis is investigated on mRNA, protein, and functional level. Zinc deficiency and glutaminase (GLS) inhibition decrease immune responses in vitro. Furthermore, extracellular zinc and glutamine levels both modulate glutaminolysis by changing the expression of glutamine transporters and key enzymes. Intriguingly, zinc directly interferes with the activity of GLS both in a cell free system and in the cytosol. CONCLUSION Besides T cell subset differentiation, zinc also impacts on the cellular metabolism by inhibiting glutaminolysis. This suggests that zinc deficiency can contribute to the development of autoimmune diseases whereas zinc supplementation can support their therapy.
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Affiliation(s)
- Nergis Güzel
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
| | - Lothar Rink
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
| | - Henrike Josephine Fischer
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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7
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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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Cassano A, Chong AS, Alegre ML. Tregs in transplantation tolerance: role and therapeutic potential. FRONTIERS IN TRANSPLANTATION 2023; 2:1217065. [PMID: 38993904 PMCID: PMC11235334 DOI: 10.3389/frtra.2023.1217065] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/14/2023] [Indexed: 07/13/2024]
Abstract
CD4+ Foxp3+ regulatory T cells (Tregs) are indispensable for preventing autoimmunity, and they play a role in cancer and transplantation settings by restraining immune responses. In this review, we describe evidence for the importance of Tregs in the induction versus maintenance of transplantation tolerance, discussing insights into mechanisms of Treg control of the alloimmune response. Further, we address the therapeutic potential of Tregs as a clinical intervention after transplantation, highlighting engineered CAR-Tregs as well as expansion of donor and host Tregs.
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Affiliation(s)
- Alexandra Cassano
- Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Anita S. Chong
- Department of Surgery, University of Chicago, Chicago, IL, United States
| | - Maria-Luisa Alegre
- Department of Medicine, University of Chicago, Chicago, IL, United States
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9
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Li Q, Wang X, Song Q, Yang S, Wu X, Yang D, Marié IJ, Qin H, Zheng M, Nasri U, Kong X, Wang B, Lizhar E, Cassady K, Tompkins J, Levy D, Martin PJ, Zhang X, Zeng D. Donor T cell STAT3 deficiency enables tissue PD-L1-dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity. J Clin Invest 2023; 133:e165723. [PMID: 37526084 PMCID: PMC10378157 DOI: 10.1172/jci165723] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 06/02/2023] [Indexed: 08/02/2023] Open
Abstract
STAT3 deficiency (STAT3-/-) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3-/- donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose-dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling. In GVHD target tissues, STAT3 deficiency amplified PD-L1/PD-1 inhibition of glutathione (GSH)/Myc pathways that regulate metabolic reprogramming in activated T cells, with decreased glycolytic and mitochondrial ATP production and increased mitochondrial ROS production and dysfunction, leading to tissue-specific deletion of host-reactive T cells and prevention of GVHD. Mitochondrial STAT3 deficiency alone did not reduce GSH expression or prevent GVHD. In lymphoid tissues, the lack of host-tissue PD-L1 interaction with PD-1 reduced the inhibition of the GSH/Myc pathway despite reduced GSH production caused by STAT3 deficiency and allowed donor T cell functions that mediate GVL activity. Therefore, STAT3 deficiency in donor T cells augments PD-1 signaling-mediated inhibition of GSH/Myc pathways and augments dysfunction of T cells in GVHD target tissues while sparing T cells in lymphoid tissues, leading to prevention of GVHD while preserving GVL effects.
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Affiliation(s)
- Qinjian Li
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Qingxiao Song
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, China
| | - Shijie Yang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Xiwei Wu
- Department of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Dongyun Yang
- Department of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Isabelle J Marié
- Department of Pathology, NYU Grossman School of Medicine, New York, USA
| | - Hanjun Qin
- Department of Computational and Quantitative Medicine, Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Moqian Zheng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Ubaydah Nasri
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Xiaohui Kong
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Bixin Wang
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, and Fujian Medical University Union Hospital, Fuzhou, China
| | - Elizabeth Lizhar
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
| | - Kaniel Cassady
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
| | - Josh Tompkins
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
| | - David Levy
- Department of Pathology, NYU Grossman School of Medicine, New York, USA
| | - Paul J Martin
- Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, State Key Laboratory of Trauma, Burn and Combined Injury, Army Medical University, Chongqing, China
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute of City of Hope, Duarte, California, USA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, California, USA
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10
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Brandstadter JD, Outen R, Maillard I. Having it both ways: how STAT3 deficiency blocks graft-versus-host disease while preserving graft-versus-leukemia activity. J Clin Invest 2023; 133:e172251. [PMID: 37526083 PMCID: PMC10378150 DOI: 10.1172/jci172251] [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] [Indexed: 08/02/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation can cure patients with high-risk leukemia through graft-versus-leukemia (GVL) effects, the process by which malignant leukemic cells are cleared by donor-derived immune cells from the graft. The problem of harnessing GVL effects while controlling inflammation and host-organ damage linked with graft-versus-host disease (GVHD) has been the most formidable hurdle facing allogeneic hematopoietic cell transplantation. This powerful, curative-intent therapy remains among the most toxic treatments in the hematologist's armamentarium due to the combined risks of GVHD-related morbidity, infections, and leukemia relapse. In this issue of the JCI, Li, Wang, et al. report that T cell Stat3 deficiency can extricate GVL effects from GVHD through tissue-specific programmed death-ligand 1/programmed cell death protein 1-dependent (PD-L1/PD-1-dependent) bioenergetic alterations that blunt harmful T cell effects in GVHD target organs, while preserving their beneficial antitumor activity in lymphohematopoietic tissues.
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11
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Wu H, Huang H, Zhao Y. Interplay between metabolic reprogramming and post-translational modifications: from glycolysis to lactylation. Front Immunol 2023; 14:1211221. [PMID: 37457701 PMCID: PMC10338923 DOI: 10.3389/fimmu.2023.1211221] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023] Open
Abstract
Cellular metabolism plays a critical role in determining the fate and function of cells. Metabolic reprogramming and its byproducts have a complex impact on cellular activities. In quiescent T cells, oxidative phosphorylation (OXPHOS) is the primary pathway for survival. However, upon antigen activation, T cells undergo rapid metabolic reprogramming, characterized by an elevation in both glycolysis and OXPHOS. While both pathways are induced, the balance predominantly shifts towards glycolysis, enabling T cells to rapidly proliferate and enhance their functionality, representing the most distinctive signature during activation. Metabolic processes generate various small molecules resulting from enzyme-catalyzed reactions, which also modulate protein function and exert regulatory control. Notably, recent studies have revealed the direct modification of histones, known as lactylation, by lactate derived from glycolysis. This lactylation process influences gene transcription and adds a novel variable to the regulation of gene expression. Protein lactylation has been identified as an essential mechanism by which lactate exerts its diverse functions, contributing to crucial biological processes such as uterine remodeling, tumor proliferation, neural system regulation, and metabolic regulation. This review focuses on the metabolic reprogramming of T cells, explores the interplay between lactate and the immune system, highlights the impact of lactylation on cellular function, and elucidates the intersection of metabolic reprogramming and epigenetics.
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Affiliation(s)
- Hengwei Wu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, People's Government of Zhejiang Province, Hangzhou, Zhejiang, China
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, People's Government of Zhejiang Province, Hangzhou, Zhejiang, China
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
| | - Yanmin Zhao
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, People's Government of Zhejiang Province, Hangzhou, Zhejiang, China
- Zhejiang Laboratory for Systems & Precision Medicine, Zhejiang University Medical Center, Hangzhou, Zhejiang, China
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12
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Ramgopal A, Braverman EL, Sun LK, Monlish D, Wittmann C, Ramsey MJ, Caitley R, Hawse W, Byersdorfer CA. AMPK Drives Both Glycolytic and Oxidative Metabolism in T Cells During Graft-versus-host Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.12.544686. [PMID: 37398326 PMCID: PMC10312647 DOI: 10.1101/2023.06.12.544686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
Allogeneic T cells reprogram their metabolism during acute graft-versus-host disease (GVHD) in a process reliant on the cellular energy sensor AMP-activated protein kinase (AMPK). Deletion of AMPK in donor T cells limits GVHD but still preserves homeostatic reconstitution and graft-versus-leukemia (GVL) effects. In the current studies, murine T cells lacking AMPK decreased oxidative metabolism at early timepoints post-transplant and were also unable to mediate a compensatory increase in glycolysis following inhibition of the electron transport chain. Human T cells lacking AMPK gave similar results, with glycolytic compensation impaired both in vitro and following expansion in vivo in a modified model of GVHD. Immunoprecipitation of proteins from day 7 allogeneic T cells, using an antibody specific to phosphorylated AMPK targets, recovered lower levels of multiple glycolysis-related proteins including the glycolytic enzymes aldolase, enolase, pyruvate kinase M (PKM), and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Functionally, murine T cells lacking AMPK exhibited impaired aldolase activity following anti-CD3/CD28 stimulation and a decrease in GAPDH activity on day 7 post-transplant. Importantly, these changes in glycolysis correlated with an impaired ability of AMPK KO T cells to produce significant amounts of interferon gamma (IFNγ) upon antigenic re-stimulation. Together these data highlight a significant role for AMPK in controlling oxidative and glycolytic metabolism in both murine and human T cells during GVHD and endorse further study of AMPK inhibition as a potential target for future clinical therapies. KEY POINTS AMPK plays a key role in driving both and oxidative and glycolytic metabolism in T cells during graft-versus-host disease (GVHD)Absence of AMPK simultaneously impairs both glycolytic enzyme activity, most notably by aldolase, and interferon gamma (IFNγ) production.
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13
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Wen Q, Xu ZL, Wang Y, Lv M, Song Y, Lyv ZS, Xing T, Xu LP, Zhang XH, Huang XJ, Kong Y. Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease. SCIENCE CHINA. LIFE SCIENCES 2023; 66:528-544. [PMID: 36166182 DOI: 10.1007/s11427-022-2170-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 07/27/2022] [Indexed: 10/14/2022]
Abstract
Although glucorticosteroids (GCs) are the standard first-line therapy for acute graft-versus-host disease (aGvHD), nearly 50% of aGvHD patients have no response to GCs. The role of T cell metabolism in murine aGvHD was recently reported. However, whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate aGvHD remains to be elucidated. Increased glycolysis, characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and higher rates of glucose consumption and lactate production were found in T cells from aGvHD patients. Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory cells. In a humanized mouse model, PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented aGvHD, respectively. Importantly, our integrated data from patient samples in vitro, in a humanized xenogeneic murine model of aGvHD and graft-versus-leukaemia (GVL) demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate aGvHD without loss of GVL effects. Together, the current study indicated that glycolysis is critical for T cell activation and induction of human aGvHD. Therefore, the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for aGvHD patients. GCs combined with glycolysis inhibitors promises to be a novel first-line combination therapy for aGvHD patients.
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Affiliation(s)
- Qi Wen
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Zheng-Li Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Meng Lv
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Yang Song
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100044, China
| | - Zhong-Shi Lyv
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100044, China
| | - Tong Xing
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Lan-Ping Xu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Xiao-Hui Zhang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100044, China
| | - Yuan Kong
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Collaborative Innovation Center of Hematology, Peking University, Beijing, 100044, China.
