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Gupta SK, Yadav S, Sharma D, Sandur SK, Khattry N, Goda JS, Gota V. Effect of the radioprotector chlorophyllin on graft versus leukemia response in experimental allogeneic hematopoietic stem cell transplantation. J Ayurveda Integr Med 2025; 16:101109. [PMID: 39919359 PMCID: PMC11851190 DOI: 10.1016/j.jaim.2024.101109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 09/28/2024] [Accepted: 11/06/2024] [Indexed: 02/09/2025] Open
Affiliation(s)
- Saurabh Kumar Gupta
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai, 400094, Maharashtra, India
| | - Subhash Yadav
- Department of Pathology, Tata Memorial Hospital, Parel, Mumbai, 400012, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai, 400094, Maharashtra, India
| | - Deepak Sharma
- Radiation Biology and Health Science Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, 400094, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai, 400094, Maharashtra, India
| | - Santosh Kumar Sandur
- Radiation Biology and Health Science Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai, 400094, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai, 400094, Maharashtra, India
| | - Navin Khattry
- Department of Medical Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai, 400094, Maharashtra, India
| | - Jayant Sastri Goda
- Department of Radiation Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai, 400094, Maharashtra, India.
| | - Vikram Gota
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai, 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai, 400094, Maharashtra, India.
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Zhu J, Yang L, Xia J, Zhou N, Zhu J, Zhu H, Chen J, Qing K, Duan CW. Interleukin-27 Promotes the Generation of Myeloid-derived Suppressor Cells to Alleviate Graft-versus-host Disease. Transplantation 2024; 108:e404-e416. [PMID: 38773837 DOI: 10.1097/tp.0000000000005069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/24/2024]
Abstract
BACKGROUND Stimulation of myeloid-derived suppressor cell (MDSC) formation represents a potential curative therapeutic approach for graft-versus-host disease (GVHD), which significantly impacts the prognosis of allogeneic hematopoietic stem cell transplantation. However, the lack of an effective strategy for inducing MDSC production in vivo has hindered their clinical application. In our previous study, MDSC expansion was observed in interleukin (IL)-27-treated mice. METHODS In this study, we overexpressed exogenous IL-27 in mice using a recombinant adeno-associated virus vector to investigate its therapeutic and exacerbating effects in murine GVHD models. RESULTS In our study, we demonstrated that exogenous administration of IL-27 significantly suppressed GVHD development in a mouse model. We found that IL-27 treatment indirectly inhibited the proliferation and activation of donor T cells by rapidly expanding recipient and donor myeloid cells, which act as MDSCs after irradiation or under inflammatory conditions, rather than through regulatory T-cell expansion. Additionally, IL-27 stimulated MDSC expansion by enhancing granulocyte-monocyte progenitor generation. Notably, we verified that IL-27 signaling in donor T cells exerted an antagonistic effect on GVHD prevention and treatment. Further investigation revealed that combination therapy involving IL-27 and T-cell depletion exhibited remarkable preventive effects on GVHD in both mouse and xenogeneic GVHD models. CONCLUSIONS Collectively, these findings suggest that IL-27 promotes MDSC generation to reduce the incidence of GVHD, whereas targeted activation of IL-27 signaling in myeloid progenitors or its combination with T-cell depletion represents a potential strategy for GVHD therapy.
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Affiliation(s)
- Jianmin Zhu
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liting Yang
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Xia
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Neng Zhou
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiayao Zhu
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hua Zhu
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Chen
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Department of Hematology and Oncology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Kai Qing
- Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cai-Wen Duan
- Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Key Laboratory of Pediatric Hematology and Oncology Ministry of Health, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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Guan Q, Gilpin SG, Doerksen J, Bath L, Lam T, Li Y, Lambert P, Wall DA. The Interactions of T Cells with Myeloid-Derived Suppressor Cells in Peripheral Blood Stem Cell Grafts. Cells 2024; 13:1545. [PMID: 39329729 PMCID: PMC11429538 DOI: 10.3390/cells13181545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/06/2024] [Accepted: 09/09/2024] [Indexed: 09/28/2024] Open
Abstract
The interaction of myeloid-derived suppressor cells (MDSCs) with T cells within G-CSF-mobilized peripheral blood stem cell (PBSC) grafts in patients undergoing autologous or allogeneic hematopoietic stem cell transplantation remains to be elucidated. Through studying allo- and auto-PBSC grafts, we observed grafts containing large numbers of T cells and MDSCs with intergraft variability in their percentage and number. T cells from autologous grafts compared to allografts expressed relative higher percentages of inhibitory receptors PD-1, CTLA-4, TIM-3, LAG-3, TIGIT and BTLA. Autograft T cells had decreased cell proliferation and IFN-γ secretion, which supported the possible presence of T cell exhaustion. On the contrary, graft monocytic MDSCs (M-MDSCs) expressed multiple inhibitory receptor ligands, including PD-L1, CD86, Galectin-9, HVEM and CD155. The expression of inhibitory receptor ligands on M-MDSCs was correlated with their corresponding inhibitory receptors on T cells in the grafts. Isolated M-MDSCs had the ability to suppress T cell proliferation and IFN-γ secretion and/or promote Treg expansion. Blocking the PD-L1-PD-1 signaling pathway partially reversed the functions of M-MDSCs. Taken together, our data indicated that T cells and M-MDSCs in PBSC grafts express complementary inhibitory receptor-ligand pairing, which may impact the quality of immune recovery and clinical outcome post transplantation.
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Affiliation(s)
- Qingdong Guan
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
- Department of Immunology, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Manitoba Center for Advanced Cell and Tissue Therapy, Winnipeg, MB R3A 1R9, Canada
- Paul Albreachtsen Research Institute, CancerCare Manitoba, Winnipeg, MB R3A 1R9, Canada
| | - Scott G. Gilpin
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - James Doerksen
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Lauren Bath
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Tracy Lam
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Yun Li
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
| | - Pascal Lambert
- Department of Epidemiology and Cancer Registry, CancerCare Manitoba, Winnipeg, MB R3A 1R9, Canada;
| | - Donna A. Wall
- Manitoba Blood and Marrow Transplant Program, Departments of Pediatrics and Child Health and Internal Medicine, University of Manitoba, Winnipeg, MB R3T 2N2, Canada (D.A.W.)
- Department of Immunology, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
- Manitoba Center for Advanced Cell and Tissue Therapy, Winnipeg, MB R3A 1R9, Canada
- Paul Albreachtsen Research Institute, CancerCare Manitoba, Winnipeg, MB R3A 1R9, Canada
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Mei D, Xue Z, Zhang T, Yang Y, Jin L, Yu Q, Hong J, Zhang X, Ge J, Xu L, Wang H, Zhang Z, Zhao Y, Zhai Y, Tao Q, Zhai Z, Li Q, Li H, Zhang L. Immune isolation-enabled nanoencapsulation of donor T cells: a promising strategy for mitigating GVHD and treating AML in preclinical models. J Immunother Cancer 2024; 12:e008663. [PMID: 39242117 PMCID: PMC11381671 DOI: 10.1136/jitc-2023-008663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND In allogeneic-hematopoietic stem cell transplantation for acute myeloid leukemia (AML), donor T cells combat leukemia through the graft-versus-leukemia (GVL) effect, while they also pose a risk of triggering life-threatening graft-versus-host disease (GVHD) by interacting with recipient cells. The onset of GVHD hinges on the interplay between donor T cells and recipient antigen-presenting cells (APCs), sparking T-cell activation. However, effective methods to balance GVHD and GVL are lacking. METHODS In our study, we crafted nanocapsules by layering polycationic aminated gelatin and polyanionic alginate onto the surface of T cells, examining potential alterations in their fundamental physiological functions. Subsequently, we established an AML mouse model and treated it with transplantation of bone marrow cells (BMCs) combined with encapsulated T cells to investigate the GVL and anti-GVHD effects of encapsulated T cells. In vitro co-culture was employed to probe the effects of encapsulation on immune synapses, co-stimulatory molecules, and tumor-killing pathways. RESULTS Transplantation of BMCs combined with donor T cells selectively encapsulated onto AML mice significantly alleviates GVHD symptoms while preserving essential GVL effects. Encapsulated T cells exerted their immunomodulatory effects by impeding the formation of immune synapses with recipient APCs, thereby downregulating co-stimulatory signals such as CD28-CD80, ICOS-ICOSL, and CD40L-CD40. Recipient mice receiving encapsulated T-cell transplantation exhibited a marked increase in donor Ly-5.1-BMC cell numbers, accompanied by unaltered in vivo expression levels of perforin and granzyme B. While transient inhibition of donor T-cell cytotoxicity in the tumor microenvironment was observed in vitro following single-cell nanoencapsulation, subsequent restoration to normal antitumor activity ensued, attributed to selective permeability of encapsulated vesicle shells and material degradation. Moreover, the expression of apoptotic proteins and FAS-FAS ligand pathway at normal levels was still observed in leukemia tumor cells. CONCLUSIONS Encapsulated donor T cells effectively mitigate GVHD while preserving the GVL effect by minimizing co-stimulatory signaling with APCs through early immune isolation. Subsequent degradation of nanocapsules restores T-cell cytotoxic efficacy against AML cells, mediated by cytotoxic pathways. Using transplant-encapsulated T cells offers a promising strategy to suppress GVHD while preserving the GVL effect.
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Affiliation(s)
- Dan Mei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Ziyang Xue
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Tianjing Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Yining Yang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Lin Jin
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Qianqian Yu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Jian Hong
- Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xianzheng Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jinru Ge
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Li Xu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Han Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Ziwei Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Yuchen Zhao
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Yuanfang Zhai
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
| | - Qianshan Tao
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Zhimin Zhai
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qingsheng Li
- Department of Hematology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hongxia Li
- Department of Hematology and Oncology, The Third Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Lingling Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China
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Su L, Wei ZF, Pi CC, Qin TX, Song F, Zhang YW, Gao SJ. Icariin protects against acute graft-versus-host disease while preserving graft-versus-leukemia activity after allogeneic hematopoietic stem cell transplantation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 132:155901. [PMID: 39067193 DOI: 10.1016/j.phymed.2024.155901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 05/27/2024] [Accepted: 07/17/2024] [Indexed: 07/30/2024]
Abstract
BACKGROUND Acute graft-versus-host disease (aGVHD), which is mainly mediated by allogeneic T cells, is a decisive factor in the success of allogeneic hematopoietic stem cell transplantation (allo-HCT). Prophylaxis for aGVHD in clinical patients is unsatisfactory, and there is still a huge unmet need for novel approaches. Icariin (ICA) shows potent anti-inflammatory activity and suppresses T cell-mediated immune responses. Thus, ICA is a potential drug for the prevention of aGVHD. However, there is no data assessing the impact of ICA on aGVHD after allo-HCT. PURPOSE This study aimed to investigate the protective effect of ICA against aGVHD and its mechanisms. Moreover, the impact of ICA on the graft-versus-leukemia (GVL) effect and engraftment of donor hematopoietic and immune cells were assessed. METHODS Different murine models of allo-HCT were developed to study the influence of the ICA on GVHD and GVL effect. Flow cytometry was used to analyze the growth of leukemia cells, alterations in different immune cells, and apoptosis. Cell proliferation was determined using a CCK-8 assay. RNA sequencing and quantitative proteomic analysis were performed to elucidate the underlying mechanisms, which were further verified by polymerase chain reaction or functional experiments. RESULTS Different concentrations of ICA exhibited opposite effects: low-concentration ICA promoted, while high concentrations suppressed the proliferation and function of T cells. A high dose of ICA administration during days +3 to +5 post-allo-HCT can alleviate murine aGVHD but does not affect the course of chronic GVHD (cGVHD), the GVL effect against both acute myeloid and lymphoblastic leukemia, or the recovery of donor hematological and immune cells. ICA extensively represses the expansion, function, and infiltration of donor alloreactive T cells, while preserving regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC). Quantitative proteomic analysis showed that downregulation of integrin-linked kinase (ILK) and lymphocyte cytosolic protein 2 (LCP2) expression was possibly associated with ICA-mediated aGVHD protective effects. Furthermore, an inhibitor of ILK, which can alleviate murine aGVHD administered early after allo-HCT. CONCLUSION These findings suggest that the bioactivities of ICA are associated with its concentration and that ICA can effectively mitigate aGVHD without losing GVL activity or engraftment of donor hematopoietic and immune cells. Thus, ICA may be a promising drug for preventing aGVHD in clinical settings.
