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1
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Sato Y. The Role of Tregs in the Tumor Microenvironment. Biomedicines 2025; 13:1173. [PMID: 40427000 PMCID: PMC12108874 DOI: 10.3390/biomedicines13051173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2025] [Revised: 05/06/2025] [Accepted: 05/08/2025] [Indexed: 05/29/2025] Open
Abstract
The tumor microenvironment (TME) is a unique ecosystem that surrounds tumor tissues. The TME is composed of extracellular matrix, immune cells, blood vessels, stromal cells, and fibroblasts. These environments enhance cancer development, progression, and metastasis. Recent success in immune checkpoint blockade also supports the importance of the TME and immune cells residing in the tumor niche. Although the TME can be identified in almost all cancer types, the role of the TME may not be similar among different cancer types. Regulatory T cells (Tregs) play a pivotal role in immune homeostasis and are frequently found in the TME. Owing to their suppressive function, Tregs are often considered unfavorable factors that allow the immune escape of cancer cells. However, the presence of Tregs is not always linked to an unfavorable phenotype, which can be explained by the heterogeneity and plasticity of Tregs. In this review, the current understanding of the role of Tregs in TME is addressed for each cancer cell type. Moreover, recently a therapeutic approach targeting Tregs infiltrating in the TME has been developed including drug antibody conjugate, immunotoxin, and FOXP3 inhibiting peptide. Thus, understanding the role of Tregs in the TME may lead to the development of novel therapies that directly target the TME.
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Affiliation(s)
- Yohei Sato
- Laboratory of Immune Cell Therapy, Project Research Unit, The Jikei University School of Medicine, Tokyo 105-8461, Japan; ; Tel.: +81-3-3433-1111 (ext. 2430)
- Core Research Facilities, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo 105-8461, Japan
- Immunology and Allergy Research Unit, Division of Otorhinolaryngology Head & Neck Surgery, Faculty of Medicine, University of Fukui, Fukui 910-1193, Japan
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2
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Cui J, Liu W, Zhong S, Fang Y, Xu P, Xu C, Wang R, Hu X, Zhou W, Li K, Hong M, Qian S, Sun Q. Blockade of TIGAR prevents CD8 + T cell dysfunction and elicits anti-AML immunity. Cancer Immunol Immunother 2025; 74:183. [PMID: 40285889 PMCID: PMC12033161 DOI: 10.1007/s00262-025-04042-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 04/01/2025] [Indexed: 04/29/2025]
Abstract
Acute myeloid leukemia (AML) cells and activated T cells rely on aerobic glycolysis for energy metabolism. The TP53-induced glycolysis and apoptosis regulator (TIGAR) inhibits glycolysis and protects AML cells from apoptosis. Preliminary studies suggest that combining TIGAR inhibition with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) may offer a therapeutic strategy for AML. However, it remains unclear whether silencing TIGAR can enhance T cell function and thereby improve AML prognosis. This study aims to investigate whether TIGAR silencing in host can eliminate AML cells and rejuvenate dysfunctional T cells with mouse models. TIGAR knockout mice on the C57BL/6J background were generated and AML mouse models were established through intravenous injection of C1498 cells. We found that TIGAR depletion enhanced CD8+ T cell counts and raised CD4/CD8 ratio, downregulating CD44 and immune checkpoints CTLA-4, LAG-3, PD-1 on cell surface of CD8+ T cells. TIGAR depletion boosted cytokine secretion (IFN-γ, perforin, granzyme B, TNF-α) by CD8+ T cells and IL-2, TNF-α by CD4+ T cells, improving cytotoxicity against AML cells, proliferation, and reducing apoptosis. TIGAR suppression in host with 2-DG prolonged AML mouse survival, decreased tumor burden, and leukemic infiltration. TIGAR suppression restored thymic T cell development and peripheral immune balance. Single-cell RNA sequencing analysis also revealed that high TIGAR expression influences the glycolysis pathway, and correlates with markers of T cell exhaustion. This study indicates that blocking TIGAR prevents CD8+ T cell dysfunction and induces anti-AML immunity.