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14
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Baur R, Karl F, Böttcher-Loschinski R, Stoll A, Völkl S, Gießl A, Flamann C, Bruns H, Schlötzer-Schrehardt U, Böttcher M, Schewe DM, Fischer T, Jitschin R, Mackensen A, Mougiakakos D. Accumulation of T-cell-suppressive PD-L1 high extracellular vesicles is associated with GvHD and might impact GvL efficacy. J Immunother Cancer 2023; 11:jitc-2022-006362. [PMID: 36898735 PMCID: PMC10008446 DOI: 10.1136/jitc-2022-006362] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/17/2023] [Indexed: 03/12/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for a number of hemato-oncological disorders. In fact, allo-HSCT is considered as one of the most successful immunotherapies as its clinical efficacy is based on the donor T-cells' capacity to control residual disease. This process is known as the graft-versus-leukemia (GvL) reaction. However, alloreactive T-cells can also recognize the host as foreign and trigger a systemic potentially life-threatening inflammatory disorder termed graft-versus-host disease (GvHD). A better understanding of the underlying mechanisms that lead to GvHD or disease relapse could help us to improve efficacy and safety of allo-HSCT. In recent years, extracellular vesicles (EVs) have emerged as critical components of intercellular crosstalk. Cancer-associated EVs that express the immune checkpoint molecule programmed death-ligand 1 (PD-L1) can suppress T-cell responses and thus contribute to immune escape. At the same time, it has been observed that inflammation triggers PD-L1 expression as part of a negative feedback network.Here, we investigated whether circulating EVs following allo-HSCT express PD-L1 and tested their efficacy to suppress the ability of (autologous) T-cells to effectively target AML blasts. Finally, we assessed the link between PD-L1 levels on EVs to (T-)cell reconstitution, GvHD, and disease relapse.We were able to detect PD-L1+ EVs that reached a peak PD-L1 expression at 6 weeks post allo-HSCT. Development of acute GvHD was linked to the emergence of PD-L1high EVs following allo-HSCT. Moreover, PD-L1 levels correlated positively with GvHD grade and declined (only) on successful therapeutic intervention. T-cell-inhibitory capacity was higher in PD-L1high EVs as compared with their PD-L1low counterparts and could be antagonized using PD-L1/PD-1 blocking antibodies. Abundance of T-cell-suppressive PD-L1high EVs appears to also impact GvL efficacy as patients were at higher risk for relapse. Finally, patients of PD-L1high cohort displayed a reduced overall survival.Taken together, we show that PD-L1-expressing EVs are present following allo-HSCT. PD-L1 levels on EVs correlate with their ability to suppress T-cells and the occurrence of GvHD. The latter observation may indicate a negative feedback mechanism to control inflammatory (GvHD) activity. This intrinsic immunosuppression could subsequently promote disease relapse.
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Affiliation(s)
- Rebecca Baur
- Department of Hematology and Clinical Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
| | - Franziska Karl
- Department of Hematology and Clinical Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
| | | | - Andrej Stoll
- Department of Hematology and Clinical Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
| | - Simon Völkl
- Department of Hematology and Clinical Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
| | - Andreas Gießl
- Department of Ophthalmology, Friedrich-Alexander-Universitat, Erlangen, Germany
| | - Cindy Flamann
- Department of Hematology and Clinical Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
| | - Heiko Bruns
- Department of Hematology and Clinical Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
| | | | - Martin Böttcher
- Department of Hematology and Oncology, Otto von Guericke Universitat, Magdeburg, Germany
| | - Denis M Schewe
- Pediatrics, Otto von Guericke Universitat, Magdeburg, Germany
| | - Thomas Fischer
- Institute for Molecular and Clinical Immunology, Otto von Guericke Universitat, Magdeburg, Germany
| | - Regina Jitschin
- Department of Hematology and Clinical Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
| | - Andreas Mackensen
- Department of Hematology and Clinical Oncology, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen, Germany
| | - Dimitrios Mougiakakos
- Department of Hematology and Oncology, Otto von Guericke Universitat, Magdeburg, Germany
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15
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Yoshikawa S, Taniguchi K, Sawamura H, Ikeda Y, Tsuji A, Matsuda S. Advantageous tactics with certain probiotics for the treatment of graft-versus-host-disease after hematopoietic stem cell transplantation. World J Hematol 2023; 10:15-24. [DOI: 10.5315/wjh.v10.i2.15] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/03/2022] [Accepted: 11/23/2022] [Indexed: 01/17/2023] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) becomes a standard form of cellular therapy for patients with malignant diseases. HSCT is the first-choice of immunotherapy, although HSCT can be associated with many complications such as graft-versus-host disease (GVHD) which is a major cause of morbidity and mortality after allogeneic HSCT. It has been shown that certain gut microbiota could exert protective and/or regenerative immunomodulatory effects by the production of short-chain fatty acids (SCFAs) such as butyrate in the experimental models of GVHD after allogeneic HSCT. Loss of gut commensal bacteria which can produce SCFAs may worsen dysbiosis, increasing the risk of GVHD. Expression of G-protein coupled receptors such as GPR41 seems to be upre-gulated in the presence of commensal bacteria, which might be associated with the biology of regulatory T cells (Tregs). Treg cells are a suppressive subset of CD4 positive T lymphocytes implicated in the prevention of GVHD after allogeneic HSCT. Here, we discuss the current findings of the relationship between the modification of gut microbiota and the GVHD-related immunity, which suggested that tactics with certain probiotics for the beneficial symbiosis in gut-immune axis might lead to the elevation of safety in the allogeneic HSCT.
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Affiliation(s)
- Sayuri Yoshikawa
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Kurumi Taniguchi
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Haruka Sawamura
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Yuka Ikeda
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Ai Tsuji
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
| | - Satoru Matsuda
- Food Science and Nutrition, Nara Women's University, Nara 630-8506, Japan
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16
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Tian L, Wu Y, Choi HJ, Sui X, Li X, Sofi MH, Kassir MF, Chen X, Mehrotra S, Ogretmen B, Yu XZ. S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission. Cell Mol Immunol 2022; 19:1235-1250. [PMID: 36071219 PMCID: PMC9622814 DOI: 10.1038/s41423-022-00921-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 08/15/2022] [Indexed: 01/27/2023] Open
Abstract
Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the biogenetic processes of different immune cells. In the current study, we demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P. Using genetic and pharmacologic approaches, we demonstrated that inhibition of Sphk1 or S1PR1 substantially attenuated acute GVHD (aGVHD) while retaining the graft-versus-leukemia (GVL) effect. At the cellular level, the Sphk1/S1P/S1PR1 pathway differentially modulated the alloreactivity of CD4+ and CD8+ T cells; it facilitated T-cell differentiation into Th1/Th17 cells but not Tregs and promoted CD4+ T-cell infiltration into GVHD target organs but was dispensable for the CTL activity of allogeneic CD8+ T cells. At the molecular level, the Sphk1/S1P/S1PR1 pathway augmented mitochondrial fission and increased mitochondrial mass in allogeneic CD4+ but not CD8+ T cells by activating the AMPK/AKT/mTOR/Drp1 pathway, providing a mechanistic basis for GVL maintenance when S1P signaling was inhibited. For translational purposes, we detected the regulatory efficacy of pharmacologic inhibitors of Sphk1 and S1PR1 in GVHD induced by human T cells in a xenograft model. Our study provides novel mechanistic insight into how the Sphk1/S1P/S1PR1 pathway modulates T-cell alloreactivity and validates Sphk1 or S1PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse. This novel strategy may be readily translated into the clinic to benefit patients with hematologic malignancies and disorders.
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Affiliation(s)
- Linlu Tian
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yongxia Wu
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Hee-Jin Choi
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Xiaohui Sui
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Xinlei Li
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - M Hanief Sofi
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Mohamed Faisal Kassir
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Xiao Chen
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Shikhar Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Besim Ogretmen
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Xue-Zhong Yu
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
- The Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
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17
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Tian L, Wu Y, Choi HJ, Sui X, Li X, Sofi MH, Kassir MF, Chen X, Mehrotra S, Ogretmen B, Yu XZ. S1P/S1PR1 signaling differentially regulates the allogeneic response of CD4 and CD8 T cells by modulating mitochondrial fission. Cell Mol Immunol 2022. [PMID: 36071219 DOI: 10.1038/s41423-022-00921] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2023] Open
Abstract
Graft-versus-host disease (GVHD) significantly contributes to patient morbidity and mortality after allogeneic hematopoietic cell transplantation (allo-HSCT). Sphingosine-1-phosphate (S1P) signaling is involved in the biogenetic processes of different immune cells. In the current study, we demonstrated that recipient sphingosine kinase 1 (Sphk1), but not Sphk2, was required for optimal S1PR1-dependent donor T-cell allogeneic responses by secreting S1P. Using genetic and pharmacologic approaches, we demonstrated that inhibition of Sphk1 or S1PR1 substantially attenuated acute GVHD (aGVHD) while retaining the graft-versus-leukemia (GVL) effect. At the cellular level, the Sphk1/S1P/S1PR1 pathway differentially modulated the alloreactivity of CD4+ and CD8+ T cells; it facilitated T-cell differentiation into Th1/Th17 cells but not Tregs and promoted CD4+ T-cell infiltration into GVHD target organs but was dispensable for the CTL activity of allogeneic CD8+ T cells. At the molecular level, the Sphk1/S1P/S1PR1 pathway augmented mitochondrial fission and increased mitochondrial mass in allogeneic CD4+ but not CD8+ T cells by activating the AMPK/AKT/mTOR/Drp1 pathway, providing a mechanistic basis for GVL maintenance when S1P signaling was inhibited. For translational purposes, we detected the regulatory efficacy of pharmacologic inhibitors of Sphk1 and S1PR1 in GVHD induced by human T cells in a xenograft model. Our study provides novel mechanistic insight into how the Sphk1/S1P/S1PR1 pathway modulates T-cell alloreactivity and validates Sphk1 or S1PR1 as a therapeutic target for the prevention of GVHD and leukemia relapse. This novel strategy may be readily translated into the clinic to benefit patients with hematologic malignancies and disorders.
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Affiliation(s)
- Linlu Tian
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yongxia Wu
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Hee-Jin Choi
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Xiaohui Sui
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Xinlei Li
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - M Hanief Sofi
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Mohamed Faisal Kassir
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Xiao Chen
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Shikhar Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Besim Ogretmen
- Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Xue-Zhong Yu
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA.
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
- The Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA.
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18
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Schutt SD, Wu Y, Kharel A, Bastian D, Choi HJ, Hanief Sofi M, Mealer C, McDaniel Mims B, Nguyen H, Liu C, Helke K, Cui W, Zhang X, Ben-David Y, Yu XZ. The druggable transcription factor Fli-1 regulates T cell immunity and tolerance in graft-versus-host disease. J Clin Invest 2022; 132:143950. [PMID: 36074578 PMCID: PMC9621143 DOI: 10.1172/jci143950] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2020] [Accepted: 09/06/2022] [Indexed: 11/17/2022] Open
Abstract
Graft-versus-host disease (GVHD), manifesting as either acute (aGVHD) or chronic (cGVHD), presents significant life-threatening complications following allogeneic hematopoietic cell transplantation. Here, we investigated Friend virus leukemia integration 1 (Fli-1) in GVHD pathogenesis and validated Fli-1 as a therapeutic target. Using genetic approaches, we found that Fli-1 dynamically regulated different T cell subsets in allogeneic responses and pathogenicity in the development of aGVHD and cGVHD. Compared with homozygous Fli1-deficient or WT T cells, heterozygous Fli1-deficient T cells induced the mildest GVHD, as evidenced by the lowest Th1 and Th17 cell differentiation. Single-cell RNA-Seq analysis revealed that Fli-1 differentially regulated CD4+ and CD8+ T cell responses. Fli-1 promoted the transcription of Th1/Th17 pathways and T cell receptor-inducible (TCR-inducible) transcription factors in CD4+ T cells, while suppressing activation- and function-related gene pathways in CD8+ T cells. Importantly, a low dose of camptothecin, topotecan, or etoposide acted as a potent Fli-1 inhibitor and significantly attenuated GVHD severity, while preserving the graft-versus-leukemia (GVL) effect. This observation was extended to a xenograft model, in which GVHD was induced by human T cells. In conclusion, we provide evidence that Fli-1 plays a crucial role in alloreactive CD4+ T cell activation and differentiation and that targeting Fli-1 may be an attractive strategy for treating GVHD without compromising the GVL effect.