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Affiliation(s)
- Long Su
- Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Hematology Precision Medicine of Jilin Province, The First Hospital of Jilin University, Changchun 130021, China
| | - Zhi-Feng Wei
- Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Hematology Precision Medicine of Jilin Province, The First Hospital of Jilin University, Changchun 130021, China
| | - Chen-Chen Pi
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun 130061, China
| | - Tian-Xue Qin
- Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Hematology Precision Medicine of Jilin Province, The First Hospital of Jilin University, Changchun 130021, China
| | - Fei Song
- Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Hematology Precision Medicine of Jilin Province, The First Hospital of Jilin University, Changchun 130021, China
| | - Yun-Wei Zhang
- Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Hematology Precision Medicine of Jilin Province, The First Hospital of Jilin University, Changchun 130021, China
| | - Su-Jun Gao
- Department of Hematology, The First Hospital of Jilin University, Changchun 130021, China; Key Laboratory of Hematology Precision Medicine of Jilin Province, The First Hospital of Jilin University, Changchun 130021, China.
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Ni M, Cui J, Yang X, Ding Y, Zhao P, Hu T, Zhan Y, Kang Q, Hu X, Zhao J, Xu Y, Chen L, Liu M, Zhao M, Zhang F, Huang S, Li Y, Yang X, Zhang L, Zhang T, Deng B, Yang B, Lu D, Wang J. Dual roles of CD11b +CD33 +HLA-DR -/lowCD14 - myeloid-derived suppressor cells with a granulocytic morphology following allogeneic hematopoietic stem cell transplantation: from inflammation promoters to immune suppressors within 90 days. Front Immunol 2024; 15:1403272. [PMID: 39040102 PMCID: PMC11260618 DOI: 10.3389/fimmu.2024.1403272] [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: 03/19/2024] [Accepted: 06/25/2024] [Indexed: 07/24/2024] Open
Abstract
Introduction Granulocytic myeloid-derived suppressor cells (G-MDSCs) show fast recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) constituting the major part of peripheral blood in the early phase. Although G-MDSCs mediate immune suppression through multiple mechanisms, they may also promote inflammation under specific conditions. Methods G-MDSCs were isolated from 82 patients following allo-HSCT within 90 days after allo-HSCT, and their interactions with autologous CD3+ T-cells were examined. T-cell proliferation was assessed by flow cytometry following CFSE staining, while differentiation and interferon-γ secretion were characterized using chemokine receptor profiling and ELISpot assays, respectively. NK cell cytotoxicity was evaluated through co-culture with K562 cells. An aGVHD xenogeneic model in humanized mice was employed to study the in vivo effects of human leukocytes. Furthermore, transcriptional alterations in G-MDSCs were analyzed via RNA sequencing to investigate functional transitions. Results G-MDSCs promoted inflammation in the early-stage, by facilitating cytokine secretion and proliferation of T cells, as well as their differentiation into pro-inflammatory T helper subsets. At day 28, patients with a higher number of G-MDSCs exhibited an increased risk of developing grades II-IV aGvHD. Besides, adoptive transfer of G-MDSCs from patients at day 28 into humanized mice exacerbated aGvHD. However, at day 90, G-MDSCs led to immunosuppression, characterized by upregulated expression of indoleamine 2,3-dioxygenase gene and interleukin-10 secretion, coupled with the inhibition of T cell proliferation. Furthermore, transcriptional analysis of G-MDSCs at day 28 and day 90 revealed that 1445 genes were differentially expressed. These genes were associated with various pathways, revealing the molecular signatures of early post-transplant differentiation in G-MDSCs. In addition, genes linked to the endoplasmic reticulum stress were upregulated in patients without aGvHD. The acquisition of immunosuppressive function by G-MDSCs may depend on the activation of CXCL2 and DERL1 genes. Conclusion Our findings revealed the alteration in the immune characteristics of G-MDSCs within the first 90 days post-allo-HSCT. Moreover, the quantity of G-MDSCs at day 28 may serve as a predictive indicator for the development of aGvHD.
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Affiliation(s)
- Ming Ni
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jing Cui
- Department of Dermatology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xin Yang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
- Department of Hematology, The Second Affiliated Hospital of Guizhou Medical University, Kaili, China
| | - Yuntian Ding
- Department of Internal Medicine V, University Clinic Heidelberg, Heidelberg, Germany
| | - Peng Zhao
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Tianzhen Hu
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yun Zhan
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Qian Kang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xiuying Hu
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Jiangyuan Zhao
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Yao Xu
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Lu Chen
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Min Liu
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Mei Zhao
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Fengqi Zhang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Shisi Huang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Ya Li
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Xueying Yang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Luxin Zhang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Tianzhuo Zhang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Bo Deng
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Bing Yang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
| | - Deqin Lu
- Department of Pathophysiology, Guizhou Medical University, Guiyang, China
| | - Jishi Wang
- Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang, China
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Restelli C, Ruella M, Paruzzo L, Tarella C, Pelicci PG, Colombo E. Recent Advances in Immune-Based Therapies for Acute Myeloid Leukemia. Blood Cancer Discov 2024; 5:234-248. [PMID: 38904305 PMCID: PMC11215380 DOI: 10.1158/2643-3230.bcd-23-0202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 02/16/2024] [Accepted: 05/20/2024] [Indexed: 06/22/2024] Open
Abstract
Despite advancements, acute myeloid leukemia (AML) remains unconquered by current therapies. Evidence of immune evasion during AML progression, such as HLA loss and T-cell exhaustion, suggests that antileukemic immune responses contribute to disease control and could be harnessed by immunotherapy. In this review, we discuss a spectrum of AML immunotherapy targets, encompassing cancer cell-intrinsic and surface antigens as well as targeting in the leukemic milieu, and how they can be tailored for personalized approaches. These targets are overviewed across major immunotherapy modalities applied to AML: immune checkpoint inhibitors, antibody-drug conjugates, therapeutic vaccines, bispecific/trispecific antibodies, and chimeric antigen receptor (CAR)-T and CAR-NK cells. Significance: Immune therapies in AML treatment show evolving promise. Ongoing research aims to customize approaches for varied patient profiles and clinical scenarios. This review covers immune surveillance mechanisms, therapy options like checkpoint inhibitors, antibodies, CAR-T/NK cells, and vaccines, as well as resistance mechanisms and microenvironment considerations.
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Affiliation(s)
- Cecilia Restelli
- Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, Milan, Italy.
| | - Marco Ruella
- Center for Cellular Immunotherapies and Cellular Therapy and Transplant, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
- Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
| | - Luca Paruzzo
- Center for Cellular Immunotherapies and Cellular Therapy and Transplant, University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
- Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, PA, USA.
| | - Corrado Tarella
- Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, Milan, Italy.
| | - Pier Giuseppe Pelicci
- Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, Milan, Italy.
- Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy.
| | - Emanuela Colombo
- Department of Experimental Oncology, European Institute of Oncology (IEO), IRCCS, Milan, Italy.
- Department of Oncology and Haemato-Oncology, University of Milan, Milan, Italy.
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Notarantonio AB, Bertrand A, Piucco R, Fievet G, Sartelet H, Boulangé L, de Isla N, De Carvalho Bittencourt M, Hergalant S, Rubio MT, D'Aveni M. Highly immunosuppressive myeloid cells correlate with early relapse after allogeneic stem cell transplantation. Exp Hematol Oncol 2024; 13:50. [PMID: 38734654 PMCID: PMC11088072 DOI: 10.1186/s40164-024-00516-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 04/27/2024] [Indexed: 05/13/2024] Open
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for myeloid malignancies such as some acute myeloid leukemias (AML) and high-risk myelodysplastic syndromes (MDS). It aims to eradicate the malignant clone using immunocompetent donor cells (graft-versus-leukemia effect, GVL). Unfortunately, relapse is the primary cause of transplant failure mainly related on HLA loss or downregulation and upregulation of inhibitory ligands on blasts which result in donor immune effector dysfunctions. METHODS Between 2018 and 2021, we conducted a monocentric prospective study including 61 consecutive patients transplanted for AML or high-risk MDS. We longitudinally investigated immune cells at days + 30, + 90 and + 180 post-transplant from bone marrow and peripheral blood. We assessed the dynamics between myeloid derived suppressor cells (MDSCs) and T-cells. RESULTS Among the 61 patients, 45 did not relapse over the first 12 months while 16 relapsed during the first year post-transplant. Through months 1 to 6, comparison with healthy donors revealed an heterogenous increase in MDSC frequency. In all recipients, the predominant MDSC subset was granulocytic with no specific phenotypic relapse signature. However, in relapsed patients, in vitro and in vivo functional analyses revealed that MDSCs from peripheral blood were highly immunosuppressive from day + 30 onwards, with an activated NLRP3 inflammasome signature. Only circulating immunosuppressive MDSCs were statistically correlated to circulating double-positive Tim3+LAG3+ exhausted T cells. CONCLUSION Our simple in vitro functional assay defining MDSC immunosuppressive properties might serve as an early biomarker of relapse and raise the question of new preventive treatments targeting MDSCs in the future. Trial registration NCT03357172.