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Affiliation(s)
- Jialin Cui
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Wenjie Liu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Shiyang Zhong
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huaian, China
| | - Yiran Fang
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Pei Xu
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Cheng Xu
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Rong Wang
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Xingfei Hu
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huaian, China
| | - Wanting Zhou
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huaian, China
| | - Kening Li
- Department of Bioinformatics, Nanjing Medical University, Nanjing, China
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Northern Jiangsu Institute of Clinical Medicine, Huaian, China
| | - Ming Hong
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China
| | - Sixuan Qian
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
| | - Qian Sun
- Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
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Mohy El-Din AMM, AlShaarawy BA, Kandeel EZ, AlDewi DM, Refaat LAA, Arneth B, Sabit H. Immunopathological Dysregulation in Acute Myeloid Leukemia: The Impact of T-bet, RORγt, and FOXP3 on Disease Dynamics. Cells 2025; 14:528. [PMID: 40214482 PMCID: PMC11988856 DOI: 10.3390/cells14070528] [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: 03/04/2025] [Revised: 03/26/2025] [Accepted: 03/27/2025] [Indexed: 04/14/2025] Open
Abstract
The etiology of acute myeloid leukemia (AML) is complex, including genetic and environmental abnormalities. The immune system anomalies play an essential role in the process of leukemogenesis. However, the immunopathological factors, including abnormal T helper (Th) subsets, contributing to the initiation and progression of this neoplasm, require further investigation. Considering the previously mentioned data, we decided to study the expression pattern of transcription factors T-bet, Foxp3, and RORγt that regulate Th1, Treg, and Th17, respectively, in acute myeloid leukemia with correlation to clinical and other investigation data and treatment outcomes. This study was conducted on 80 newly diagnosed patients with AML recruited from the National Cancer Institute, Cairo University, and 25 healthy control subjects. The AML patient cohort consisted of 30 females (37.5%) and 50 males (62.5%), ranging from 18 to 74 years old. The control group was 8 females (32%) and 17 males (68%), with ages ranging from 23 to 40 years old. Samples were provided from the bone marrow of donor cases for allogeneic bone marrow transplantation. The diagnosis of acute myeloid leukemia was based on morphologic and cytochemical evaluation, immunophenotyping, and complementary cytogenetics according to WHO criteria. Upshift from the normal T-bet intensity of power (MFI), RORγt+ CD4+ T lymphocyte frequency (%) with downshift from the normal FOXP3 intensity of power (MFI), may suggest a state of inflammation. In contrast, an upshift from the normal FOXP3+ CD4+ T lymphocyte frequency (%) may reflect a state of immunosuppression in the bone marrow microenvironment of AML. Combined, they constitute a sophisticated scenario of immunological disorder in AML. Co-expression of T-bet and RORγt transcription factors in CD4+ T lymphocytes in both normal and AML groups may suggest CD4+ T lymphocyte plasticity.
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Affiliation(s)
- Amira M. Mohamed Mohy El-Din
- Clinical and Chemical Pathology Department, Faculty of Medicine, Misr University for Science and Technology, Giza P.O. Box 77, Egypt;
| | - Buthayna Ahmad AlShaarawy
- Clinical and Chemical Pathology Department, Girls Faculty of Medicine, Al-Azhar University, Cairo 11651, Egypt (D.M.A.)
| | - Eman Zaghloul Kandeel
- Clinical and Chemical Pathology Department, National Cancer Institute, Cairo University, Giza 12613, Egypt
| | - Dalia Mahmoud AlDewi
- Clinical and Chemical Pathology Department, Girls Faculty of Medicine, Al-Azhar University, Cairo 11651, Egypt (D.M.A.)