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Affiliation(s)
- Steven D. Schutt
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA
| | - Yongxia Wu
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA.,Department of Microbiology and Immunology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin, USA
| | - Arjun Kharel
- Department of Microbiology and Immunology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin, USA
| | - David Bastian
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA
| | - Hee-Jin Choi
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA.,Department of Microbiology and Immunology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin, USA
| | - Mohammed Hanief Sofi
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA
| | - Corey Mealer
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA
| | - Brianyell McDaniel Mims
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA
| | - Hung Nguyen
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA
| | - Chen Liu
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA
| | | | - Weiguo Cui
- Department of Microbiology and Immunology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin, USA
| | - Xian Zhang
- Department of Medicine at MUSC, Charleston, South Carolina, USA
| | - Yaacov Ben-David
- Guizhou Medical University and the Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academic of Sciences, Guiyang, China
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Medical University of South Carolina (MUSC), Charleston, South Carolina, USA.,Department of Microbiology and Immunology, Medical College of Wisconsin (MCW), Milwaukee, Wisconsin, USA.,Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, USA.,The Cancer Center in MCW, Milwaukee, Wisconsin, USA
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19
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Franchon Marques Tejada N, Ziroldo Lopes JV, Duarte Gonçalves LE, Mamede Costa Andrade da Conceição I, Franco GR, Ghirotto B, Câmara NOS. AIM2 as a putative target in acute kidney graft rejection. Front Immunol 2022; 13:839359. [PMID: 36248890 PMCID: PMC9561248 DOI: 10.3389/fimmu.2022.839359] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 09/06/2022] [Indexed: 11/13/2022] Open
Abstract
Acute rejection (AR) is a process triggered via the recognition of grafted organ-derived antigens by the immune system, which could present as a life-threatening condition. In the context of a kidney transplant, despite improvement with immunosuppressive therapies, AR maintains a significant incidence of 10%, and currently available drugs generally act in similar and canonical pathways of lymphocyte activation. This prompted the research for different approaches to identify potential novel targets that could improve therapeutic interventions. Here, we conducted a transcriptome analysis comparing groups of acute rejection (including T cell-mediated rejection and antibody-mediated rejection) to stable grafts that included differentially expressed genes, transcription factor and kinase enrichment, and Gene Set Enrichment Analysis. These analyses revealed inflammasome enhancement in rejected grafts and AIM2 as a potential component linked to acute rejection, presenting a positive correlation to T-cell activation and a negative correlation to oxidative phosphorylation metabolism. Also, the AIM2 expression showed a global accuracy in discerning acute rejection grafts (area under the curve (AUC) = 0.755 and 0.894, p < 0.0001), and meta-analysis comprising different studies indicated a considerable enhancement of AIM2 in rejection (standardized mean difference (SMD) = 1.45, [CI 95%, 1.18 to 1.71]), especially for T cell-mediated rejection (TCMR) (SMD = 2.01, [CI 95%, 1.58 to 2.45]). These findings could guide future studies of AIM2 as either an adjuvant target for immunosuppression or a potential biomarker for acute rejection and graft survival.
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Affiliation(s)
- Nathália Franchon Marques Tejada
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, Brazil
| | - João Vitor Ziroldo Lopes
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, Brazil
| | - Luis Eduardo Duarte Gonçalves
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, Brazil
| | - Izabela Mamede Costa Andrade da Conceição
- Laboratory of Biochemical Genetics, Department of Biochemistry and Immunology, Institute of Biomedical Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Glória Regina Franco
- Laboratory of Biochemical Genetics, Department of Biochemistry and Immunology, Institute of Biomedical Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | - Bruno Ghirotto
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, Brazil
| | - Niels Olsen Saraiva Câmara
- Laboratory of Transplantation Immunobiology, Institute of Biomedical Sciences, Department of Immunology, University of São Paulo, São Paulo, Brazil
- Laboratory of Biochemical Genetics, Department of Biochemistry and Immunology, Institute of Biomedical Sciences, Federal University of Minas Gerais, Belo Horizonte, Brazil
- *Correspondence: Niels Olsen Saraiva Câmara, ;
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20
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Wu Y, Mealer C, Schutt S, Wilson CL, Bastian D, Sofi MH, Zhang M, Luo Z, Choi HJ, Yang K, Tian L, Nguyen H, Helke K, Schnapp LM, Wang H, Yu XZ. MicroRNA-31 regulates T-cell metabolism via HIF1α and promotes chronic GVHD pathogenesis in mice. Blood Adv 2022; 6:3036-3052. [PMID: 35073581 PMCID: PMC9131913 DOI: 10.1182/bloodadvances.2021005103] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Accepted: 01/10/2022] [Indexed: 11/20/2022] Open
Abstract
Chronic graft-versus-host disease (cGVHD) remains a major obstacle impeding successful allogeneic hematopoietic cell transplantation (HCT). MicroRNAs (miRs) play key roles in immune regulation during acute GVHD development. Preclinical studies to identify miRs that affect cGVHD pathogenesis are required to develop these as potential lifesaving interventions. Using oligonucleotide array, we identified miR-31, which was significantly elevated in allogeneic T cells after HCT in mice. Using genetic and pharmacologic approaches, we demonstrated a key role for miR-31 in mediating donor T-cell pathogenicity in cGVHD. Recipients of miR-31-deficient T cells displayed improved cutaneous and pulmonary cGVHD. Deficiency of miR-31 reduced T-cell expansion and T helper 17 (Th17) cell differentiation but increased generation and function of regulatory T cells (Tregs). MiR-31 facilitated neuropilin-1 downregulation, Foxp3 loss, and interferon-γ production in alloantigen-induced Tregs. Mechanistically, miR-31 was required for hypoxia-inducible factor 1α (HIF1α) upregulation in allogeneic T cells. Therefore, miR-31-deficient CD4 T cells displayed impaired activation, survival, Th17 cell differentiation, and glycolytic metabolism under hypoxia. Upregulation of factor-inhibiting HIF1, a direct target of miR-31, in miR-31-deficient T cells was essential for attenuating T-cell pathogenicity. However, miR-31-deficient CD8 T cells maintained intact glucose metabolism, cytolytic activity, and graft-versus-leukemia response. Importantly, systemic administration of a specific inhibitor of miR-31 effectively reduced donor T-cell expansion, improved Treg generation, and attenuated cGVHD. Taken together, miR-31 is a key driver for T-cell pathogenicity in cGVHD but not for antileukemia activity. MiR-31 is essential in driving cGVHD pathogenesis and represents a novel potential therapeutic target for controlling cGVHD.
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Affiliation(s)
- Yongxia Wu
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Corey Mealer
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
| | - Steven Schutt
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
| | | | - David Bastian
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
| | - M. Hanief Sofi
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
| | - Mengmeng Zhang
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
| | - Zhenwu Luo
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
| | - Hee-Jin Choi
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Kaipo Yang
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Linlu Tian
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI
| | - Hung Nguyen
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
| | - Kris Helke
- Department of Comparative Medicine, Medical University of South Carolina, Charleston, SC
| | | | - Honglin Wang
- Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xue-Zhong Yu
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC
- Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, WI
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC; and
- Cancer Center, Medical College of Wisconsin, Milwaukee, WI
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21
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Zhou RQ, Wang X, Ye YB, Lu B, Wang J, Guo ZW, Mo WJ, Yang Z, Srisuk P, Yan LP, Xu XJ. Prevention of acute graft‑vs.‑host disease by targeting glycolysis and mTOR pathways in activated T cells. Exp Ther Med 2022; 24:448. [PMID: 35720623 PMCID: PMC9199067 DOI: 10.3892/etm.2022.11375] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 02/18/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Rui-Qing Zhou
- Department of Hematology, Guangzhou First People's Hospital, The Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong 510180, P.R. China
| | - Xiaobo Wang
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat‑sen University, Shenzhen, Guangdong 518107, P.R. China
| | - Yong-Bin Ye
- Department of Hematology, Zhongshan Hospital of Sun Yat‑Sen University and Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
| | - Bo Lu
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat‑sen University, Shenzhen, Guangdong 518107, P.R. China
| | - Jing Wang
- Nanfang‑Chunfu Children's Institute of Hematology and Oncology, TaiXin Hospital, Dongguan, Guangdong 523128, P.R. China
| | - Zi-Wen Guo
- Department of Hematology, Zhongshan Hospital of Sun Yat‑Sen University and Zhongshan City People's Hospital, Zhongshan, Guangdong 528403, P.R. China
| | - Wen-Jian Mo
- Department of Hematology, Guangzhou First People's Hospital, The Second Affiliated Hospital of South China University of Technology, Guangzhou, Guangdong 510180, P.R. China
| | - Zheng Yang
- Department of Pathology, The Seventh Affiliated Hospital, Sun Yat‑sen University, Shenzhen, Guangdong 518107, P.R. China
| | - Pathomthat Srisuk
- Division of Pharmaceutical Technology, Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Le-Ping Yan
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat‑sen University, Shenzhen, Guangdong 518107, P.R. China
| | - Xiao-Jun Xu
- Department of Hematology, The Seventh Affiliated Hospital, Sun Yat‑sen University, Shenzhen, Guangdong 518107, P.R. China
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22
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Pan Z, Huang A, He Y, Zhang Z, Jiang C, Wang L, Qing K, Zhang S, Wang J, Hu X. Metabolic Reprogramming of Alloreactive T Cells Through TCR/MYC/mTORC1/E2F6 Signaling in aGvHD Patients. Front Immunol 2022; 13:850177. [PMID: 35401560 PMCID: PMC8989838 DOI: 10.3389/fimmu.2022.850177] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 03/01/2022] [Indexed: 11/21/2022] Open
Abstract
Acute graft-versus-host disease (aGvHD) is the most common complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and significantly linked with morbidity and mortality. Although much work has been engaged to investigate aGvHD pathogenesis, the understanding of alloreactive T-cell activation remains incomplete. To address this, we studied transcriptional activation of carbohydrate, nucleotide, tricarboxylic acid (TCA) cycle, and amino acid metabolism of T cells before aGvHD onset by mining the Gene Expression Omnibus (GEO) datasets. Glycolysis had the most extensive correlation with other activated metabolic sub-pathways. Through Pearson correlation analyses, we found that glycolytic activation was positively correlated with activated CD4 memory T-cell subset and T-cell proliferation and migration. T-cell receptor (TCR), mechanistic target of rapamycin complex 1 (mTORC1), myelocytomatosis oncogene (MYC) signaling pathways and E2F6 might be “master regulators” of glycolytic activity. aGvHD predictive model constructed by glycolytic genes (PFKP, ENO3, and GAPDH) through logistic regression showed high predictive and discriminative value. Furthermore, higher expressions of PFKP, ENO3, and GAPDH in alloreactive T cells were confirmed in our pre-aGvHD patient cohort. And the predictive value of the aGvHD risk model was also validated. In summary, our study demonstrated that glycolytic activation might play a pivotal function in alloreactive T-cell activation before aGvHD onset and would be the potential target for aGvHD therapy.