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Affiliation(s)
- Anne-Béatrice Notarantonio
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
- Hematology Department, CHRU Nancy, Université de Lorraine, 54000, Nancy, France
| | - Allan Bertrand
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
| | - Romain Piucco
- Inserm UMR_S 1256 NGERE, Université de Lorraine, 54500, Vandœuvre-les-Nancy, France
| | - Ghislain Fievet
- Inserm UMR_S 1256 NGERE, Université de Lorraine, 54500, Vandœuvre-les-Nancy, France
| | - Hervé Sartelet
- Anatomopathology Department, CHRU Nancy, Université de Lorraine, 54000, Nancy, France
| | - Laura Boulangé
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
| | - Natalia de Isla
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
| | - Marcelo De Carvalho Bittencourt
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
- Immunology Laboratory, CHRU Nancy, Université de Lorraine, 54000, Nancy, France
| | - Sébastien Hergalant
- Inserm UMR_S 1256 NGERE, Université de Lorraine, 54500, Vandœuvre-les-Nancy, France
| | - Marie-Thérèse Rubio
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France
- Hematology Department, CHRU Nancy, Université de Lorraine, 54000, Nancy, France
| | - Maud D'Aveni
- UMR 7365 CNRS, IMoPA, Université de Lorraine, 54000, Nancy, France.
- Hematology Department, CHRU Nancy, Université de Lorraine, 54000, Nancy, France.
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9
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Pacini CP, Soares MVD, Lacerda JF. The impact of regulatory T cells on the graft-versus-leukemia effect. Front Immunol 2024; 15:1339318. [PMID: 38711496 PMCID: PMC11070504 DOI: 10.3389/fimmu.2024.1339318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 04/08/2024] [Indexed: 05/08/2024] Open
Abstract
Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is the only curative therapy for many hematologic malignancies, whereby the Graft-versus-Leukemia (GVL) effect plays a pivotal role in controlling relapse. However, the success of GVL is hindered by Graft-versus-Host Disease (GVHD), where donor T cells attack healthy tissues in the recipient. The ability of natural regulatory T cells (Treg) to suppress immune responses has been exploited as a therapeutical option against GVHD. Still, it is crucial to evaluate if the ability of Treg to suppress GVHD does not compromise the benefits of GVL. Initial studies in animal models suggest that Treg can attenuate GVHD while preserving GVL, but results vary according to tumor type. Human trials using Treg as GVHD prophylaxis or treatment show promising results, emphasizing the importance of infusion timing and Treg/Tcon ratios. In this review, we discuss strategies that can be used aiming to enhance GVL post-Treg infusion and the proposed mechanisms for the maintenance of the GVL effect upon the adoptive Treg transfer. In order to optimize the therapeutic outcomes of Treg administration in allo-HSCT, future efforts should focus on refining Treg sources for infusion and evaluating their specificity for antigens mediating GVHD while preserving GVL responses.
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Affiliation(s)
- Carolina P. Pacini
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Maria V. D. Soares
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - João F. Lacerda
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
- Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, ULS Santa Maria, Lisbon, Portugal
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10
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Gupta SK, Gohil D, Momin MB, Yadav S, Chichra A, Punatar S, Gokarn A, Mirgh S, Jindal N, Nayak L, Hingorani L, Khattry N, Gota V. Withania Somnifera Extract Mitigates Experimental Acute Graft versus Host Disease Without Abrogating Graft Versus Leukemia Effect. Cell Transplant 2024; 33:9636897241226573. [PMID: 38258793 PMCID: PMC10807391 DOI: 10.1177/09636897241226573] [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: 11/07/2023] [Revised: 12/26/2023] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
Acute graft versus host disease (aGvHD) is the major contributor of nonrelapse mortality in alloHSCT. It is associated with an inflammatory immune response manifesting as cytokine storm with ensuing damage to target organs such as liver, gut, and skin. Prevention of aGvHD while retaining the beneficial graft versus leukemia (GvL) effect remains a major challenge. Withania somnifera extract (WSE) is known for its anti-inflammatory, immune-modulatory, and anticancer properties, which are appealing in the context of aGvHD. Herein, we demonstrated that prophylactic and therapeutic use of WSE in experimental model of alloHSCT mitigates aGvHD-associated morbidity and mortality. In the prophylaxis study, a dose of 75 mg/kg of WSE offered greatest protection against death due to aGvHD (hazard ratio [HR] = 0.15 [0.03-0.68], P ≤ .01), whereas 250 mg/kg was most effective for the treatment of aGvHD (HR = 0.16 [0.05-0.5], P ≤ .01). WSE treatment protected liver, gut, and skin from damage by inhibiting cytokine storm and lymphocytic infiltration to aGvHD target organs. In addition, WSE did not compromise the GvL effect, as alloHSCT with or without WSE did not allow the leukemic A20 cells to grow. In fact, WSE showed marginal antileukemic effect in vivo. WSE is currently under clinical investigation for the prevention and treatment of aGvHD.
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Affiliation(s)
- Saurabh Kumar Gupta
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Dievya Gohil
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
| | - Mohd Bashar Momin
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Subhash Yadav
- Homi Bhabha National Institute, Mumbai, India
- Department of Pathology, Tata Memorial Hospital, Mumbai, India
| | - Akanksha Chichra
- Homi Bhabha National Institute, Mumbai, India
- Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Sachin Punatar
- Homi Bhabha National Institute, Mumbai, India
- Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Anant Gokarn
- Homi Bhabha National Institute, Mumbai, India
- Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Sumeet Mirgh
- Homi Bhabha National Institute, Mumbai, India
- Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Nishant Jindal
- Homi Bhabha National Institute, Mumbai, India
- Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Lingaraj Nayak
- Homi Bhabha National Institute, Mumbai, India
- Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | | | - Navin Khattry
- Homi Bhabha National Institute, Mumbai, India
- Department of Medical Oncology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
| | - Vikram Gota
- Department of Clinical Pharmacology, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India
- Homi Bhabha National Institute, Mumbai, India
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11
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Kumar Gupta S, Gohil D, Dutta D, Panigrahi GC, Gupta P, Dalvi K, Khanka T, Yadav S, Kumar Kaushal R, Chichra A, Punatar S, Gokarn A, Mirgh S, Jindal N, Nayak L, Tembhare PR, Khizer Hasan S, Kumar Sandur S, Hingorani L, Khattry N, Gota V. Withaferin-A alleviates acute graft versus host disease without compromising graft versus leukemia effect. Int Immunopharmacol 2023; 121:110437. [PMID: 37311352 DOI: 10.1016/j.intimp.2023.110437] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 05/20/2023] [Accepted: 05/30/2023] [Indexed: 06/15/2023]
Abstract
Acute graft versus host disease (aGvHD) contributes to a significant proportion of non-relapse mortality and morbidity in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT). Withaferin-A (WA), a phytomolecule obtained from Withania somnifera (Ashwagandha), is known to have anti-inflammatory, anti-proliferative and immunomodulatory properties. The efficacy of WA for the prevention and treatment of aGvHD was evaluated using a murine model of alloHSCT. Prophylactic administration of WA to mice mitigated the clinical symptoms of aGvHD and improved survival significantly compared to the GvHD control [HR = 0.07 (0.01-0.35); P < 0.001]. Furthermore, WA group had better overall survival compared to standard prophylactic regimen of CSA + MTX [HR = 0.19 (0.03-1.1), P < 0.05]. At the same time, WA did not compromise the beneficial GvL effect. In addition, WA administered to animals after the onset of aGvHD could reverse the clinical severity and improved survival, thus establishing its therapeutic potential. Our findings suggest that WA reduced the systemic levels of Th1, Th2 and Th17 inflammatory cytokine and increased the anti-inflammatory cytokine IL-10 levels significantly (P < 0.05). WA also inhibited lymphocytes migration to gut, liver, skin and lung and protected these organs from damage. Ex-vivo, WA inhibited proliferation of human peripheral blood mononuclear cells (hPBMCs), modulated immune cell phenotype and decreased cytokine release. In addition, WA inhibited pJAK2 and pSTAT3 protein levels in mouse splenocytes and hPBMCs. In conclusion, our study demonstrates the utility of WA for the prevention and treatment of aGvHD, which should be further evaluated in a clinical setting.
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Affiliation(s)
- Saurabh Kumar Gupta
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Dievya Gohil
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Deepshikha Dutta
- Cell and Tumor Biology Group, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Girish Ch Panigrahi
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Puja Gupta
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Kajal Dalvi
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Twinkle Khanka
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India
| | - Subhash Yadav
- Department of Pathology, Tata Memorial Hospital, Parel, Mumbai 400012, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Rajiv Kumar Kaushal
- Department of Pathology, Tata Memorial Hospital, Parel, Mumbai 400012, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Akanksha Chichra
- Department of Medical Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Sachin Punatar
- Department of Medical Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Anant Gokarn
- Department of Medical Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Sumeet Mirgh
- Department of Medical Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Nishant Jindal
- Department of Medical Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Lingaraj Nayak
- Department of Medical Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Prashant R Tembhare
- Hematopathology Laboratory, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Syed Khizer Hasan
- Cell and Tumor Biology Group, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Santosh Kumar Sandur
- Radiation Biology and Health Science Division, Bio-science Group, Bhabha Atomic Research Centre, Mumbai 400094, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Lal Hingorani
- Pharmanza Herbal Pvt. Ltd., Anand 388435, Gujarat, India
| | - Navin Khattry
- Department of Medical Oncology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India
| | - Vikram Gota
- Department of Clinical Pharmacology, ACTREC, Tata Memorial Centre, Kharghar, Navi Mumbai 410210, Maharashtra, India; Homi Bhabha National Institute, BARC Training School Complex, Anushakti Nagar, Mumbai 400094, Maharashtra, India.
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12
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Ostrand-Rosenberg S, Lamb TJ, Pawelec G. Here, There, and Everywhere: Myeloid-Derived Suppressor Cells in Immunology. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 210:1183-1197. [PMID: 37068300 PMCID: PMC10111205 DOI: 10.4049/jimmunol.2200914] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Accepted: 01/06/2023] [Indexed: 04/19/2023]
Abstract
Myeloid-derived suppressor cells (MDSCs) were initially identified in humans and mice with cancer where they profoundly suppress T cell- and NK cell-mediated antitumor immunity. Inflammation is a central feature of many pathologies and normal physiological conditions and is the dominant driving force for the accumulation and function of MDSCs. Therefore, MDSCs are present in conditions where inflammation is present. Although MDSCs are detrimental in cancer and conditions where cellular immunity is desirable, they are beneficial in settings where cellular immunity is hyperactive. Because MDSCs can be generated ex vivo, they are being exploited as therapeutic agents to reduce damaging cellular immunity. In this review, we discuss the detrimental and beneficial roles of MDSCs in disease settings such as bacterial, viral, and parasitic infections, sepsis, obesity, trauma, stress, autoimmunity, transplantation and graft-versus-host disease, and normal physiological settings, including pregnancy and neonates as well as aging. The impact of MDSCs on vaccination is also discussed.