| | - Lobna Abdel Azeem Refaat
- Clinical and Chemical Pathology Department, National Cancer Institute, Cairo University, Giza 12613, Egypt
| | - Borros Arneth
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Hospital of the Universities of Giessen and Marburg (UKGM), Philipps University Marburg, Baldingerstr 1, 35043 Marburg, Germany
- Institute of Laboratory Medicine and Pathobiochemistry, Molecular Diagnostics, Hospital of the Universities of Giessen and Marburg (UKGM), Justus Liebig University Giessen, Feulgenstr. 12, 35392 Giessen, Germany
| | - Hussein Sabit
- Department of Medical Biotechnology, College of Biotechnology, Misr University for Science and Technology, Giza P.O. Box 77, Egypt
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Haubner S, Subklewe M, Sadelain M. Honing CAR T cells to tackle acute myeloid leukemia. Blood 2025; 145:1113-1125. [PMID: 39630061 DOI: 10.1182/blood.2024024063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/15/2024] [Indexed: 03/14/2025] Open
Abstract
ABSTRACT Acute myeloid leukemia (AML) remains a dismal disease with poor prognosis, particularly in the relapsed/refractory (R/R) setting. Chimeric antigen receptor (CAR) therapy has yielded remarkable clinical results in other leukemias and thus has, in principle, the potential to achieve similar outcomes in R/R AML. Redirecting the approved CD19-specific CAR designs against the myeloid antigens CD33, CD123, or CLEC12A has occasionally yielded morphologic leukemia-free states but has so far been marred by threatening myeloablation and early relapses. These safety and efficacy limitations are largely due to the challenge of identifying suitable target antigens and designing adequate receptors for effective recognition and safe elimination of AML. Building on lessons learned from the initial clinical attempts, a new wave of CAR strategies relying on alternative target antigens and innovative CAR designs is about to enter clinical evaluation. Adapted multiantigen targeting, logic gating, and emerging cell engineering solutions offer new possibilities to better direct T-cell specificity and sensitivity toward AML. Pharmacologic modulation and genetic epitope engineering may extend these approaches by augmenting target expression in AML cells or minimizing target expression in normal hematopoietic cells. On/off switches or CAR T-cell depletion may curb excessive or deleterious CAR activity. Investigation of AML-intrinsic resistance and leukemic microenvironmental factors is poised to reveal additional targetable AML vulnerabilities. We summarize here the findings, challenges, and new developments of CAR therapy for AML. These illustrate the need to specifically adapt CAR strategies to the complex biology of AML to achieve better therapeutic outcomes.
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MESH Headings
- Humans
- Leukemia, Myeloid, Acute/therapy
- Leukemia, Myeloid, Acute/immunology
- Immunotherapy, Adoptive/methods
- Receptors, Chimeric Antigen/immunology
- Receptors, Chimeric Antigen/genetics
- T-Lymphocytes/immunology
- Animals
- Antigens, Neoplasm/immunology
- Receptors, Antigen, T-Cell/immunology
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Affiliation(s)
- Sascha Haubner
- Columbia Initiative in Cell Engineering and Therapy, Department of Medicine, Columbia University, New York, NY
| | - Marion Subklewe
- Department of Medicine III, University Hospital, Ludwig Maximilian University Munich, Munich, Germany
| | - Michel Sadelain
- Columbia Initiative in Cell Engineering and Therapy, Department of Medicine, Columbia University, New York, NY
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Wang Y, Yang X, Liu Y, Li Y. A review of common immunotherapy and nano immunotherapy for acute myeloid leukemia. Front Immunol 2025; 16:1505247. [PMID: 40129984 PMCID: PMC11931025 DOI: 10.3389/fimmu.2025.1505247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2024] [Accepted: 02/24/2025] [Indexed: 03/26/2025] Open
Abstract
Acute myeloid leukemia (AML) is a highly aggressive hematological malignancy. Traditional chemotherapy methods not only bring serious side effects, but also lead to high recurrence rate and drug resistance in some patients. However, as an emerging therapeutic strategy, immunotherapy has shown great potential in the field of AML treatment in recent years. At present, common immunotherapy methods for AML include monoclonal antibodies, CAR-T cell therapy, and immune checkpoint inhibitors. With the deepening of research and technological progress, especially the application of nanotechnology in medicine, new immunotherapy is expected to become one of the important means for the treatment of acute myeloid leukemia in the future.