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Affiliation(s)
- Zengkai Pan
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Aijie Huang
- Department of Hematology, Changhai Hospital, Shanghai, China
| | - Yang He
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zilu Zhang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chuanhe Jiang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Luxiang Wang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Qing
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sujiang Zhang
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jianmin Wang
- Department of Hematology, Changhai Hospital, Shanghai, China
| | - Xiaoxia Hu
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,Collaborative Innovation Center of Hematology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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23
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Huang Y, Zou Y, Jiao Y, Shi P, Nie X, Huang W, Xiong C, Choi M, Huang C, Macintyre AN, Nichols A, Li F, Li CY, MacIver NJ, Cardona D, Brennan TV, Li Z, Chao NJ, Rathmell J, Chen BJ. Targeting Glycolysis in Alloreactive T Cells to Prevent Acute Graft- Versus-Host Disease While Preserving Graft-Versus-Leukemia Effect. Front Immunol 2022; 13:751296. [PMID: 35296079 PMCID: PMC8920494 DOI: 10.3389/fimmu.2022.751296] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 02/03/2022] [Indexed: 02/02/2023] Open
Abstract
Alloreactive donor T cells undergo extensive metabolic reprogramming to become activated and induce graft-versus-host disease (GVHD) upon alloantigen encounter. It is generally thought that glycolysis, which promotes T cell growth and clonal expansion, is employed in this process. However, conflicting data have been reported regarding the requirement of glycolysis to induce T cell-mediated GVHD due to the lack of T cell-specific treatments using glycolysis inhibitors. Importantly, previous studies have not evaluated whether graft-versus-leukemia (GVL) activity is preserved in donor T cells deficient for glycolysis. As a critical component affecting the clinical outcome, it is necessary to assess the anti-tumor activity following treatment with metabolic modulators in preclinical models. In the present study, we utilized T cells selectively deficient for glucose transporter 1 (Glut1T-KO), to examine the role of glycolysis exclusively in alloreactive T cells without off-targeting effects from antigen presenting cells and other cell types that are dependent on glycolysis. We demonstrated that transfer of Glut1T-KO T cells significantly improved acute GVHD outcomes through increased apoptotic rates, impaired expansion, and decreased proinflammatory cytokine production. In addition to impaired GVHD development, donor Glut1T-KO T cells mediated sufficient GVL activity to protect recipients from tumor development. A clinically relevant approach using donor T cells treated with a small molecule inhibitor of glycolysis, 2-Deoxy-D-glucose ex vivo, further demonstrated protection from tumor development. These findings indicate that treatment with glycolysis inhibitors prior to transplantation selectively eliminates alloreactive T cells, but spares non-alloreactive T cells including those that protect against tumor growth. The present study has established a definitive role for glycolysis in acute GVHD and demonstrated that acute GVHD can be selectively prevented through targeting glycolysis.
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Affiliation(s)
- Ying Huang
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Yujing Zou
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Yiqun Jiao
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Peijie Shi
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Xiaoli Nie
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Wei Huang
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Chuanfeng Xiong
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Michael Choi
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Charles Huang
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States
| | - Andrew N. Macintyre
- Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United States
| | - Amanda Nichols
- Department of Pediatrics, Duke University Medical Center, Durham, NC, United States
| | - Fang Li
- Department of Dermatology, Duke University Medical Center, Durham, NC, United States
| | - Chuan-Yuan Li
- Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United States,Department of Dermatology, Duke University Medical Center, Durham, NC, United States,Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States
| | - Nancie J. MacIver
- Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, United States,Department of Pediatrics, Duke University Medical Center, Durham, NC, United States,Department of Immunology, Duke University Medical Center, Durham, NC, United States
| | - Diana M. Cardona
- Department of Pathology, Duke University Medical Center, Durham, NC, United States
| | - Todd V. Brennan
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, United States
| | - Zhiguo Li
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, United States
| | - Nelson J. Chao
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States,Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States,Department of Immunology, Duke University Medical Center, Durham, NC, United States,Department of Pathology, Duke University Medical Center, Durham, NC, United States
| | - Jeffrey C. Rathmell
- Vanderbilt Center for Immunobiology, Departments of Pathology, Microbiology, and Immunology, Cancer Biology, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Benny J. Chen
- Division of Hematologic Malignancies and Cellular Therapy/Bone Marrow Transplantation (BMT), Department of Medicine, Duke University Medical Center, Durham, NC, United States,Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States,*Correspondence: Benny J. Chen,
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24
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McCurdy SR, Radojcic V, Tsai HL, Vulic A, Thompson E, Ivcevic S, Kanakry CG, Powell JD, Lohman B, Adom D, Paczesny S, Cooke KR, Jones RJ, Varadhan R, Symons HJ, Luznik L. Signatures of GVHD and relapse after posttransplant cyclophosphamide revealed by immune profiling and machine learning. Blood 2022; 139:608-623. [PMID: 34657151 PMCID: PMC8796655 DOI: 10.1182/blood.2021013054] [Citation(s) in RCA: 57] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 09/24/2021] [Indexed: 01/29/2023] Open
Abstract
The key immunologic signatures associated with clinical outcomes after posttransplant cyclophosphamide (PTCy)-based HLA-haploidentical (haplo) and HLA-matched bone marrow transplantation (BMT) are largely unknown. To address this gap in knowledge, we used machine learning to decipher clinically relevant signatures from immunophenotypic, proteomic, and clinical data and then examined transcriptome changes in the lymphocyte subsets that predicted major posttransplant outcomes. Kinetics of immune subset reconstitution after day 28 were similar for 70 patients undergoing haplo and 75 patients undergoing HLA-matched BMT. Machine learning based on 35 candidate factors (10 clinical, 18 cellular, and 7 proteomic) revealed that combined elevations in effector CD4+ conventional T cells (Tconv) and CXCL9 at day 28 predicted acute graft-versus-host disease (aGVHD). Furthermore, higher NK cell counts predicted improved overall survival (OS) due to a reduction in both nonrelapse mortality and relapse. Transcriptional and flow-cytometric analyses of recovering lymphocytes in patients with aGVHD identified preserved hallmarks of functional CD4+ regulatory T cells (Tregs) while highlighting a Tconv-driven inflammatory and metabolic axis distinct from that seen with conventional GVHD prophylaxis. Patients developing early relapse displayed a loss of inflammatory gene signatures in NK cells and a transcriptional exhaustion phenotype in CD8+ T cells. Using a multimodality approach, we highlight the utility of systems biology in BMT biomarker discovery and offer a novel understanding of how PTCy influences alloimmune responses. Our work charts future directions for novel therapeutic interventions after these increasingly used GVHD prophylaxis platforms. Specimens collected on NCT0079656226 and NCT0080927627 https://clinicaltrials.gov/.
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Affiliation(s)
- Shannon R McCurdy
- Abramson Cancer Center and the Division of Hematology and Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Vedran Radojcic
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Hua-Ling Tsai
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ante Vulic
- Division of Biostatistics and Bioinformatics and the Sidney Kimmel Comprehensive Cancer Center and The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Elizabeth Thompson
- Division of Biostatistics and Bioinformatics and the Sidney Kimmel Comprehensive Cancer Center and The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Sanja Ivcevic
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Christopher G Kanakry
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Jonathan D Powell
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Brian Lohman
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
| | - Djamilatou Adom
- Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Sophie Paczesny
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN; and
- Department of Microbiology and Immunology and Pediatrics, Medical University of South Carolina, Charleston, SC
| | - Kenneth R Cooke
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Richard J Jones
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Ravi Varadhan
- Division of Biostatistics and Bioinformatics and the Sidney Kimmel Comprehensive Cancer Center and The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Heather J Symons
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
| | - Leo Luznik
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD
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25
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Rozmus J, Bhatt ST, Buxbaum NP, Cuvelier GDE, Li AM, Kitko CL, Schultz KR. Is It Possible to Separate the Graft-Versus-Leukemia (GVL) Effect Against B Cell Acute Lymphoblastic Leukemia From Graft-Versus-Host Disease (GVHD) After Hematopoietic Cell Transplant? Front Pediatr 2022; 10:796994. [PMID: 35402356 PMCID: PMC8987503 DOI: 10.3389/fped.2022.796994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Accepted: 01/31/2022] [Indexed: 11/13/2022] Open
Abstract
Hematopoietic cell transplant is a curative therapy for many pediatric patients with high risk acute lymphoblastic leukemia. Its therapeutic mechanism is primarily based on the generation of an alloreactive graft-versus-leukemia effect that can eliminate residual leukemia cells thus preventing relapse. However its efficacy is diminished by the concurrent emergence of harmful graft-versus-host disease disease which affects healthly tissue leading to significant morbidity and mortality. The purpose of this review is to describe the interventions that have been trialed in order to augment the beneficial graft-versus leukemia effect post-hematopoietic cell transplant while limiting the harmful consequences of graft-versus-host disease. This includes many emerging and promising strategies such as ex vivo and in vivo graft manipulation, targeted cell therapies, T-cell engagers and multiple pharmacologic interventions that stimulate specific donor effector cells.
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Affiliation(s)
- Jacob Rozmus
- Division of Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, Faculty of Medicine, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Sima T Bhatt
- Washington University, Saint Louis, MO, United States
| | | | - Geoffrey D E Cuvelier
- Pediatric Blood and Marrow Transplantation, Cancer Care Manitoba, University of Manitoba, Winnipeg, MB, Canada
| | - Amanda M Li
- Division of Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, Faculty of Medicine, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Carrie L Kitko
- Pediatric Hematology/Oncology Division, Vanderbilt University Medical Center, Nashville, TN, United States
| | - Kirk R Schultz
- Division of Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, Faculty of Medicine, British Columbia Children's Hospital, University of British Columbia, Vancouver, BC, Canada
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26
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Braun LM, Zeiser R. Kinase Inhibition as Treatment for Acute and Chronic Graft- Versus-Host Disease. Front Immunol 2021; 12:760199. [PMID: 34868001 PMCID: PMC8635802 DOI: 10.3389/fimmu.2021.760199] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/28/2021] [Indexed: 01/25/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies via the donor immune system driven graft-versus-leukemia effect. However, the therapy is mainly limited by severe acute and chronic graft-versus-host disease (GvHD), both being life-threatening complications after allo-HCT. GvHD develops when donor T cells do not only recognize remaining tumor cells as foreign, but also the recipient’s tissue, leading to a severe inflammatory disease. Typical GvHD target organs include the skin, liver and intestinal tract. Currently all approved strategies for GvHD treatment are immunosuppressive therapies, with the first-line therapy being glucocorticoids. However, therapeutic options for glucocorticoid-refractory patients are still limited. Novel therapeutic approaches, which reduce GvHD severity while preserving GvL activity, are urgently needed. Targeting kinase activity with small molecule inhibitors has shown promising results in preclinical animal models and clinical trials. Well-studied kinase targets in GvHD include Rho-associated coiled-coil-containing kinase 2 (ROCK2), spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) to control B- and T-cell activation in acute and chronic GvHD. Janus Kinase 1 (JAK1) and 2 (JAK2) are among the most intensively studied kinases in GvHD due to their importance in cytokine production and inflammatory cell activation and migration. Here, we discuss the role of kinase inhibition as novel treatment strategies for acute and chronic GvHD after allo-HCT.
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Affiliation(s)
- Lukas M Braun
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg (CCCF), University of Freiburg, Freiburg, Germany.,Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
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27
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Inamoto Y, Zeiser R, Chan GCF. Novel Treatment for Graft-versus-Host Disease. BLOOD CELL THERAPY 2021; 4:101-109. [PMID: 36714067 PMCID: PMC9847314 DOI: 10.31547/bct-2021-022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 10/16/2021] [Indexed: 02/01/2023]
Abstract
Allogeneic hematopoietic cell transplantation is a curative therapy for a variety of hematological diseases, but its success is hampered by acute and chronic graft-versus-host disease (GvHD). In the last five years, multiple novel therapeutic approaches for GvHD have entered the arena. The National Institutes of Health consensus criteria for chronic GvHD have set standards for designing and reporting clinical trials, and preclinical experiments of chronic GvHD have revealed the central roles of regulatory T cells, B-cell signaling, Th17 cells, Tc17 cells, follicular helper T cells, follicular regulatory T cells, and fibrosis-promoting factors. These scientific efforts and the resulting clinical studies led to the approval of ibrutinib, belumosudil and ruxolitinib for the treatment of refractory chronic GvHD. Recently, large randomized phase III trials showed that ruxolitinib was superior to the best available therapy for glucocorticoid-refractory acute GvHD (REACH2 trial) and glucocorticoid-refractory chronic GvHD (REACH3 trial). Furthermore, novel regenerative approaches, including IL-22, R-spondin, and glucogon-like peptide-2, and cellular therapies, such as the transfer of mesenchymal stem cells and regulatory T cells, are under intensive investigation. GvHD prevention using abatacept, dipeptidyl peptidase 4 inhibition, and post-transplant cyclophosphamide are also promising strategies that require further evaluation. In this article, we summarize the emerging knowledge of acute GvHD, chronic GvHD, and preclinical and clinical data of mesenchymal stem cells as GvHD therapy. In the next five years, basic and clinical studies will further advance the field, and dramatic changes in GvHD management will be encountered.