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Affiliation(s)
- Suzanne Ostrand-Rosenberg
- Division of Microbiology and Immunology, Department of Pathology, University of Utah 84112, Salt Lake City, UT
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA
| | - Tracey J. Lamb
- Division of Microbiology and Immunology, Department of Pathology, University of Utah 84112, Salt Lake City, UT
| | - Graham Pawelec
- Department of Immunology, Interfaculty Institute for Cell Biology, University of Tübingen, Tübingen, Germany, and Health Sciences North Research Institute, Sudbury, ON, Canada
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13
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Bhardwaj V, Ansell SM. Modulation of T-cell function by myeloid-derived suppressor cells in hematological malignancies. Front Cell Dev Biol 2023; 11:1129343. [PMID: 37091970 PMCID: PMC10113446 DOI: 10.3389/fcell.2023.1129343] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 03/15/2023] [Indexed: 04/08/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are pathologically activated neutrophils and monocytes that negatively regulate the immune response to cancer and chronic infections. Abnormal myelopoiesis and pathological activation of myeloid cells generate this heterogeneous population of myeloid-derived suppressor cells. They are characterized by their distinct transcription, phenotypic, biochemical, and functional features. In the tumor microenvironment (TME), myeloid-derived suppressor cells represent an important class of immunosuppressive cells that correlate with tumor burden, stage, and a poor prognosis. Myeloid-derived suppressor cells exert a strong immunosuppressive effect on T-cells (and a broad range of other immune cells), by blocking lymphocyte homing, increasing production of reactive oxygen and nitrogen species, promoting secretion of various cytokines, chemokines, and immune regulatory molecules, stimulation of other immunosuppressive cells, depletion of various metabolites, and upregulation of immune checkpoint molecules. Additionally, the heterogeneity of myeloid-derived suppressor cells in cancer makes their identification challenging. Overall, they serve as a major obstacle for many cancer immunotherapies and targeting them could be a favorable strategy to improve the effectiveness of immunotherapeutic interventions. However, in hematological malignancies, particularly B-cell malignancies, the clinical outcomes of targeting these myeloid-derived suppressor cells is a field that is still to be explored. This review summarizes the complex biology of myeloid-derived suppressor cells with an emphasis on the immunosuppressive pathways used by myeloid-derived suppressor cells to modulate T-cell function in hematological malignancies. In addition, we describe the challenges, therapeutic strategies, and clinical relevance of targeting myeloid-derived suppressor cells in these diseases.
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14
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Wang S, Zhao X, Wu S, Cui D, Xu Z. Myeloid-derived suppressor cells: key immunosuppressive regulators and therapeutic targets in hematological malignancies. Biomark Res 2023; 11:34. [PMID: 36978204 PMCID: PMC10049909 DOI: 10.1186/s40364-023-00475-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
The immunosuppressive tumor microenvironment (TME) supports the development of tumors and limits tumor immunotherapy, including hematological malignancies. Hematological malignancies remain a major public health issue with high morbidity and mortality worldwide. As an important component of immunosuppressive regulators, the phenotypic characteristics and prognostic value of myeloid-derived suppressor cells (MDSCs) have received much attention. A variety of MDSC-targeting therapeutic approaches have produced encouraging outcomes. However, the use of various MDSC-targeted treatment strategies in hematologic malignancies is still difficult due to the heterogeneity of hematologic malignancies and the complexity of the immune system. In this review, we summarize the biological functions of MDSCs and further provide a summary of the phenotypes and suppressive mechanisms of MDSC populations expanded in various types of hematological malignancy contexts. Moreover, we discussed the clinical correlation between MDSCs and the diagnosis of malignant hematological disease, as well as the drugs targeting MDSCs, and focused on summarizing the therapeutic strategies in combination with other immunotherapies, such as various immune checkpoint inhibitors (ICIs), that are under active investigation. We highlight the new direction of targeting MDSCs to improve the therapeutic efficacy of tumors.
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Affiliation(s)
- Shifen Wang
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xingyun Zhao
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Siwen Wu
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Dawei Cui
- Department of Blood Transfusion, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Zhenshu Xu
- Department of Hematology, Fujian Institute of Hematology, Fujian Provincial Key Laboratory on Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
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15
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Hess NJ, Kink JA, Hematti P. Exosomes, MDSCs and Tregs: A new frontier for GVHD prevention and treatment. Front Immunol 2023; 14:1143381. [PMID: 37063900 PMCID: PMC10090348 DOI: 10.3389/fimmu.2023.1143381] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
The development of graft versus host disease (GVHD) represents a long-standing complication of allogeneic hematopoietic cell transplantation (allo-HCT). Different approaches have been used to control the development of GVHD with most relying on variations of chemotherapy drugs to eliminate allo-reactive T cells. While these approaches have proven effective, it is generally accepted that safer, and less toxic GVHD prophylaxis drugs are required to reduce the health burden placed on allo-HCT recipients. In this review, we will summarize the emerging concepts revolving around three biologic-based therapies for GVHD using T regulatory cells (Tregs), myeloid-derived-suppressor-cells (MDSCs) and mesenchymal stromal cell (MSC) exosomes. This review will highlight how each specific modality is unique in its mechanism of action, but also share a common theme in their ability to preferentially activate and expand Treg populations in vivo. As these three GVHD prevention/treatment modalities continue their path toward clinical application, it is imperative the field understand both the biological advantages and disadvantages of each approach.
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Affiliation(s)
- Nicholas J. Hess
- Division of Hematology, Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
| | - John A. Kink
- Division of Hematology, Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
| | - Peiman Hematti
- Division of Hematology, Oncology and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
- University of Wisconsin Carbone Cancer Center, Madison, WI, United States
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16
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Mohammadpour H, Tsuji T, MacDonald CR, Sarow JL, Rosenheck H, Daneshmandi S, Choi JE, Qiu J, Matsuzaki J, Witkiewicz AK, Attwood K, Blazar BR, Odunsi K, Repasky EA, McCarthy PL. Galectin-3 expression in donor T cells reduces GvHD severity and lethality after allogeneic hematopoietic cell transplantation. Cell Rep 2023; 42:112250. [PMID: 36924493 PMCID: PMC10116561 DOI: 10.1016/j.celrep.2023.112250] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 01/05/2023] [Accepted: 02/25/2023] [Indexed: 03/17/2023] Open
Abstract
Abundant donor cytotoxic T cells that attack normal host organs remain a major problem for patients receiving allogeneic hematopoietic cell transplantation (allo-HCT). Despite an increase in our knowledge of the pathobiology of acute graft versus host disease (aGvHD), the mechanisms regulating the proliferation and function of donor T cells remain unclear. Here, we show that activated donor T cells express galectin-3 (Gal-3) after allo-HCT. In both major and minor histocompatibility-mismatched models of murine aGvHD, expression of Gal-3 is associated with decreased T cell activation and suppression of the secretion of effector cytokines, including IFN-γ and GM-CSF. Mechanistically, Gal-3 results in activation of NFAT signaling, which can induce T cell exhaustion. Gal-3 overexpression in human T cells prevents severe disease by suppressing cytotoxic T cells in xenogeneic aGvHD models. Together, these data identify the Gal-3-dependent regulatory pathway in donor T cells as a critical component of inflammation in aGvHD.
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Affiliation(s)
- Hemn Mohammadpour
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Takemasa Tsuji
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Cameron R MacDonald
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Joseph L Sarow
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Hanna Rosenheck
- Department of Medicine, Transplant and Cellular Therapy Program, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Saeed Daneshmandi
- Department of Cell Stress Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Jee Eun Choi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Jingxin Qiu
- Department of Molecular and Cellular Biology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Junko Matsuzaki
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Agnieszka K Witkiewicz
- Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Kristopher Attwood
- Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, MN 55455, USA
| | - Kunle Odunsi
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Elizabeth A Repasky
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA
| | - Philip L McCarthy
- Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
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17
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Garcia-Rosa M, Abraham A, Bertaina A, Bhoopalan SV, Bonfim C, Cohen S, DeZern A, Louis C, Oved J, Pavel-Dinu M, Purtill D, Ruggeri A, Russell A, Sharma A, Wynn R, Boelens JJ, Prockop S. International society for cell & gene therapy stem cell engineering committee: Cellular therapies for the treatment of graft-versus-host-disease after hematopoietic stem cell transplant. Cytotherapy 2023; 25:578-589. [PMID: 36941149 DOI: 10.1016/j.jcyt.2023.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/16/2023] [Accepted: 02/15/2023] [Indexed: 03/23/2023]
Abstract
BACKGROUND AIMS Allogeneic hematopoietic stem cell transplant is a curative approach for many malignant and non-malignant hematologic conditions. Despite advances in its prevention and treatment, the morbidity and mortality related to graft-versus-host disease (GVHD) remains. The mechanisms by which currently used pharmacologic agents impair the activation and proliferation of potentially alloreactive T cells reveal pathways essential for the detrimental activities of these cell populations. Importantly, these same pathways can be important in mediating the graft-versus-leukemia effect in recipients transplanted for malignant disease. This knowledge informs potential roles for cellular therapies such as mesenchymal stromal cells and regulatory T cells in preventing or treating GVHD. This article reviews the current state of adoptive cellular therapies focused on GVHD treatment. METHODS We conducted a search for scientific literature in PubMed® and ongoing clinical trials in clinicaltrial.gov with the keywords "Graft-versus-Host Disease (GVHD)," "Cellular Therapies," "Regulatory T cells (Tregs)," "Mesenchymal Stromal (Stem) Cells (MSCs)," "Natural Killer (NK) Cells," "Myeloid-derived suppressor cells (MDSCs)," and "Regulatory B-Cells (B-regs)." All the published and available clinical studies were included. RESULTS Although most of the existing clinical data focus on cellular therapies for GVHD prevention, there are observational and interventional clinical studies that explore the potential for cellular therapies to be safe modalities for GVHD treatment while maintaining the graft-versus-leukemia effect in the context of malignant diseases. However, there are multiple challenges that limit the broader use of these approaches in the clinical scenario. CONCLUSIONS There are many ongoing clinical trials to date with the promise to expand our actual knowledge on the role of cellular therapies for GVHD treatment in an attempt to improve GVHD-related outcomes in the near future.