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Affiliation(s)
- Yoshihiro Inamoto
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University (ALU), Freiburg, Germany
| | - Godfrey Chi-Fung Chan
- Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong,Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital,Department of Paediatrics and Adolescent Medicine, HKU-Shenzhen Hospital
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28
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Alarcon PC, Damen MSMA, Madan R, Deepe GS, Spearman P, Way SS, Divanovic S. Adipocyte inflammation and pathogenesis of viral pneumonias: an overlooked contribution. Mucosal Immunol 2021; 14:1224-1234. [PMID: 33958704 PMCID: PMC8100369 DOI: 10.1038/s41385-021-00404-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/18/2021] [Accepted: 03/27/2021] [Indexed: 02/06/2023]
Abstract
Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to viral respiratory pneumonias associated with H1N1 influenza and SARS-CoV-2 pandemics. Given the global obesity prevalence, a better understanding of the mechanisms behind obese susceptibility to infection is imperative. Altered immune cell metabolism and function are often perceived as a key causative factor of dysregulated inflammation. However, the contribution of adipocytes, the dominantly altered cell type in obesity with broad inflammatory properties, to infectious disease pathogenesis remains largely ignored. Thus, skewing of adipocyte-intrinsic cellular metabolism may lead to the development of pathogenic inflammatory adipocytes, which shape the overall immune responses by contributing to either premature immunosenescence, delayed hyperinflammation, or cytokine storm in infections. In this review, we discuss the underappreciated contribution of adipocyte cellular metabolism and adipocyte-produced mediators on immune system modulation and how such interplay may modify disease susceptibility and pathogenesis of influenza and SARS-CoV-2 infections in obese individuals.
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Affiliation(s)
- Pablo C Alarcon
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Divisions of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Medical Scientist Training Program, Cincinnati, OH, USA
- Immunology Graduate Program Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Michelle S M A Damen
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Divisions of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Rajat Madan
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Veterans Affairs Medical Center, Cincinnati, OH, USA
| | - George S Deepe
- Division of Infectious Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Paul Spearman
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Divisions of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Sing Sing Way
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
- Divisions of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- Divisions of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Medical Scientist Training Program, Cincinnati, OH, USA.
- Immunology Graduate Program Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA.
- Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
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29
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Karl F, Hudecek M, Berberich-Siebelt F, Mackensen A, Mougiakakos D. T-Cell Metabolism in Graft Versus Host Disease. Front Immunol 2021; 12:760008. [PMID: 34777373 PMCID: PMC8586445 DOI: 10.3389/fimmu.2021.760008] [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: 08/17/2021] [Accepted: 10/11/2021] [Indexed: 01/23/2023] Open
Abstract
Allogeneic-hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for numerous hematological malignancies. Elimination of malignant cells depends on the T-cells' Graft-versus-Tumor (GvT) effect. However, Graft-versus-Host-Disease (GvHD), often co-occurring with GvT, remains an obstacle for therapeutic efficacy. Hence, approaches, which selectively alleviate GvHD without compromising GvT activity, are needed. As already explored for autoimmune and inflammatory disorders, immuno-metabolic interventions pose a promising option to address this unmet challenge. Being embedded in a complex regulatory framework, immunological and metabolic pathways are closely intertwined, which is demonstrated by metabolic reprograming of T-cells upon activation or differentiation. In this review, current knowledge on the immuno-metabolic signature of GvHD-driving T-cells is summarized and approaches to metabolically interfere are outlined. Furthermore, we address the metabolic impact of standard medications for GvHD treatment and prophylaxis, which, in conjunction with the immuno-metabolic profile of alloreactive T-cells, could allow more targeted interventions in the future.
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Affiliation(s)
- Franziska Karl
- Department of Medicine 5, Hematology and Clinical Oncology, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
| | - Michael Hudecek
- Medizinische Klinik und Poliklinik II, Universitätsklinikum Würzburg, Würzburg, Germany
| | | | - Andreas Mackensen
- Department of Medicine 5, Hematology and Clinical Oncology, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
| | - Dimitrios Mougiakakos
- Department of Medicine 5, Hematology and Clinical Oncology, Friedrich Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Deutsches Zentrum für Immuntherapie (DZI), Erlangen, Germany
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30
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Mhandire K, Saggu K, Buxbaum NP. Immunometabolic Therapeutic Targets of Graft-versus-Host Disease (GvHD). Metabolites 2021; 11:736. [PMID: 34822394 PMCID: PMC8619522 DOI: 10.3390/metabo11110736] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/22/2021] [Accepted: 10/26/2021] [Indexed: 01/17/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative option in the treatment of aggressive malignant and non-malignant blood disorders. However, the benefits of allo-HSCT can be compromised by graft-versus-host disease (GvHD), a prevalent and morbid complication of allo-HSCT. GvHD occurs when donor immune cells mount an alloreactive response against host antigens due to histocompatibility differences between the donor and host, which may result in extensive tissue injury. The reprogramming of cellular metabolism is a feature of GvHD that is associated with the differentiation of donor CD4+ cells into the pathogenic Th1 and Th17 subsets along with the dysfunction of the immune-suppressive protective T regulatory cells (Tregs). The activation of glycolysis and glutaminolysis with concomitant changes in fatty acid oxidation metabolism fuel the anabolic activities of the proliferative alloreactive microenvironment characteristic of GvHD. Thus, metabolic therapies such as glycolytic enzyme inhibitors and fatty acid metabolism modulators are a promising therapeutic strategy for GvHD. We comprehensively review the role of cellular metabolism in GvHD pathogenesis, identify candidate therapeutic targets, and describe potential strategies for augmenting immunometabolism to ameliorate GvHD.
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31
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Metabolomic Identification of Alpha-Ketoglutaric Acid Elevation in Pediatric Chronic Graft-versus-Host Disease. Blood 2021; 139:287-299. [PMID: 34534280 DOI: 10.1182/blood.2021013244] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/03/2021] [Indexed: 11/20/2022] Open
Abstract
Chronic graft versus host disease (cGvHD) is the most common cause for non-relapse mortality post allogenic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGvHD or late acute GvHD (aGvHD). This study is a longitudinal evaluation of metabolomic patterns of cGvHD and late aGvHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day+100 on subjects who later developed either cGvHD or late aGvHD after day 114 to non-cGvHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGvHD at onset to time matched non-cGvHD controls. A metabolomic biomarker was considered biologically relevant only if it met all three selection criteria: a) p value ≤0.05, b) effect ratio of ≥1.3 or ≤0.75, and c) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma alpha-ketoglutaric acid before (Day + 100) and at the onset of cGvHD, not impacted by cGvHD severity, pubertal status, or previous aGvHD. In addition, late aGvHD had a unique metabolomic pattern at day+100 compared to cGvHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGvHD. Alpha-ketoglutaric acid emerged as the single most significant metabolite associated with cGvHD, both in the day +100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGvHD. Future validation of these exploratory results are needed.
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32
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High Throughput Analysis Reveals Changes in Gut Microbiota and Specific Fecal Metabolomic Signature in Hematopoietic Stem Cell Transplant Patients. Microorganisms 2021; 9:microorganisms9091845. [PMID: 34576740 PMCID: PMC8469814 DOI: 10.3390/microorganisms9091845] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 08/02/2021] [Accepted: 08/23/2021] [Indexed: 12/29/2022] Open
Abstract
There is mounting evidence for the emerging role of gut microbiota (GM) and its metabolites in profoundly impacting allogenic hematopoietic stem cell transplantation (allo-HSCT) and its subsequent complications, mainly infections and graft versus host-disease (GvHD). The present study was performed in order to investigate changes in GM composition and fecal metabolic signature between transplant patients (n = 15) and healthy controls (n = 18). The intestinal microbiota was characterized by NGS and gas chromatography-mass spectrometry was employed to perform untargeted analysis of fecal metabolites. We found lower relative abundances of Actinobacteria, Firmicutes, and Bacteroidetes and a higher abundance of Proteobacteria phylum after allo-HSCT. Particularly, the GvHD microbiota was characterized by a lower relative abundance of the short-chain fatty acid-producing bacteria, namely, the Feacalibacterium, Akkermansia, and Veillonella genera and the Lachnospiraceae family, and an enrichment in multidrug-resistant bacteria belonging to Escherichia, Shigella, and Bacteroides. Moreover, network analysis showed that GvHD was linked to a higher number of positive interactions of Blautia and a significant mutual-exclusion rate of Citrobacter. The fecal metabolome was dominated by lipids in the transplant group when compared with the healthy individuals (p < 0.05). Overall, 76 metabolites were significantly altered within transplant recipients, of which 24 were selected as potential biomarkers. Furthermore, the most notable altered metabolic pathways included the TCA cycle; butanoate, propanoate, and pyruvate metabolisms; steroid biosynthesis; and glycolysis/gluconeogenesis. Specific biomarkers and altered metabolic pathways were correlated to GvHD onset. Our results showed significant shifts in gut microbiota structure and fecal metabolites characterizing allo-HSCT.
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33
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Li X, Li Y, Yu Q, Qian P, Huang H, Lin Y. Metabolic reprogramming of myeloid-derived suppressor cells: An innovative approach confronting challenges. J Leukoc Biol 2021; 110:257-270. [PMID: 34075637 PMCID: PMC8361984 DOI: 10.1002/jlb.1mr0421-597rr] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 04/11/2021] [Accepted: 04/12/2021] [Indexed: 02/06/2023] Open
Abstract
Immune cells such as T cells, macrophages, dendritic cells, and other immunoregulatory cells undergo metabolic reprogramming in cancer and inflammation-derived microenvironment to meet specific physiologic and functional demands. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that are characterized by immunosuppressive activity, which plays a key role in host immune homeostasis. In this review, we have discussed the core metabolic pathways, including glycolysis, lipid and fatty acid biosynthesis, and amino acid metabolism in the MDSCs under various pathologic situations. Metabolic reprogramming is a determinant of the phenotype and functions of MDSCs, and is therefore a novel therapeutic possibility in various diseases.
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Affiliation(s)
- Xiaoqing Li
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Yixue Li
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Qinru Yu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Pengxu Qian
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
| | - Yu Lin
- Bone Marrow Transplantation Center, the First Affiliated Hospital, School of MedicineZhejiang UniversityHangzhouZhejiangChina
- Institute of HematologyZhejiang UniversityHangzhouZhejiangChina
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity TherapyHangzhouZhejiangChina
- Liangzhu LaboratoryZhejiang University Medical CenterHangzhouZhejiangChina
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34
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Lemasters JJ. Metabolic implications of non-electrogenic ATP/ADP exchange in cancer cells: A mechanistic basis for the Warburg effect. BIOCHIMICA ET BIOPHYSICA ACTA. BIOENERGETICS 2021; 1862:148410. [PMID: 33722515 PMCID: PMC8096716 DOI: 10.1016/j.bbabio.2021.148410] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/07/2021] [Indexed: 12/20/2022]
Abstract
In post-mitotic cells, mitochondrial ATP/ADP exchange occurs by the adenine nucleotide translocator (ANT). Driven by membrane potential (ΔΨ), ANT catalyzes electrogenic exchange of ATP4- for ADP3-, leading to higher ATP/ADP ratios in the cytosol than mitochondria. In cancer cells, ATP/ADP exchange occurs not by ANT but likely via the non-electrogenic ATP-Mg/phosphate carrier. Consequences of non-electrogenic exchange are: 1) Cytosolic ATP/ADP decreases to stimulate aerobic glycolysis. 2) Without proton utilization for exchange, ATP/O increases by 35% for complete glucose oxidation. 3) Decreased cytosolic ATP/ADPPi increases NAD(P)H/NAD(P)+. Increased NADH increases lactate/pyruvate, and increased NADPH promotes anabolic metabolism. Fourth, increased mitochondrial NADH/NAD+ magnifies the redox span across Complexes I and III, which increases ΔΨ, reactive oxygen species generation, and susceptibility to ferroptosis. 5) Increased mitochondrial NADPH/NADP+ favors a reverse isocitrate dehydrogenase-2 reaction with citrate accumulation and export for biomass formation. Consequently, 2-oxoglutarate formation occurs largely via oxidation of glutamine, the preferred respiratory substrate of cancer cells. Overall, non-electrogenic ATP/ADP exchange promotes aerobic glycolysis (Warburg effect) and confers specific growth advantages to cancer cells.
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Affiliation(s)
- John J Lemasters
- Center for Cell Death, Injury & Regeneration, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States of America; Department of Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, United States of America.
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35
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Spector LG, Spellman SR, Thyagarajan B, Beckman KB, Hoffmann C, Garbe J, Hahn T, Sucheston-Campbell L, Richardson M, De For TE, Tolar J, Verneris MR. Neither Donor nor Recipient Mitochondrial Haplotypes Are Associated with Unrelated Donor Transplant Outcomes: A Validation Study from the CIBMTR. Transplant Cell Ther 2021; 27:836.e1-836.e7. [PMID: 34174468 DOI: 10.1016/j.jtct.2021.06.019] [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: 04/14/2021] [Revised: 06/04/2021] [Accepted: 06/16/2021] [Indexed: 11/18/2022]
Abstract
Graft-versus-host-disease (GVHD) is a multistep process that involves T-cell recognition and priming toward alloantigen, expansion, acquisition of effector function, and repeated tissue injury, resulting in clinical manifestations of the disease. All of these processes have considerable metabolic demands and understanding the key role of mitochondria in cellular metabolism as it relates to GVHD has increased significantly. Mitochondrial DNA (mtDNA) haplotypes have been linked to functional differences in vitro, suggesting they have functional differences at an organismal level. We previously used mtDNA typing to assess the impact of mtDNA haplotypes on outcomes of ~400 allo-HCT patients. This pilot study identified uncommon mtDNA haplotypes potentially associated with inferior outcomes. We sought to validate pilot findings of associations between donor and recipient mitochondrial haplotypes and transplant outcome. We examined a cohort of 4143 donor-recipient pairs obtained from the Center for International Blood and Marrow Transplant Research. MtDNA was extracted from whole blood or peripheral blood mononuclear cells from donors and recipients and sequenced to discern haplotype. We used multiple regression analysis to examine the independent association of mtDNA haplotype with overall survival and grade III-IV acute GVHD (aGVHD) adjusting for known risk factors for poor transplant outcome. Neither recipient nor donor mtDNA haplotype reached groupwise significance for overall survival (P =.26 and .39, respectively) or grade III-IV aGVHD (P = .68 and.57, respectively). Adjustment for genomically determined ancestry in the subset of donor-recipient pairs for which this was available did not materially change results. We conclude that our original finding was due to chance in a small sample size and that there is essentially no evidence that mtDNA haplotype or haplotype mismatch contributes to risk of serious outcomes after allogeneic transplantation.
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Affiliation(s)
- Logan G Spector
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota.
| | - Stephen R Spellman
- Center for International Blood and Marrow Transplant Research, Milwaukee, Wisconsin
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Kenneth B Beckman
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota
| | - Cody Hoffmann
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota
| | - John Garbe
- University of Minnesota Genomics Center, University of Minnesota, Minneapolis, Minnesota
| | - Theresa Hahn
- Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York
| | | | - Michaela Richardson
- Division of Epidemiology and Clinical Research, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Todd E De For
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Jakub Tolar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota Medical School, Minneapolis, Minnesota
| | - Michael R Verneris
- University of Colorado Denver, Children's Cancer and Blood Disorders, Denver, Colorado
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36
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Socié G, Kean LS, Zeiser R, Blazar BR. Insights from integrating clinical and preclinical studies advance understanding of graft-versus-host disease. J Clin Invest 2021; 131:149296. [PMID: 34101618 PMCID: PMC8203454 DOI: 10.1172/jci149296] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
As a result of impressive increases in our knowledge of rodent and human immunology, the understanding of the pathophysiologic mechanisms underlying graft-versus-host disease (GVHD) has dramatically improved in the past 15 years. Despite improved knowledge, translation to clinical care has not proceeded rapidly, and results from experimental models have been inconsistent in their ability to predict the clinical utility of new therapeutic agents. In parallel, new tools in immunology have allowed in-depth analyses of the human system and have recently been applied in the field of clinical GVHD. Notwithstanding these advances, there is a relative paucity of mechanistic insights into human translational research, and this remains an area of high unmet need. Here we review selected recent advances in both preclinical experimental transplantation and translational human studies, including new insights into human immunology, the microbiome, and regenerative medicine. We focus on the fact that both approaches can interactively improve our understanding of both acute and chronic GVHD biology and open the door to improved therapeutics and successes.
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Affiliation(s)
- Gérard Socié
- Hematology-Transplantation, Assistance Publique–Hôpitaux de Paris (APHP), Hospital Saint Louis, Paris, France
- INSERM UMR 976 (Team Insights) and University of Paris, Paris, France
| | - Leslie S. Kean
- Division of Pediatric Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Robert Zeiser
- Department of Medicine I, Faculty of Medicine, Medical Center–University of Freiburg, Freiburg, Germany
| | - Bruce R. Blazar
- Masonic Cancer Center and Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, Minnesota, USA
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Moreno-Fernandez ME, Giles DA, Oates JR, Chan CC, Damen MSMA, Doll JR, Stankiewicz TE, Chen X, Chetal K, Karns R, Weirauch MT, Romick-Rosendale L, Xanthakos SA, Sheridan R, Szabo S, Shah AS, Helmrath MA, Inge TH, Deshmukh H, Salomonis N, Divanovic S. PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease. Cell Metab 2021; 33:1187-1204.e9. [PMID: 34004162 PMCID: PMC8237408 DOI: 10.1016/j.cmet.2021.04.018] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 03/31/2021] [Accepted: 04/27/2021] [Indexed: 12/12/2022]
Abstract
Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3+Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cell accrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically, the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility, glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulation of glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverse ihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics, CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved in human NAFLD. Together, our data show that the steatotic liver microenvironment regulates Th17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation of these pathways holds potential for development of novel therapeutic strategies for NAFLD.
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Affiliation(s)
- Maria E Moreno-Fernandez
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Daniel A Giles
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Jarren R Oates
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Calvin C Chan
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Medical Scientist Training Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Michelle S M A Damen
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Jessica R Doll
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Traci E Stankiewicz
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Xiaoting Chen
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; The Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Kashish Chetal
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Rebekah Karns
- Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Matthew T Weirauch
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Center for Autoimmune Genomics and Etiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Lindsey Romick-Rosendale
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; NMR Metabolomics Core, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Stavra A Xanthakos
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Rachel Sheridan
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Sara Szabo
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Amy S Shah
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Michael A Helmrath
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Center for Stem Cell & Organoid Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Thomas H Inge
- Department of Surgery, Children's Hospital Colorado, Aurora, CO 80045, USA
| | - Hitesh Deshmukh
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Neonatology and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; The Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Nathan Salomonis
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Senad Divanovic
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Medical Scientist Training Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; Immunology Graduate Program, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA; The Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
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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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Zeng F, Zhang Y, Han X, Zeng M, Gao Y, Weng J. Employing hypoxia characterization to predict tumour immune microenvironment, treatment sensitivity and prognosis in hepatocellular carcinoma. Comput Struct Biotechnol J 2021; 19:2775-2789. [PMID: 34093992 PMCID: PMC8134035 DOI: 10.1016/j.csbj.2021.03.033] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/24/2021] [Accepted: 03/25/2021] [Indexed: 12/11/2022] Open
Abstract
The hypoxic microenvironment was recognized as a major driving force of the malignant phenotype in hepatocellular carcinoma (HCC), which contributes to tumour immune microenvironment (TIM) remodeling and tumor progression. Dysregulated hypoxia-related genes (HRGs) result in treatment resistance and poor prognosis by reshaping tumor cellular activities and metabolism. Approaches to identify the relationship between hypoxia and tumor progression provided new sight for improving tumor treatment and prognosis. But, few practical tools, forecasting relationship between hypoxia, TIM, treatment sensitivity and prognosis in HCC were reported. Here, we pooled mRNA transcriptome and clinical pathology data from the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), and later developed a hypoxia risk model including four HRGs (DCN, DDIT4, PRKCA and NDRG1). The high-risk group displayed poor clinical characteristics, a malignant phenotype with carcinogenesis/proliferation pathways activation (MTORC1 and E2F) and immunosuppressive TIM (decreased immune cell infiltrations and upregulated immunosuppressive cytokines). Meanwhile, activated B cells, effector memory CD8 T cells and EZH2 deregulation were associated with patient’s survival, which might be the core changes of HCC hypoxia. Finally, we validated the ability of the hypoxia risk model to predict treatment sensitivity and found high hypoxia risk patients had poor responses to HCC treatment, including surgical resection, Sorafenib, Transarterial Chemoembolization (TACE) and immunotherapy. In conclusion, based on 4 HRGs, we developed and validated a hypoxia risk model to reflect pathological features, evaluate TIM landscape, predict treatment sensitivity and compounds specific to hypoxia signatures in HCC patients.
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Affiliation(s)
- Fanhong Zeng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Yue Zhang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Xu Han
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Min Zeng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Jun Weng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
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Basso PJ, Andrade-Oliveira V, Câmara NOS. Targeting immune cell metabolism in kidney diseases. Nat Rev Nephrol 2021; 17:465-480. [PMID: 33828286 DOI: 10.1038/s41581-021-00413-7] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/25/2021] [Indexed: 02/06/2023]
Abstract
Insights into the relationship between immunometabolism and inflammation have enabled the targeting of several immunity-mediated inflammatory processes that underlie infectious diseases and cancer or drive transplant rejection, but this field remains largely unexplored in kidney diseases. The kidneys comprise heterogeneous cell populations, contain distinct microenvironments such as areas of hypoxia and hypersalinity, and are responsible for a functional triad of filtration, reabsorption and secretion. These distinctive features create myriad potential metabolic therapeutic targets in the kidney. Immune cells have crucial roles in the maintenance of kidney homeostasis and in the response to kidney injury, and their function is intricately connected to their metabolic properties. Changes in nutrient availability and biomolecules, such as cytokines, growth factors and hormones, initiate cellular signalling events that involve energy-sensing molecules and other metabolism-related proteins to coordinate immune cell differentiation, activation and function. Disruption of homeostasis promptly triggers the metabolic reorganization of kidney immune and non-immune cells, which can promote inflammation and tissue damage. The metabolic differences between kidney and immune cells offer an opportunity to specifically target immunometabolism in the kidney.