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Affiliation(s)
- Moises Garcia-Rosa
- Pediatric Hematology-Oncology Fellow, Memorial Sloan Kettering Cancer Center, and Department of Pediatrics, Weill Cornell Medical College of Cornell University, New York, New York, USA.
| | - Allistair Abraham
- Center for Cancer and Immunology Research, CETI, Children's National Hospital, Washington, District of Columbia, USA
| | - Alice Bertaina
- Division of Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, California, USA
| | - Senthil Velan Bhoopalan
- Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Carmem Bonfim
- Pediatric Blood and Marrow Transplantation Division and Pele Pequeno Principe Research Institute, Hospital Pequeno Principe, Curitiba, Brazil
| | - Sandra Cohen
- Universite de Montreal and Maisonneuve Rosemont Hospital, Montreal, Quebec, Canada
| | - Amy DeZern
- Bone Marrow Failure and MDS Program, John Hopkins Medicine Baltimore, Maryland, USA
| | | | - Joseph Oved
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Mara Pavel-Dinu
- Department of Pediatrics, Division of Stem Cell Transplantation and Regenerative Medicine, Redwood City, California, USA
| | - Duncan Purtill
- Department of Haematology, Fiona Stanley Hospital, Perth, Western Australia, Australia
| | | | - Athena Russell
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Akshay Sharma
- Department of Bone Marrow Transplantation and Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Robert Wynn
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Jaap Jan Boelens
- Stem Cell Transplantation and Cellular Therapies, Memorial Sloan Kettering Cancer Center, and Department of Pediatrics, Weill Cornell Medical College of Cornell University, New York, New York, USA
| | - Susan Prockop
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts USA
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18
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Chen YF, Li J, Xu LL, Găman MA, Zou ZY. Allogeneic stem cell transplantation in the treatment of acute myeloid leukemia: An overview of obstacles and opportunities. World J Clin Cases 2023; 11:268-291. [PMID: 36686358 PMCID: PMC9850970 DOI: 10.12998/wjcc.v11.i2.268] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 12/02/2022] [Accepted: 01/05/2023] [Indexed: 01/12/2023] Open
Abstract
As an important treatment for acute myeloid leukemia, allogeneic hematopoietic stem cell transplantation (allo-HSCT) plays an important role in reducing relapse and improving long-term survival. With rapid advancements in basic research in molecular biology and immunology and with deepening understanding of the biological characteristics of hematopoietic stem cells, allo-HSCT has been widely applied in clinical practice. During allo-HSCT, preconditioning, the donor, and the source of stem cells can be tailored to the patient's conditions, greatly broadening the indications for HSCT, with clear survival benefits. However, the risks associated with allo-HSCT remain high, i.e. hematopoietic reconstitution failure, delayed immune reconstitution, graft-versus-host disease, and post-transplant relapse, which are bottlenecks for further improvements in allo-HSCT efficacy and have become hot topics in the field of HSCT. Other bottlenecks recognized in the current treatment of individuals diagnosed with acute myeloid leukemia and subjected to allo-HSCT include the selection of the most appropriate conditioning regimen and post-transplantation management. In this paper, we reviewed the progress of relevant research regarding these aspects.
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Affiliation(s)
- Yong-Feng Chen
- Department of Basic Medical Sciences, School of Medicine of Taizhou University, Taizhou University, Taizhou 318000, Zhejiang Province, China
| | - Jing Li
- Department of Histology and Embryology, North Sichuan Medical College, Nanchong 637000, Sichuan Province, China
| | - Ling-Long Xu
- Department of Hematology, Taizhou Central Hospital, Taizhou 318000, Zhejiang Province, China
| | - Mihnea-Alexandru Găman
- Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest 050474, Romania
| | - Zhen-You Zou
- Department of Scientific Research,Brain Hospital of Guangxi Zhuang Autonomous Region, Liuzhou 545005, Guangxi Zhuang Autonomous Region, China
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19
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Granulocytic myeloid-derived suppressor cells to prevent and treat murine immune-mediated bone marrow failure. Blood Adv 2022; 7:73-86. [PMID: 35895513 PMCID: PMC9827041 DOI: 10.1182/bloodadvances.2022007254] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 06/22/2022] [Accepted: 07/15/2022] [Indexed: 01/18/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that originate in the bone marrow (BM) and have immunoregulatory functions. MDSCs have been implicated in the pathogenesis of several autoimmune diseases but have not been investigated in immune aplastic anemia (AA). We examined the roles of granulocytic-MDSCs (G-MDSCs) in murine models of human AA and BM failure (BMF). As both prophylaxis and therapy, BM-derived G-MDSCs improved pancytopenia and BM cellularity and suppressed BM T-cell infiltration in major histocompatibility complex (MHC)-matched C.B10 BMF mice. These effects were not obtained in the MHC-mismatched CByB6F1 AA model, likely because of MHC disparity between G-MDSCs and donor T cells. Single-cell RNA sequencing demonstrated that G-MDSCs downregulated cell cycle-related genes in BM-infiltrated T cells, consistent with suppression of T-cell proliferation by G-MDSCs through reactive oxygen species pathways. Clearance of G-MDSCs in the MHC-mismatched CByB6F1 model using anti-Ly6G antibody facilitated T cell-mediated BM destruction, suggesting an intrinsic immunosuppressive property of G-MDSCs. However, the same anti-Ly6G antibody in the MHC-matched C.B10 AA model mildly mitigated BMF, associated with expansion of an intermediate Ly6G population. Our results demonstrate that G-MDSC eradication and therapeutic efficacy are immune context-dependent.
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20
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Yu S, Ren X, Li L. Myeloid-derived suppressor cells in hematologic malignancies: two sides of the same coin. Exp Hematol Oncol 2022; 11:43. [PMID: 35854339 PMCID: PMC9295421 DOI: 10.1186/s40164-022-00296-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 07/13/2022] [Indexed: 12/15/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of bone marrow cells originating from immature myeloid cells. They exert potent immunosuppressive activity and are closely associated with the development of various diseases such as malignancies, infections, and inflammation. In malignant tumors, MDSCs, one of the most dominant cellular components comprising the tumor microenvironment, play a crucial role in tumor growth, drug resistance, recurrence, and immune escape. Although the role of MDSCs in solid tumors is currently being extensively studied, little is known about their role in hematologic malignancies. In this review, we comprehensively summarized and reviewed the different roles of MDSCs in hematologic malignancies and hematopoietic stem cell transplantation, and finally discussed current targeted therapeutic strategies.Affiliation: Kindly check and confirm the processed affiliations are correct. Amend if any.correct
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Affiliation(s)
- Shunjie Yu
- Department of Hematology, Tianjin Medical University General Hospital, Heping district 154 Anshan Road, Tianjin, China
| | - Xiaotong Ren
- Department of Hematology, Tianjin Medical University General Hospital, Heping district 154 Anshan Road, Tianjin, China
| | - Lijuan Li
- Department of Hematology, Tianjin Medical University General Hospital, Heping district 154 Anshan Road, Tianjin, China.
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21
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Li X, Kong D, Yu Q, Si X, Yang L, Zeng X, Li Y, Shi J, Qian P, Huang H, Lin Y. Cyclosporine A regulates PMN-MDSCs viability and function through MPTP in acute GVHD: Old medication, new target. Transplant Cell Ther 2022; 28:411.e1-411.e9. [PMID: 35430420 DOI: 10.1016/j.jtct.2022.04.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 04/05/2022] [Accepted: 04/09/2022] [Indexed: 12/29/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs), a population of myeloid lineage cells with immunosuppressive capacity, can mitigate acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We previously found that the immunosuppressive function of polymorphonuclear population (PMN-MDSCs) was impaired in aGVHD milieu. The aim of this study was to explore the intrinsic mechanism regulating the fate and function of donor-derived PMN-MDSCs during allo-HSCT. We firstly found that mitochondrial permeability transition pore (MPTP) opened in the PMN-MDSCs in response to the intense inflammatory environment of aGVHD, which induced mitochondrial damage, oxidative stress, and apoptosis of PMN-MDSCs. Inhibiting MPTP opening by a traditional immunosuppressant, cyclosporine A (CsA), could restore the immunosuppressive function and viability of PMN-MDSCs in vitro and in vivo, which reveals a new mechanism of CsA application.
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Affiliation(s)
- Xiaoqing Li
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Delin Kong
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Qiru Yu
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Xiaohui Si
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Lin Yang
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Xiangjun Zeng
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Yixue Li
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Jimin Shi
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - Pengxu Qian
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.
| | - Yu Lin
- Bone Marrow Transplantation Center, the First Affiliated Hospital, Zhejiang University, School of Medicine, No. 79 Qingchun Road, Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China; Institute of Hematology, Zhejiang University, Hangzhou, China; Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China.
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22
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Michniacki TF, Choi SW, Peltier DC. Immune Suppression in Allogeneic Hematopoietic Stem Cell Transplantation. Handb Exp Pharmacol 2022; 272:209-243. [PMID: 34628553 PMCID: PMC9055779 DOI: 10.1007/164_2021_544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for high-risk hematologic disorders. There are multiple immune-mediated complications following allo-HSCT that are prevented and/or treated by immunosuppressive agents. Principal among these immune-mediated complications is acute graft-versus-host disease (aGVHD), which occurs when the new donor immune system targets host tissue antigens. The immunobiology of aGVHD is complex and involves all aspects of the immune system. Due to the risk of aGVHD, immunosuppressive aGVHD prophylaxis is required for nearly all allogeneic HSCT recipients. Despite prophylaxis, aGVHD remains a major cause of nonrelapse mortality. Here, we discuss the clinical features of aGVHD, the immunobiology of aGVHD, the immunosuppressive therapies used to prevent and treat aGVHD, how to mitigate the side effects of these immunosuppressive therapies, and what additional immune-mediated post-allo-HSCT complications are also treated with immunosuppression.
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Affiliation(s)
- Thomas F Michniacki
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA
| | - Sung Won Choi
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
| | - Daniel C Peltier
- Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplantation Program, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
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23
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Li X, Li Y, Yu Q, Xu L, Fu S, Wei C, Wang L, Luo Y, Shi J, Qian P, Huang H, Lin Y. mTOR Signaling Regulates the Development and Therapeutic Efficacy of PMN-MDSCs in Acute GVHD. Front Cell Dev Biol 2021; 9:741911. [PMID: 35004668 PMCID: PMC8733691 DOI: 10.3389/fcell.2021.741911] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 11/19/2021] [Indexed: 12/13/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) represent a population of heterogeneous myeloid cells, which are characterized by their remarkable ability to suppress T cells and natural killer cells. MDSCs have been proven to play a positive role in protecting acute graft-versus-host disease (aGVHD). Here, we aimed to describe the mechanism behind how mTOR signaling regulates MDSCs' generation and explore its prophylactic and therapeutic potential in aGVHD. Reducing mTOR expression retains myeloid cells with immature characteristics and promotes polymorphonuclear MDSC (PMN-MDSC) immunosuppressive function through STAT3-C/EBPβ pathway. Prophylactic transfusion of mTORKO PMN-MDSCs could alleviate aGVHD while maintaining the graft-versus-leukemia (GVL) effect, which could downregulate the Th1/Th2 ratio, decrease serum proinflammatory cytokines, and increase the proportion of regulatory T cells (Tregs) in aGVHD models at the early stage after transplantation. Moreover, transfusion therapy could promote the reconstruction and function of donor-derived PMN-MDSCs. Not only the percentage and the absolute number of donor-derived PMN-MDSCs significantly increased but also the immunosuppressive ability was much more robust compared to other groups. Altogether, these findings indicated that mTOR is an intrinsic regulator for PMN-MDSCs' differentiation and immunosuppressive function. Together, mTORKO PMN-MDSC transfusion can play a protective role in alleviating cytokine storm at the initial stage and promoting the quantitative and functional recoveries of donor-derived PMN-MDSCs in aGVHD.
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Affiliation(s)
- Xiaoqing Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yixue Li
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Qinru Yu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Lin Xu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Shan Fu
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Cong Wei
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Limengmeng Wang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yi Luo
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Jimin Shi
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Pengxu Qian
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - He Huang
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
| | - Yu Lin
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Liangzhu Laboratory, Zhejiang University Medical Center, Hangzhou, China
- Zhejiang Province Engineering Laboratory for Stem Cell and Immunity Therapy, Hangzhou, China
- Institute of Hematology, Zhejiang University, Hangzhou, China
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24
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Scheurer J, Kitt K, Huber HJ, Fundel-Clemens K, Pflanz S, Debatin KM, Strauss G. Graft-Versus-Host Disease Prevention by In Vitro-Generated Myeloid-Derived Suppressor Cells Is Exclusively Mediated by the CD11b+CD11c+ MDSC Subpopulation. Front Immunol 2021; 12:754316. [PMID: 34721430 PMCID: PMC8551363 DOI: 10.3389/fimmu.2021.754316] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 09/21/2021] [Indexed: 01/09/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid progenitor cells that dampen overwhelming adaptive immune responses through multiple mechanisms and are recognized as an attractive novel immune intervention therapy for counteracting the destructive effects of graft-
versus
-host disease (GVHD) developing after allogeneic bone marrow transplantation (BMT). MDSCs can be produced in great numbers for cellular therapy, but they present a mixture of subsets whose functions in GVHD prevention are undefined. Here, we generated MDSCs in vitro from murine BM cells in the presence of GM-CSF and defined the integrin CD11c as a marker to subdivide MDSCs into two functional subgroups: CD11b+CD11c+ and CD11b+CD11c− MDSCs. Isolated CD11b+CD11c+ and CD11b+CD11c− MDSCs both inhibited alloantigen-stimulated T-cell proliferation in vitro, although CD11b+CD11c+ MDSCs were more efficient and expressed higher levels of different immunosuppressive molecules. Likewise, expression of surface markers such as MHC class II, CD80, CD86, or PD-L1 further delineated both subsets. Most importantly, only the adoptive transfer of CD11b+CD11c+ MDSCs into a single MHC class I-disparate allogeneic BMT model prevented GVHD development and strongly decreased disease-induced mortality, while CD11b+CD11c− MDSCs were totally ineffective. Surprisingly, allogeneic T-cell homing and expansion in lymphatic and GVHD target organs were not affected by cotransplanted CD11b+CD11c+ MDSCs indicating a clear contradiction between in vitro and in vivo functions of MDSCs. However, CD11b+CD11c+ MDSCs shifted immune responses towards type 2 immunity reflected by increased Th2-specific cytokine expression of allogeneic T cells. Induction of type 2 immunity was mandatory for GVHD prevention, since CD11b+CD11c+ MDSCs were ineffective if recipients were reconstituted with STAT6-deficient T cells unable to differentiate into Th2 cells. Most importantly, the beneficial graft-
versus
-tumor (GVT) effect was maintained in the presence of CD11b+CD11c+ MDSCs since syngeneic tumor cells were efficiently eradicated. Strong differences in the transcriptomic landscape of both subpopulations underlined their functional differences. Defining CD11b+CD11c+ MDSCs as the subset of in vitro-generated MDSCs able to inhibit GVHD development might help to increase efficiency of MDSC therapy and to further delineate relevant target molecules and signaling pathways responsible for GVHD prevention.
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Affiliation(s)
- Jasmin Scheurer
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Kerstin Kitt
- Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma Co KG, Biberach an der Riss, Germany
| | - Heinrich J Huber
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma Co KG, Biberach an der Riss, Germany.,Drug Discovery Services, Boehringer Ingelheim Regional Center Vienna (RCV) GmbH & Co KG, Vienna, Austria
| | - Katrin Fundel-Clemens
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim Pharma Co KG, Biberach an der Riss, Germany
| | - Stefan Pflanz
- Department of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma Co KG, Biberach an der Riss, Germany
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
| | - Gudrun Strauss
- Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany
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Demosthenous C, Sakellari I, Douka V, Papayanni PG, Anagnostopoulos A, Gavriilaki E. The Role of Myeloid-Derived Suppressor Cells (MDSCs) in Graft-versus-Host Disease (GVHD). J Clin Med 2021; 10:jcm10102050. [PMID: 34064671 PMCID: PMC8150814 DOI: 10.3390/jcm10102050] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/02/2021] [Accepted: 05/06/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Myeloid-derived suppressor cells (MDSCs) are implicated in the complex interplay involving graft-versus-leukemia (GVL) effects and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HCT) in hematologic malignancies. Methods: A review of literature through PubMed was undertaken to summarize the published evidence on the pathophysiology and clinical implications of MDSCs in allo-HCT. Literature sources published in English since 1978 were searched, using the terms Natural Suppressor (NS) cells, MDSCs, GVHD, and allo-HCT. Results: In vivo studies demonstrated that MDSCs derived from mobilization protocols could strongly suppress allo-responses mediated by T cells and enhance T-Reg activity, thus inhibiting GVHD toxicity. However, the influence of MDSCs on the GVL effect is not fully defined. Conclusions: The induction or maintenance of MDSC suppressive function would be advantageous in suppressing inflammation associated with GVHD. Pathways involved in MDSC metabolism and the inflammasome signaling are a promising field of study to elucidate the function of MDSCs in the pathogenesis of GVHD and translate these findings to a clinical setting.
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Olivares-Hernández A, Figuero-Pérez L, Terán-Brage E, López-Gutiérrez Á, Velasco ÁT, Sarmiento RG, Cruz-Hernández JJ, Miramontes-González JP. Resistance to Immune Checkpoint Inhibitors Secondary to Myeloid-Derived Suppressor Cells: A New Therapeutic Targeting of Haematological Malignancies. J Clin Med 2021; 10:jcm10091919. [PMID: 33925214 PMCID: PMC8124332 DOI: 10.3390/jcm10091919] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Revised: 04/17/2021] [Accepted: 04/23/2021] [Indexed: 01/11/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a set of immature myeloid lineage cells that include macrophages, granulocytes, and dendritic cell precursors. This subpopulation has been described in relation to the tumour processes at different levels, including resistance to immunotherapy, such as immune checkpoint inhibitors (ICIs). Currently, multiple studies at the preclinical and clinical levels seek to use this cell population for the treatment of different haematological neoplasms, together with ICIs. This review addresses the different points in ongoing studies of MDSCs and ICIs in haematological malignancies and their future significance in routine clinical practice.
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Affiliation(s)
- Alejandro Olivares-Hernández
- Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain; (L.F.-P.); (E.T.-B.); (Á.L.-G.); (J.J.C.-H.)
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
- Correspondence: (A.O.-H.); (J.P.M.-G.); Tel.: +34-923-29-11-00 (A.O.-H.); +34-983-42-04-00 (J.P.M.-G.); Fax: +34-923-29-13-25 (A.O.-H.); +34-983-21-53-65 (J.P.M.-G.)
| | - Luis Figuero-Pérez
- Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain; (L.F.-P.); (E.T.-B.); (Á.L.-G.); (J.J.C.-H.)
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Eduardo Terán-Brage
- Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain; (L.F.-P.); (E.T.-B.); (Á.L.-G.); (J.J.C.-H.)
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Álvaro López-Gutiérrez
- Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain; (L.F.-P.); (E.T.-B.); (Á.L.-G.); (J.J.C.-H.)
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
| | - Álvaro Tamayo Velasco
- Department of Haematology, University Hospital of Valladolid, 47003 Valladolid, Spain;
| | - Rogelio González Sarmiento
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
- Department of Medicine, University of Salamanca, 37007 Salamanca, Spain
| | - Juan Jesús Cruz-Hernández
- Department of Medical Oncology, University Hospital of Salamanca, 37007 Salamanca, Spain; (L.F.-P.); (E.T.-B.); (Á.L.-G.); (J.J.C.-H.)
- Institute for Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain;
- Department of Medicine, University of Salamanca, 37007 Salamanca, Spain
| | - José Pablo Miramontes-González
- Department of Internal Medicine, University Hospital Rio Hortega, 47012 Valladolid, Spain
- Department of Medicine, University of Valladolid, 45005 Valladolid, Spain
- Correspondence: (A.O.-H.); (J.P.M.-G.); Tel.: +34-923-29-11-00 (A.O.-H.); +34-983-42-04-00 (J.P.M.-G.); Fax: +34-923-29-13-25 (A.O.-H.); +34-983-21-53-65 (J.P.M.-G.)
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Stokes J, Molina MS, Hoffman EA, Simpson RJ, Katsanis E. Immunomodulatory Effects of Bendamustine in Hematopoietic Cell Transplantation. Cancers (Basel) 2021; 13:1702. [PMID: 33916711 PMCID: PMC8038415 DOI: 10.3390/cancers13071702] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/25/2021] [Accepted: 04/01/2021] [Indexed: 12/22/2022] Open
Abstract
Bendamustine (BEN) is a unique alkylating agent with efficacy against a broad range of hematological malignancies, although investigations have only recently started to delve into its immunomodulatory effects. These immunomodulatory properties of BEN in the context of hematopoietic cell transplantation (HCT) are reviewed here. Pre- and post-transplant use of BEN in multiple murine models have consistently resulted in reduced GvHD and enhanced GvL, with significant changes to key immunological cell populations, including T-cells, myeloid derived suppressor cells (MDSCs), and dendritic cells (DCs). Further, in vitro studies find that BEN enhances the suppressive function of MDSCs, skews DCs toward cDC1s, enhances Flt3 expression on DCs, increases B-cell production of IL-10, inhibits STAT3 activation, and suppresses proliferation of T- and B-cells. Overall, BEN has a broad range of immunomodulatory effects that, as they are further elucidated, may be exploited to improve clinical outcomes. As such, clinical trials are currently underway investigating new potential applications of BEN in the setting of allogeneic HCT.
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Affiliation(s)
- Jessica Stokes
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
| | - Megan S. Molina
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
- Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA
| | - Emely A. Hoffman
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
| | - Richard J. Simpson
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
- Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA
- Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85721, USA
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
| | - Emmanuel Katsanis
- Department of Pediatrics, University of Arizona, Tucson, AZ 85721, USA; (J.S.); (M.S.M.); (E.A.H.); (R.J.S.)
- Department of Immunobiology, University of Arizona, Tucson, AZ 85721, USA
- The University of Arizona Cancer Center, Tucson, AZ 85721, USA
- Department of Medicine, University of Arizona, Tucson, AZ 85721, USA
- Department of Pathology, University of Arizona, Tucson, AZ 85721, USA
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Zhang R, Tu J, Liu S. Novel molecular regulators of breast cancer stem cell plasticity and heterogeneity. Semin Cancer Biol 2021; 82:11-25. [PMID: 33737107 DOI: 10.1016/j.semcancer.2021.03.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 11/19/2020] [Accepted: 03/11/2021] [Indexed: 12/12/2022]
Abstract
Tumors consist of heterogeneous cell populations, and tumor heterogeneity plays key roles in regulating tumorigenesis, metastasis, recurrence and resistance to anti-tumor therapies. More and more studies suggest that cancer stem cells (CSCs) promote tumorigenesis, metastasis, recurrence and drug resistance as well as are the major source for heterogeneity of cancer cells. CD24-CD44+ and ALDH+ are the most common markers for breast cancer stem cells (BCSCs). Previous studies showed that different BCSC markers label different BCSC populations, indicating the heterogeneity of BCSCs. Therefore, defining the regulation mechanisms of heterogeneous BCSCs is essential for precisely targeting BCSCs and treating breast cancer. In this review, we summarized the novel regulators existed in BCSCs and their niches for BCSC heterogeneity which has been discovered in recent years, and discussed their regulation mechanisms and the latest corresponding cancer treatments, which will extend our understanding on BCSC heterogeneity and plasticity, and provide better prognosis prediction and more efficient novel therapeutic strategies for breast cancer.