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Affiliation(s)
- Paulo José Basso
- Laboratory of Immunobiology of Transplantation, Department of Immunology, Universidade de São Paulo, São Paulo, São Paulo, Brazil
| | | | - Niels Olsen Saraiva Câmara
- Laboratory of Immunobiology of Transplantation, Department of Immunology, Universidade de São Paulo, São Paulo, São Paulo, Brazil. .,Laboratory of Clinical and Experimental Immunology, Division of Nephrology, Universidade Federal de São Paulo, São Paulo, São Paulo, Brazil.
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41
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Zhang W, Liu Z, Xu X. Navigating immune cell immunometabolism after liver transplantation. Crit Rev Oncol Hematol 2021; 160:103227. [PMID: 33675906 DOI: 10.1016/j.critrevonc.2021.103227] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 12/18/2020] [Accepted: 01/16/2021] [Indexed: 11/15/2022] Open
Abstract
Liver transplantation (LT) is the most effective treatment for end-stage liver diseases. The immunometabolism microenvironment undergoes massive changes at the interface of immune functionalities and metabolic regulations after LT. These changes considerably modify post-transplant complications, and immune cells play an influential role in the hepatic immunometabolism microenvironment after LT. Therefore, adequate studies on the complex pathobiology of immune cells are critical to prevent post-transplant complications, and the interplay between cellular metabolism and immune function is evident. Furthermore, immune cells perform their specified functions, such as activation or differentiation, accompanied by alterations in metabolic pathways, such as metabolic reprogramming. This transformation remarkably affects post-transplant complications like rejection. By targeting different metabolic pathways, regulations of metabolism are employed to shape immune responses. These differences of metabolic pathways allow for selective regulation of immune responses to further develop effective therapies that prevent graft loss after LT. This review examines immune cells in the hepatic immunometabolism microenvironment after LT, summarizes possible mechanisms and potential prevention on rejection to acquire immune tolerance, and offers some insight into references for scientific research along with clinical treatment.
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Affiliation(s)
- Wenhui Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang University Cancer Center, Hangzhou 310058, China
| | - Zhikun Liu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang University Cancer Center, Hangzhou 310058, China.
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42
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Rozmus J. Monogenic Immune Diseases Provide Insights Into the Mechanisms and Treatment of Chronic Graft-Versus-Host Disease. Front Immunol 2021; 11:574569. [PMID: 33613511 PMCID: PMC7889949 DOI: 10.3389/fimmu.2020.574569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 12/07/2020] [Indexed: 12/22/2022] Open
Abstract
Chronic graft-versus-host disease (GvHD) has become a leading cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT) and can burden patients with devastating and lifelong health effects. Our understanding of the pathogenic mechanisms underlying chronic GvHD remains incomplete and this lack of understanding is reflected by lack of clear therapeutic approaches to steroid refractory disease. Observations predominantly from mouse models and human correlative studies currently support a three phase model for the initiation and development of chronic GvHD: 1) early inflammation and tissue damage triggers the innate immune system. This leads to inflammatory cytokine/chemokine patterns that recruit effector immune cell populations; 2) chronic inflammation causes the loss of central and peripheral tolerance mechanisms leading to emergence of pathogenic B and T cell populations that promote autoimmune and alloimmune reactions; 3) the dysregulated immunity causes altered macrophage polarization, aberrant tissue repair leading to scarring and end organ fibrosis. This model has led to the evaluation of many new therapies aimed at limiting inflammation, targeting dysregulated signaling pathways and restoring tolerance mechanisms. However, chronic GvHD is a multisystem disease with complex clinical phenotypes and it remains unclear as to which cluster of patients will respond best to specific therapeutic strategies. However, it is possible to gain novel insights from immune-related monogenic diseases. These diseases either share common clinical manifestations, replicate steps from the three phase chronic GvHD model or serve as surrogates for perfectly targeted drugs being investigated in chronic GvHD therapy. In this review, we will summarize the evidence from these monogenic immune related diseases that provide insight into pathogenic pathways in chronic GvHD, rationales for current therapies and novel directions for future drug discovery.
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Affiliation(s)
- Jacob Rozmus
- Division of Pediatric Hematology, Oncology & BMT, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.,Michael Cuccione Childhood Cancer Research Program, BC Children's Hospital Research Institute, Vancouver, BC, Canada
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43
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Assmann JC, Farthing DE, Saito K, Maglakelidze N, Oliver B, Warrick KA, Sourbier C, Ricketts CJ, Meyer TJ, Pavletic SZ, Linehan WM, Krishna MC, Gress RE, Buxbaum NP. Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI. Blood 2021; 137:126-137. [PMID: 32785680 PMCID: PMC7808015 DOI: 10.1182/blood.2020005770] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 08/01/2020] [Indexed: 02/06/2023] Open
Abstract
Graft-versus-host disease (GVHD) is a prominent barrier to allogeneic hematopoietic stem cell transplantation (AHSCT). Definitive diagnosis of GVHD is invasive, and biopsies of involved tissues pose a high risk of bleeding and infection. T cells are central to GVHD pathogenesis, and our previous studies in a chronic GVHD mouse model showed that alloreactive CD4+ T cells traffic to the target organs ahead of overt symptoms. Because increased glycolysis is an early feature of T-cell activation, we hypothesized that in vivo metabolic imaging of glycolysis would allow noninvasive detection of liver GVHD as activated CD4+ T cells traffic into the organ. Indeed, hyperpolarized 13C-pyruvate magnetic resonance imaging detected high rates of conversion of pyruvate to lactate in the liver ahead of animals becoming symptomatic, but not during subsequent overt chronic GVHD. Concomitantly, CD4+ T effector memory cells, the predominant pathogenic CD4+ T-cell subset, were confirmed to be highly glycolytic by transcriptomic, protein, metabolite, and ex vivo metabolic activity analyses. Preliminary data from single-cell sequencing of circulating T cells in patients undergoing AHSCT also suggested that increased glycolysis may be a feature of incipient acute GVHD. Metabolic imaging is being increasingly used in the clinic and may be useful in the post-AHSCT setting for noninvasive early detection of GVHD.
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Affiliation(s)
| | - Don E Farthing
- Experimental Transplantation and Immunotherapy Branch and
| | - Keita Saito
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | | | | | | | - Carole Sourbier
- Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD
| | | | - Thomas J Meyer
- CCR Collaborative Bioinformatics Resource, National Cancer Institute, National Institutes of Health, Bethesda, MD
- Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD; and
| | - Steven Z Pavletic
- Immune Deficiency Cellular Therapy Program, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | | | - Murali C Krishna
- Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Ronald E Gress
- Experimental Transplantation and Immunotherapy Branch and
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Kumari R, Palaniyandi S, Hildebrandt GC. Metabolic Reprogramming-A New Era How to Prevent and Treat Graft Versus Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation Has Begun. Front Pharmacol 2020; 11:588449. [PMID: 33343357 PMCID: PMC7748087 DOI: 10.3389/fphar.2020.588449] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 09/29/2020] [Indexed: 12/19/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is the solitary therapeutic therapy for many types of hematological cancers. The benefits of this procedure are challenged by graft vs. host disease (GVHD), causing significant morbidity and mortality. Recent advances in the metabolomics field have revolutionized our understanding of complex human diseases, clinical diagnostics and allow to trace the de novo biosynthesis of metabolites. There is growing evidence for metabolomics playing a role in different aspects of GVHD, and therefore metabolomic reprogramming presents a novel tool for this disease. Pre-transplant cytokine profiles and metabolic status of allogeneic transplant recipients is shown to be linked with a threat of acute GVHD. Immune reactions underlying the pathophysiology of GVHD involve higher proliferation and migration of immune cells to the target site, requiring shifts in energy supply and demand. Metabolic changes and reduced availability of oxygen result in tissue and cellular hypoxia which is extensive enough to trigger transcriptional and translational changes. T cells, major players in acute GVHD pathophysiology, show increased glucose uptake and glycolytic activity. Effector T (Teff) cells activated during nutrient limiting conditions in vitro or multiplying during GVHD in vivo, depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO). Dyslipidemia, such as the increase of medium and long chain fatty and polyunsaturated acids in plasma of GVHD patients, has been observed. Sphingolipids associate with inflammatory conditions and cancer. Chronic GVHD (cGVHD) patients show reduced branched-chain amino acids (BCAAs) and increased sulfur-containing metabolites post HSCT. Microbiota-derived metabolites such as aryl hydrocarbon receptor (AhR) ligands, bile acids, plasmalogens and short chain fatty acids vary significantly and affect allogeneic immune responses during acute GVHD. Considering the multitude of possibilities, how altered metabolomics are involved in GVHD biology, multi-timepoints related and multivariable biomarker panels for prognosticating and understanding GVHD are needed. In this review, we will discuss the recent work addressing metabolomics reprogramming to control GVHD in detail.
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Affiliation(s)
| | | | - Gerhard C. Hildebrandt
- Division of Hematology and Blood and Marrow Transplantation, Markey Cancer Center, University of Kentucky, Lexington, KY, United States
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45
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Nguyen HD, Ticer T, Bastian D, Kuril S, Li H, Du H, Yan C, Yu XZ. Lysosomal Acid Lipase Is Required for Donor T Cells to Induce Graft-versus-Host Disease. Cell Rep 2020; 33:108316. [PMID: 33113360 PMCID: PMC7706352 DOI: 10.1016/j.celrep.2020.108316] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 08/28/2020] [Accepted: 10/06/2020] [Indexed: 12/14/2022] Open
Abstract
Graft-versus-host disease (GVHD) limits the success of allogeneic hematopoietic cell transplantation (allo-HCT). Lysosomal acid lipase (LAL) mediates the intrinsic lipolysis of cells to generate free fatty acids (FFAs), which play an essential role in the development, proliferation, and function of T cells. Here, we find that LAL is essential for donor T cells to induce GVHD in murine models of allo-HCT. Specifically, LAL is required for donor T cell survival, differentiation, and alloreactivity in GVHD target organs, but not in lymphoid organs. LAL induces the differentiation of donor T cells toward GVHD pathogenic Th1/Tc1 and Th17 while suppressing regulatory T cell generation. LAL-/- T cells succumb to oxidative stress and become anergic in target organs. Pharmacologically targeting LAL effectively prevents GVHD development while preserving the GVL activity. Thus, the present study reveals the role of LAL in T cell alloresponse and pathogenicity and validates LAL as a target for controlling GVHD and tumor relapse after allo-HCT.
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Affiliation(s)
- Hung D Nguyen
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Taylor Ticer
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - David Bastian
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Sandeepkumar Kuril
- Department of Pediatric Hematology-Oncology, Medical University of South Carolina, Charleston SC 29425, USA
| | - Hong Li
- Department of Public Health, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Hong Du
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indianapolis, IN 46202, USA
| | - Cong Yan
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indianapolis, IN 46202, USA
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
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Vandenhove B, Canti L, Schoemans H, Beguin Y, Baron F, Graux C, Kerre T, Servais S. How to Make an Immune System and a Foreign Host Quickly Cohabit in Peace? The Challenge of Acute Graft- Versus-Host Disease Prevention After Allogeneic Hematopoietic Cell Transplantation. Front Immunol 2020; 11:583564. [PMID: 33193397 PMCID: PMC7609863 DOI: 10.3389/fimmu.2020.583564] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Accepted: 09/21/2020] [Indexed: 01/16/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) has been used as cellular immunotherapy against hematological cancers for more than six decades. Its therapeutic efficacy relies on the cytoreductive effects of the conditioning regimen but also on potent graft-versus-tumor (GVT) reactions mediated by donor-derived immune cells. However, beneficial GVT effects may be counterbalanced by acute GVHD (aGVHD), a systemic syndrome in which donor immune cells attack healthy tissues of the recipient, resulting in severe inflammatory lesions mainly of the skin, gut, and liver. Despite standard prophylaxis regimens, aGVHD still occurs in approximately 20–50% of alloHCT recipients and remains a leading cause of transplant-related mortality. Over the past two decades, advances in the understanding its pathophysiology have helped to redefine aGVHD reactions and clinical presentations as well as developing novel strategies to optimize its prevention. In this review, we provide a brief overview of current knowledge on aGVHD immunopathology and discuss current approaches and novel strategies being developed and evaluated in clinical trials for aGVHD prevention. Optimal prophylaxis of aGVHD would prevent the development of clinically significant aGVHD, while preserving sufficient immune responsiveness to maintain beneficial GVT effects and immune defenses against pathogens.
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Affiliation(s)
- Benoît Vandenhove
- Laboratory of Hematology, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Lorenzo Canti
- Laboratory of Hematology, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium
| | - Hélène Schoemans
- Department of Clinical Hematology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Yves Beguin
- Laboratory of Hematology, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, CHU of Liège, University of Liège, Liège, Belgium
| | - Frédéric Baron
- Laboratory of Hematology, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, CHU of Liège, University of Liège, Liège, Belgium
| | - Carlos Graux
- Department of Clinical Hematology, CHU UCL Namur (Godinne), Université Catholique de Louvain, Yvoir, Belgium
| | - Tessa Kerre
- Hematology Department, Ghent University Hospital, Ghent University, Ghent, Belgium
| | - Sophie Servais
- Laboratory of Hematology, GIGA-I3, GIGA Institute, University of Liège, Liège, Belgium.,Department of Clinical Hematology, CHU of Liège, University of Liège, Liège, Belgium
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47
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Hesterberg RS, Beatty MS, Han Y, Fernandez MR, Akuffo AA, Goodheart WE, Yang C, Chang S, Colin CM, Alontaga AY, McDaniel JM, Mailloux AW, Billington JMR, Yue L, Russell S, Gillies RJ, Yun SY, Ayaz M, Lawrence NJ, Lawrence HR, Yu XZ, Fu J, Darville LN, Koomen JM, Ren X, Messina J, Jiang K, Garrett TJ, Rajadhyaksha AM, Cleveland JL, Epling-Burnette PK. Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes. Blood 2020; 136:857-870. [PMID: 32403132 PMCID: PMC7426646 DOI: 10.1182/blood.2019003257] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Accepted: 04/20/2020] [Indexed: 01/08/2023] Open
Abstract
Immunomodulatory drugs, such as thalidomide and related compounds, potentiate T-cell effector functions. Cereblon (CRBN), a substrate receptor of the DDB1-cullin-RING E3 ubiquitin ligase complex, is the only molecular target for this drug class, where drug-induced, ubiquitin-dependent degradation of known "neosubstrates," such as IKAROS, AIOLOS, and CK1α, accounts for their biological activity. Far less clear is whether these CRBN E3 ligase-modulating compounds disrupt the endogenous functions of CRBN. We report that CRBN functions in a feedback loop that harnesses antigen-specific CD8+ T-cell effector responses. Specifically, Crbn deficiency in murine CD8+ T cells augments their central metabolism manifested as elevated bioenergetics, with supraphysiological levels of polyamines, secondary to enhanced glucose and amino acid transport, and with increased expression of metabolic enzymes, including the polyamine biosynthetic enzyme ornithine decarboxylase. Treatment with CRBN-modulating compounds similarly augments central metabolism of human CD8+ T cells. Notably, the metabolic control of CD8+ T cells by modulating compounds or Crbn deficiency is linked to increased and sustained expression of the master metabolic regulator MYC. Finally, Crbn-deficient T cells have augmented antigen-specific cytolytic activity vs melanoma tumor cells, ex vivo and in vivo, and drive accelerated and highly aggressive graft-versus-host disease. Therefore, CRBN functions to harness the activation of CD8+ T cells, and this phenotype can be exploited by treatment with drugs.
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Affiliation(s)
- Rebecca S Hesterberg
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
| | - Matthew S Beatty
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Ying Han
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Mario R Fernandez
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Afua A Akuffo
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
| | - William E Goodheart
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Chunying Yang
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Shiun Chang
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
| | - Christelle M Colin
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Aileen Y Alontaga
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Jessica M McDaniel
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Adam W Mailloux
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Julia M R Billington
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
| | - Lanzhu Yue
- Department of Immunology, Moffitt Cancer Center and Research Institute, Tampa, FL
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China
| | - Shonagh Russell
- Cancer Biology PhD Program, University of South Florida, Tampa, FL
- Department of Cancer Physiology
| | | | | | | | - Nicholas J Lawrence
- Department of Drug Discovery, Moffitt Cancer Center and Research Institute, Tampa, FL
| | | | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC
| | - Jianing Fu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC
| | | | - John M Koomen
- Proteomics and Metabolomics Core
- Department of Molecular Oncology, and
| | - Xiubao Ren
- Department of Immunology, Tianjin Cancer Institute and Hospital, Tianjin Medical University, Tianjin, China
| | - Jane Messina
- Department of Anatomic Pathology and Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Kun Jiang
- Department of Anatomic Pathology and Cutaneous Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL
| | - Timothy J Garrett
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL; and
| | - Anjali M Rajadhyaksha
- Pediatric Neurology, Pediatrics, Weill Family Brain and Mind Research Institute, and
- Graduate Program in Neuroscience, Weill Cornell Medical College, Cornell University, Cornell, NY
| | - John L Cleveland
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL
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48
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Brown RA, Byersdorfer CA. Metabolic Pathways in Alloreactive T Cells. Front Immunol 2020; 11:1517. [PMID: 32793207 PMCID: PMC7393946 DOI: 10.3389/fimmu.2020.01517] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 06/09/2020] [Indexed: 12/11/2022] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative therapy for a range of hematologic illnesses including aplastic anemia, sickle cell disease, immunodeficiency, and high-risk leukemia, but the efficacy of aHSCT is often undermined by graft-versus-host disease (GVHD), where T cells from the donor attack and destroy recipient tissues. Given the strong interconnection between T cell metabolism and cellular function, determining the metabolic pathways utilized by alloreactive T cells is fundamental to deepening our understanding of GVHD biology, including its initiation, propagation, and potential mitigation. This review summarizes the metabolic pathways available to alloreactive T cells and highlights key metabolic proteins and pathways linking T cell metabolism to effector function. Our current knowledge of alloreactive T cell metabolism is then explored, showing support for glycolysis, fat oxidation, and glutamine metabolism but also offering a potential explanation for how these presumably contradictory metabolic findings might be reconciled. Examples of additional ways in which metabolism impacts aHSCT are addressed, including the influence of butyrate metabolism on GVHD resolution. Finally, the caveats and challenges of assigning causality using our current metabolic toolbox is discussed, as well as likely future directions in immunometabolism, both to highlight the strengths of the current evidence as well as recognize some of its limitations.
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Affiliation(s)
- Rebecca A Brown
- Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Craig A Byersdorfer
- Division of Blood and Marrow Transplant and Cellular Therapies, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
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49
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Nguyen H, Alawieh A, Bastian D, Kuril S, Dai M, Daenthanasanmak A, Zhang M, Iamsawat S, Schutt SD, Wu Y, Sleiman MM, Shetty A, Atkinson C, Sun S, Varela JC, Tomlinson S, Yu XZ. Targeting the Complement Alternative Pathway Permits Graft Versus Leukemia Activity while Preventing Graft Versus Host Disease. Clin Cancer Res 2020; 26:3481-3490. [PMID: 31919135 PMCID: PMC7334060 DOI: 10.1158/1078-0432.ccr-19-1717] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 10/03/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022]
Abstract
PURPOSE Application of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with hematologic disorders is limited by the development of GVHD. Separation of GVHD and graft-versus-leukemia (GVL) remains a great challenge in the field. We investigated the contribution of individual pathways involved in the complement cascade in GVH and GVL responses to identify specific targets by which to separate these two processes. EXPERIMENTAL DESIGN We used multiple preclinical murine and human-to-mouse xenograft models involving allo-HCT recipients lacking components of the alternative pathway (AP) or classical pathway (CP)/lectin pathway (LP) to dissect the role of each individual pathway in GVHD pathogenesis and the GVL effect. For translational purposes, we used the AP-specific complement inhibitor, CR2-fH, which localizes in injured target organs to allow specific blockade of complement activation at sites of inflammation. RESULTS Complement deposition was evident in intestines of mice and patients with GVHD. In a preclinical setting, ablation of the AP, but not the CP/LP, significantly improved GVHD outcomes. Complement activation through the AP in host hematopoietic cells, and specifically dendritic cells (DC), was required for GVHD progression. AP deficiency in recipients decreased donor T-cell migration and Th1/Th2 differentiation, while increasing the generation of regulatory T cells. This was because of decreased activation and stimulatory activity of recipient DCs in GVHD target organs. Treatment with CR2-fH effectively prevented GVHD while preserving GVL activity. CONCLUSIONS This study highlights the AP as a new therapeutic target to prevent GVHD and tumor relapse after allo-HCT. Targeting the AP by CR2-fH represents a promising therapeutic approach for GVHD treatment.
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Affiliation(s)
- Hung Nguyen
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
| | - Ali Alawieh
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Medical Scientist Training Program, College of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - David Bastian
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Sandeepkumar Kuril
- Department of Pediatric, Medical University of South Carolina, Charleston, South Carolina
| | - Min Dai
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Anusara Daenthanasanmak
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Mengmeng Zhang
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Supinya Iamsawat
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Steven D Schutt
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Yongxia Wu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - M Mahdi Sleiman
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Akshay Shetty
- Department of Pathology, Medical University of South Carolina, Charleston, South Carolina
| | - Carl Atkinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Department of Surgery, Medical University of South Carolina, Charleston, South Carolina
| | - Shaoli Sun
- Department of Pathology, Medical University of South Carolina, Charleston, South Carolina
| | - Juan Carlos Varela
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
- Ralph H. Johnson Veterans Affairs Medical Center, Medical University of South Carolina, Charleston, South Carolina
| | - Xue-Zhong Yu
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina.
- Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
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50
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Yu J, Xu H, Cui J, Chen S, Zhang H, Zou Y, Zhao J, Le S, Jiang L, Chen Z, Liu H, Zhang D, Xia J, Wu J. PLK1 Inhibition alleviates transplant-associated obliterative bronchiolitis by suppressing myofibroblast differentiation. Aging (Albany NY) 2020; 12:11636-11652. [PMID: 32541091 PMCID: PMC7343459 DOI: 10.18632/aging.103330] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 04/17/2020] [Indexed: 12/12/2022]
Abstract
Chronic allograft dysfunction (CAD) resulting from fibrosis is the major limiting factor for long-term survival of lung transplant patients. Myofibroblasts promote fibrosis in multiple organs, including the lungs. In this study, we identified PLK1 as a promoter of myofibroblast differentiation and investigated the mechanism by which its inhibition alleviates transplant-associated obliterative bronchiolitis (OB) during CAD. High-throughput bioinformatic analyses and experiments using the murine heterotopic tracheal transplantation model revealed that PLK1 is upregulated in grafts undergoing CAD as compared with controls, and that inhibiting PLK1 alleviates OB in vivo. Inhibition of PLK1 in vitro reduced expression of the specific myofibroblast differentiation marker α-smooth muscle actin (α-SMA) and decreased phosphorylation of both MEK and ERK. Importantly, we observed a similar phenomenon in human primary fibroblasts. Our results thus highlight PLK1 as a promising therapeutic target for alleviating transplant-associated OB through suppression of TGF-β1-mediated myofibroblast differentiation.
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Affiliation(s)
- Jizhang Yu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Heng Xu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Jikai Cui
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Shanshan Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Hao Zhang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Yanqiang Zou
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Jing Zhao
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Sheng Le
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Lang Jiang
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Zhang Chen
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Hao Liu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Dan Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Jiahong Xia
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
| | - Jie Wu
- Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei, China
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