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Affiliation(s)
- Rui Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Juchuanli Tu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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29
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Cellular therapies for graft-versus-host disease: a tale of tissue repair and tolerance. Blood 2021; 136:410-417. [PMID: 32525970 DOI: 10.1182/blood.2019000951] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 01/03/2020] [Indexed: 02/06/2023] Open
Abstract
The success of allogeneic hematopoietic cell transplantation depends heavily on the delicate balance between the activity of the donor immune system against malignant and nonmalignant cells of the recipient. Abrogation of alloreactivity will lead to disease relapse, whereas untamed allo-immune responses will lead to lethal graft-versus-host disease (GVHD). A number of cell types have been identified that can be used to suppress alloreactive immune cells and prevent lethal GVHD in mice. Of those, mesenchymal stromal cells and, to a lesser extent, regulatory T cells have demonstrated efficacy in humans. Ideally, cellular therapy for GVHD will not affect alloreactive immune responses against tumor cells. The importance of tissue damage in the pathophysiology of GVHD rationalizes the development of cells that support tissue homeostasis and repair, such as innate lymphoid cells. We discuss recent developments in the field of cellular therapy to prevent and treat acute and chronic GVHD, in the context of GVHD pathophysiology.
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Zhang J, Hodges A, Chen SH, Pan PY. Myeloid-derived suppressor cells as cellular immunotherapy in transplantation and autoimmune diseases. Cell Immunol 2021; 362:104300. [PMID: 33582607 DOI: 10.1016/j.cellimm.2021.104300] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 01/25/2021] [Accepted: 01/26/2021] [Indexed: 12/15/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells, which have been characterized for their immunosuppressive capacity through multiple mechanisms. These cells have been extensively studied in the field of tumor immunity. Emerging evidence has highlighted its essential role in maintaining immune tolerance in transplantation and autoimmunity. Because of their robust immune inhibitory activities, there has been growing interest in MDSC-based cellular therapy. Various pre-clinical studies have demonstrated that the adoptive transfer of MDCS represented a promising therapeutic strategy for immune-related disorders. In this review, we summarize relevant studies of MDSC-based cell therapy in transplantation and autoimmune diseases and discuss the challenges and future directions for clinical application of MDSC-based cell therapy.
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Affiliation(s)
- Jilu Zhang
- Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States.
| | - Alan Hodges
- Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States; Texas A&M College of Medicine, Bryan, TX, United States
| | - Shu-Hsia Chen
- Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States; Texas A&M College of Medicine, Bryan, TX, United States
| | - Ping-Ying Pan
- Center for Immunotherapy Research, Cancer Center of Excellence, Houston Methodist Research Institute, Houston, TX, United States; Texas A&M College of Medicine, Bryan, TX, United States.
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31
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Huo YY, Pang AM, Cheng T. [Advance in hematopoietic and immune reconstitution of allogeneic stem cell transplantation]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2021; 41:958-963. [PMID: 33333706 PMCID: PMC7767801 DOI: 10.3760/cma.j.issn.0253-2727.2020.11.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Affiliation(s)
- Y Y Huo
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - A M Pang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
| | - T Cheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China
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32
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Yu Q, Wang H, Zhang L, Wei W. Advances in the treatment of graft-versus-host disease with immunomodulatory cells. Int Immunopharmacol 2021; 92:107349. [PMID: 33486323 DOI: 10.1016/j.intimp.2020.107349] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 12/14/2020] [Accepted: 12/24/2020] [Indexed: 12/19/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been widely used to treat hematological malignancies and genetic diseases. Graft-versus-host disease (GVHD) induced by donor immune system is the most common complication, contributing to severe morbidity and mortality after allo-HSCT. Currently, in terms of the prevention and treatment of GVHD, the major first-line therapeutic drugs are corticosteroids. However, most patients with systemic corticosteroid treatment are prone to steroid-refractory and poor prognosis. The use of several immune cells including Tregs, Bregs and mesenchymal stromal cells (MSCs) as an alternative on prevention or therapy of GVHD has been demonstrated to be beneficial. However, there are still many defects to a certain degree. Based on immune cells, it is promising to develop new and better approaches to improve GVHD. In this article, we will review the current advance of immune cells (Tregs, Bregs, MSCs) with negative regulation in the treatment of GVHD and present emerging strategies for the prevention and treatment of GVHD by other immune regulatory cells and chimeric antigen receptor (CAR) Tregs. In addition, these new therapeutic options need to be further evaluated in well-designed prospective multicenter trials to determine the optimal treatment for GVHD patients and improve their prognosis.
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Affiliation(s)
- Qianqian Yu
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei 230032, China
| | - Han Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei 230032, China
| | - Lingling Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei 230032, China.
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine (Anhui Medical University), Ministry of Education, Anti-inflammatory Immune Drugs Collaborative Innovation Center, Anhui Province, Hefei 230032, China.
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Bogunia-Kubik K, Łacina P. Non-KIR NK cell receptors: Role in transplantation of allogeneic haematopoietic stem cells. Int J Immunogenet 2020; 48:157-171. [PMID: 33352617 DOI: 10.1111/iji.12523] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/29/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022]
Abstract
Natural killer (NK) cells are of major significance in patients after allogeneic haematopoietic stem cell transplantation (HSCT). They are the first subset of lymphocytes to appear in peripheral blood after transplantation and play an important role in the immune responses against cancer and viral infections. The function of NK cells is controlled by various surface receptors, of which type I integral proteins with immunoglobulin-like domains (killer-cell immunoglobulin-like receptors, KIRs) have been the most extensively studied. The present review focuses on less studied NK cell receptors, such as type II integral proteins with lectin-like domains (CD94/NKG2, NKG2D), natural cytotoxicity receptors (NCRs), immunoglobulin-like transcripts (ILTs) and their ligands. Their potential role in patients with haematological disorders subjected to HSC transplant procedure in the context of post-transplant complications such as viral reactivation and acute graft-versus-host disease (GvHD) will be presented and discussed.
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Affiliation(s)
- Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
| | - Piotr Łacina
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
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Park MJ, Baek JA, Kim SY, Jung KA, Choi JW, Park SH, Kwok SK, Cho ML. Myeloid-derived suppressor cells therapy enhance immunoregulatory properties in acute graft versus host disease with combination of regulatory T cells. J Transl Med 2020; 18:483. [PMID: 33317573 PMCID: PMC7734831 DOI: 10.1186/s12967-020-02657-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Accepted: 12/02/2020] [Indexed: 12/17/2022] Open
Abstract
Background Myeloid-derived suppressor cells (MDSCs) play a critical role in modulating the immune response and promoting immune tolerance in models of autoimmunity and transplantation. Regulatory T cells (Tregs) exert therapeutic potential due to their immunomodulatory properties, which have been demonstrated both in vitro and in clinical trials. Cell-based therapy for acute graft-versus-host disease (aGVHD) may enable induction of donor-specific tolerance in the preclinical setting. Methods We investigated whether the immunoregulatory activity of the combination of MDSCs and Tregs on T cell and B cell subset and alloreactive T cell response. We evaluated the therapeutic effects of combined cell therapy for a murine aGVHD model following MHC-mismatched bone marrow transplantation. We compared histologic analysis from the target tissues of each groups were and immune cell population by flow cytometric analysis. Results We report a novel approach to inducing immune tolerance using a combination of donor-derived MDSCs and Tregs. The combined cell-therapy modulated in vitro the proliferation of alloreactive T cells and the Treg/Th17 balance in mice and human system. Systemic infusion of MDSCs and Tregs ameliorated serverity and inflammation of aGVHD mouse model by reducing the populations of proinflammatory Th1/Th17 cells and the expression of proinflammatory cytokines in target tissue. The combined therapy promoted the differentiation of allogeneic T cells toward Foxp3 + Tregs and IL-10-producing regulatory B cells. The combination treatment control also activated human T and B cell subset. Conclusions Therefore, the combination of MDSCs and Tregs has immunomodulatory activity and induces immune tolerance to prevent of aGVHD severity. This could lead to the development of new clinical approaches to the prevent aGVHD.
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Affiliation(s)
- Min-Jung Park
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-040, South Korea
| | - Jin-Ah Baek
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-040, South Korea
| | - Se-Young Kim
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-040, South Korea
| | - Kyung-Ah Jung
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-040, South Korea
| | - Jeong Won Choi
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-040, South Korea
| | - Sung-Hwan Park
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-040, South Korea.,Divison of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Seung-Ki Kwok
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-040, South Korea.,Divison of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea
| | - Mi-La Cho
- The Rheumatism Research Center, Catholic Research Institute of Medical Science, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul, 137-040, South Korea.
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Targeting Myeloid-Derived Suppressor Cells in Cancer Immunotherapy. Cancers (Basel) 2020; 12:cancers12092626. [PMID: 32942545 PMCID: PMC7564060 DOI: 10.3390/cancers12092626] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/10/2020] [Accepted: 09/10/2020] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Myeloid-Derived Suppressor Cells (MDSCs) have been regarded as the main promoters of cancer development in recent years. They can protect tumor cells from being eliminated by neutralizing the anti-tumor response mediated by T cells, macrophages and dendritic cells (DCs). Therefore, different treatment methods targeting MDSCs, including chemotherapy, radiotherapy and immunotherapy, have been developed and proven to effectively inhibit tumor expansion. Herein, we summarize the immunosuppressive role of MDSCs in the tumor microenvironment and some effective treatments targeting MDSCs, and discuss the differences between different therapies. Abstract Myeloid-derived suppressor cells (MDSCs), which are activated under pathological conditions, are a group of heterogeneous immature myeloid cells. MDSCs have potent capacities to support tumor growth via inhibition of the antitumoral immune response and/or the induction of immunosuppressive cells. In addition, multiple studies have demonstrated that MDSCs provide potential therapeutic targets for the elimination of immunosuppressive functions and the inhibition of tumor growth. The combination of targeting MDSCs and other therapeutic approaches has also demonstrated powerful antitumor effects. In this review, we summarize the characteristics of MDSCs in the tumor microenvironment (TME) and current strategies of cancer treatment by targeting MDSCs.
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Yang S, Wei Y, Sun R, Lu W, Lv H, Xiao X, Cao Y, Jin X, Zhao M. Umbilical cord blood-derived mesenchymal stromal cells promote myeloid-derived suppressor cell proliferation by secreting HLA-G to reduce acute graft-versus-host disease after hematopoietic stem cell transplantation. Cytotherapy 2020; 22:718-733. [PMID: 32811747 DOI: 10.1016/j.jcyt.2020.07.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/23/2020] [Accepted: 07/15/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AIMS Mesenchymal stem cells (MSCs) use multiple mechanisms to constrain both innate and adaptive immune responses to prevent graft-versus-host disease (GVHD). Myeloid-derived suppressor cells (MDSCs), as a heterogeneous population of early myeloid progenitor cells originating from bone marrow, are a naturally occurring immune regulatory population associated with inhibition of ongoing inflammatory responses, indicating their potential for GVHD therapy. There is accumulating evidence that MSCs and MDSCs do not act independently, but rather establish crosstalk. However, the role of MSCs in MDSC expansion and activation in GVHD remains unexplored. METHODS In vitro experiments included 2 groups: peripheral blood mononuclear cells (PBMCs) after mobilization and human umbilical cord blood-derived MSCs (UCB-MSCs) co-cultured with PBMCs. The number and functional difference of MDSCs in PBMCs were determined by flow cytometry. The culture supernatants of co-cultured cells were analyzed to identify cytokines involved in MDSC proliferation. The relationship between MSCs and MDSCs was clarified in GVHD and graft-versus-leukemia (GVL) animal models. RESULTS In vitro experiments confirmed that UCB-MSCs secreted HLA-G protein to promote and maintain the proliferation of MDSCs in peripheral blood after granulocyte colony-stimulating factor mobilization, and UCB-MSCs mediated the function of MDSCs to inhibit the proliferation of T cells and promote the proliferation of regulatory T cells. UCB-MSCs overexpressing HLA-G induced MDSC production in recipient mice, improved the ability of MDSCs to suppress T cells and further reduced acute GVHD (aGVHD) symptoms and survival time without influencing GVL effects. CONCLUSIONS UCB-MSCs expanded MDSCs via HLA-G/Ig-like transcript 4, reducing the severity of aGVHD without affecting GVL. The immunosuppressive potential of MSCs for the treatment of aGVHD significantly affects the development of MDSCs, thereby consolidating the position of MSCs in the prevention and treatment of aGVHD.
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Affiliation(s)
- Shuo Yang
- First Center Clinic College of Tianjin Medical University, Tianjin, China; Department of Hematology, The First People's Hospital of Shangqiu, Shangqiu, China
| | - Yunxiong Wei
- First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Rui Sun
- First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Wenyi Lu
- Department of Hematology, Tianjin First Central Hospital, Tianjin, China
| | - Hairong Lv
- Department of Hematology, Tianjin First Central Hospital, Tianjin, China
| | - Xia Xiao
- Department of Hematology, Tianjin First Central Hospital, Tianjin, China
| | - Yaqing Cao
- First Center Clinic College of Tianjin Medical University, Tianjin, China
| | - Xin Jin
- School of Medicine, Nankai University, Tianjin, China
| | - Mingfeng Zhao
- Department of Hematology, Tianjin First Central Hospital, Tianjin, China.
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Mohammadpour H, Sarow JL, MacDonald CR, Chen GL, Qiu J, Sharma UC, Cao X, Herr MM, Hahn TE, Blazar BR, Repasky EA, McCarthy PL. β2-Adrenergic receptor activation on donor cells ameliorates acute GvHD. JCI Insight 2020; 5:137788. [PMID: 32437333 DOI: 10.1172/jci.insight.137788] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 05/13/2020] [Indexed: 12/12/2022] Open
Abstract
Acute graft versus host disease (aGvHD) remains a major impediment to successful allogeneic hematopoietic cell transplantation (allo-HCT). To solve this problem, a greater knowledge of factors that regulate the differentiation of donor T cells toward cytotoxic cells or Tregs is necessary. We report that the β2-adrenergic receptor (β2-AR) is critical for regulating this differentiation and that its manipulation can control aGvHD without impairing the graft-versus-tumor (GvT) effect. Donor T cell β2-AR expression and signaling is associated with decreased aGvHD when compared with recipients of β2-AR-/- donor T cells. We determined that β2-AR activation skewed CD4+ T cell differentiation in vitro and in vivo toward Tregs rather than the T helper 1 (Th1) phenotype. Treatment of allo-HCT recipients with a selective β2-agonist (bambuterol) ameliorated aGvHD severity. This was associated with increased Tregs, decreased cytotoxic T cells, and increased donor BM-derived myeloid-derived suppressor cells (MDSCs) in allogeneic and humanized xenogeneic aGvHD models. β2-AR signaling resulted in increased Treg generation through glycogen synthase kinase-3 activation. Bambuterol preserved the GvT effect by inducing NKG2D+ effector cells and central memory T cells. These data reveal how β-AR signaling can be targeted to ameliorate GvHD severity while preserving GvT effect.
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Affiliation(s)
| | | | | | - George L Chen
- Medicine, Transplant and Cellular Therapy Program, and
| | - Jingxin Qiu
- Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA
| | - Umesh C Sharma
- Department of Medicine, Jacobs School of Medicine & Biomedical Sciences, Buffalo, New York, USA
| | - Xuefang Cao
- Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland, USA
| | - Megan M Herr
- Medicine, Transplant and Cellular Therapy Program, and
| | | | - Bruce R Blazar
- Department of Pediatrics, Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, Minnesota, USA
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38
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D'Aveni M, Notarantonio AB, Bertrand A, Boulangé L, Pochon C, Rubio MT. Myeloid-Derived Suppressor Cells in the Context of Allogeneic Hematopoietic Stem Cell Transplantation. Front Immunol 2020; 11:989. [PMID: 32528476 PMCID: PMC7256196 DOI: 10.3389/fimmu.2020.00989] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 04/27/2020] [Indexed: 12/20/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses. In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), MDSCs (in the donor graft and in the recipient, after allo-HSCT) might mediate immune suppression through multiple mechanisms. However, it remains unclear how MDSCs can be distinguished from their normal myeloid counterparts in the hematopoietic stem cell donor graft and during immune reconstitution after allo-HSCT in the recipient. Our ability to understand their exact role in allo-HSCT is limited by the absence of a specific gene signature or surface markers for identifying MDSCs among myeloid cells and by their plasticity in different microenvironments. According to various studies, MDSCs might induce transplant tolerance and control graft vs. host disease (GVHD), but their impact on the graft vs. tumor effect (GVT) is not fully understood. In fact, we know that MDSCs commonly expand in patients with cancer, and they are thought to promote hematological malignancy progression. However, little is known about whether depleting them might be an effective strategy for enhancing GVT effects. Here, we review data published over the past 40 years on allo-HSCT to delineate the different MDSC subsets, and their abilities to induce transplant tolerance and preserve the GVT effect. This review will provide a basis for determining whether one MDSC subset might be proposed as the most appropriate candidate for cellular therapies, due to its ability to modulate GVHD.
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Affiliation(s)
- Maud D'Aveni
- Hematology Department, CHRU Nancy, Université de Lorraine, Nancy, France.,Université de Lorraine, UMR 7365 CNRS, IMoPA, Nancy, France
| | - Anne B Notarantonio
- Hematology Department, CHRU Nancy, Université de Lorraine, Nancy, France.,Université de Lorraine, UMR 7365 CNRS, IMoPA, Nancy, France
| | - Allan Bertrand
- Université de Lorraine, UMR 7365 CNRS, IMoPA, Nancy, France
| | - Laura Boulangé
- Université de Lorraine, UMR 7365 CNRS, IMoPA, Nancy, France
| | - Cécile Pochon
- Hematology Department, CHRU Nancy, Université de Lorraine, Nancy, France.,Université de Lorraine, UMR 7365 CNRS, IMoPA, Nancy, France
| | - Marie T Rubio
- Hematology Department, CHRU Nancy, Université de Lorraine, Nancy, France.,Université de Lorraine, UMR 7365 CNRS, IMoPA, Nancy, France
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39
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Danger-associated extracellular ATP counters MDSC therapeutic efficacy in acute GVHD. Blood 2020; 134:1670-1682. [PMID: 31533918 DOI: 10.1182/blood.2019001950] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2019] [Accepted: 08/24/2019] [Indexed: 02/07/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) can subdue inflammation. In mice with acute graft-versus-host disease (GVHD), donor MDSC infusion enhances survival that is only partial and transient because of MDSC inflammasome activation early posttransfer, resulting in differentiation and loss of suppressor function. Here we demonstrate that conditioning regimen-induced adenosine triphosphate (ATP) release is a primary driver of MDSC dysfunction through ATP receptor (P2x7R) engagement and NLR pyrin family domain 3 (NLRP3) inflammasome activation. P2x7R or NLRP3 knockout (KO) donor MDSCs provided significantly higher survival than wild-type (WT) MDSCs. Although in vivo pharmacologic targeting of NLRP3 or P2x7R promoted recipient survival, indicating in vivo biologic effects, no synergistic survival advantage was seen when combined with MDSCs. Because activated inflammasomes release mature interleukin-1β (IL-1β), we expected that IL-1β KO donor MDSCs would be superior in subverting GVHD, but such MDSCs proved inferior relative to WT. IL-1β release and IL-1 receptor expression was required for optimal MDSC function, and exogenous IL-1β added to suppression assays that included MDSCs increased suppressor potency. These data indicate that prolonged systemic NLRP3 inflammasome inhibition and decreased IL-1β could diminish survival in GVHD. However, loss of inflammasome activation and IL-1β release restricted to MDSCs rather than systemic inhibition allowed non-MDSC IL-1β signaling, improving survival. Extracellular ATP catalysis with peritransplant apyrase administered into the peritoneum, the ATP release site, synergized with WT MDSCs, as did regulatory T-cell infusion, which we showed reduced but did not eliminate MDSC inflammasome activation, as assessed with a novel inflammasome reporter strain. These findings will inform future clinical using MDSCs to decrease alloresponses in inflammatory environments.
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40
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Lv M, Wang K, Huang XJ. Myeloid-derived suppressor cells in hematological malignancies: friends or foes. J Hematol Oncol 2019; 12:105. [PMID: 31640764 PMCID: PMC6805310 DOI: 10.1186/s13045-019-0797-3] [Citation(s) in RCA: 78] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 09/25/2019] [Indexed: 12/25/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are newly identified immature myeloid cells that are characterized by the ability to suppress immune responses and expand during cancer, infection, and inflammatory diseases. Although MDSCs have attracted a lot of attention in the field of tumor immunology in recent years, little is known about their multiple roles in hematological malignancies as opposed to their roles in solid tumors. This review will help researchers better understand the various characteristics and functions of MDSCs, as well as the potential therapeutic applications of MDSCs in hematological malignancies, including lymphoma, multiple myeloma, leukemia, and hematopoietic stem cell transplantation.
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Affiliation(s)
- Meng Lv
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of HSCT, No 11 Xizhimen South Street, Beijing, 100044, China
| | - Ke Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of HSCT, No 11 Xizhimen South Street, 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 HSCT, No 11 Xizhimen South Street, Beijing, 100044, China. .,Peking-Tsinghua Center for Life Sciences, Beijing, China.
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