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Affiliation(s)
- Yaoyao Wang
- Department of Pediatrics of Yantai Affiliated Hospital, The Second Clinical Medical College of Binzhou Medical University, Yantai, Shandong, China
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong, China
| | - Xiancong Yang
- Laboratory Department, Qilu Hospital of ShanDong University Dezhou Hospital, Dezhou, Shandong, China
| | - Yalin Liu
- Department of Pediatrics of Yantai Affiliated Hospital, The Second Clinical Medical College of Binzhou Medical University, Yantai, Shandong, China
| | - Youjie Li
- Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong, China
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6
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Tasis A, Spyropoulos T, Mitroulis I. The Emerging Role of CD8 + T Cells in Shaping Treatment Outcomes of Patients with MDS and AML. Cancers (Basel) 2025; 17:749. [PMID: 40075597 PMCID: PMC11898900 DOI: 10.3390/cancers17050749] [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: 01/13/2025] [Revised: 02/13/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
CD8+ T cells are critical players in anti-tumor immunity against solid tumors, targeted by immunotherapies. Emerging evidence suggests that CD8+ T cells also play a crucial role in anti-tumor responses and determining treatment outcomes in hematologic malignancies like myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML). In this review, we focus on the implication of CD8+ T cells in the treatment response of patients with MDS and AML. First, we review reported studies of aberrant functionality and clonality of CD8+ T cells in MDS and AML, often driven by the immunosuppressive bone marrow microenvironment, which can hinder effective antitumor immunity. Additionally, we discuss the potential use of CD8+ T cell subpopulations, including memory and senescent-like subsets, as predictive biomarkers for treatment response to a variety of treatment regimens, such as hypomethylating agents, which is the standard of care for patients with higher-risk MDS, and chemotherapy which is the main treatment of patients with AML. Understanding the multifaceted role of CD8+ T cells and their interaction with malignant cells in MDS and AML will provide useful insights into their potential as prognostic/predictive biomarkers, but also uncover alternative approaches to novel treatment strategies that could reshape the therapeutic landscape, thus improving treatment efficacy, aiding in overcoming treatment resistance and improving patient survival in these challenging myeloid neoplasms.
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Affiliation(s)
- Athanasios Tasis
- Translational Research and Laboratory Medicine Unit, First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Theodoros Spyropoulos
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
| | - Ioannis Mitroulis
- Translational Research and Laboratory Medicine Unit, First Department of Internal Medicine, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
- Department of Hematology, University Hospital of Alexandroupolis, Democritus University of Thrace, 68100 Alexandroupolis, Greece;
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7
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Rady M, Mostafa M, Dida G, Sabet F, Abou-Aisha K, Watzl C. Adoptive NK cell therapy in AML: progress and challenges. Clin Exp Med 2025; 25:41. [PMID: 39820676 PMCID: PMC11748472 DOI: 10.1007/s10238-025-01559-5] [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: 11/12/2024] [Accepted: 01/03/2025] [Indexed: 01/19/2025]
Abstract
Adoptive cell therapy (ACT) using natural killer (NK) cells has emerged as a promising therapeutic strategy for acute myeloid leukemia (AML), addressing challenges such as chemotherapy resistance and high relapse rates. Over the years, clinical trials and studies have explored various sources of NK cells, including ex vivo expanded NK cell lines, CAR-NK cells, peripheral blood-derived NK cells, and umbilical cord blood-derived NK cells. These therapies have demonstrated varying degrees of therapeutic efficacy, ranging from transient anti-leukemia activity to sustained remission in select patient groups. Toxicity profiles have generally shown favorable safety outcomes, with minimal incidence of severe adverse effects such as cytokine release syndrome (CRS) or graft-versus-host disease (GVHD). However, persistent challenges remain, including limited NK cell persistence, relapse, and heterogeneity in patient responses. This review provides a comprehensive analysis of clinical outcomes and toxicity profiles provided from clinical trials, clinical studies and case reports conducted in the last 15 years to judge on the efficacy, safety and applicability of using NK cells for ACT of AML. Our review highlights the significant potential of NK cell-based therapies for AML, while addressing the technical and biological challenges that must be overcome to enhance their efficacy and safety.
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Affiliation(s)
- Mona Rady
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt.
- Faculty of Biotechnology, German International University, New Administrative Capital, Egypt.
| | - Maha Mostafa
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
| | - Gabriel Dida
- University of South Wales, Pontypridd, Wales, UK
- Department of Health Systems Management and Public Health, Technical University of Kenya, Nairobi, Kenya
| | - Fatima Sabet
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
| | - Khaled Abou-Aisha
- Microbiology, Immunology and Biotechnology Department, Faculty of Pharmacy and Biotechnology, German University in Cairo (GUC), New Cairo, Egypt
| | - Carsten Watzl
- Immunology Department, Leibniz Research Center for Working Environment and Human Factors at TU Dortmund (IfADo), Dortmund, Germany
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Naji NS, Sathish M, Karantanos T. Inflammation and Related Signaling Pathways in Acute Myeloid Leukemia. Cancers (Basel) 2024; 16:3974. [PMID: 39682161 DOI: 10.3390/cancers16233974] [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: 10/30/2024] [Revised: 11/22/2024] [Accepted: 11/22/2024] [Indexed: 12/18/2024] Open
Abstract
Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, and inflammatory signaling is involved in its pathogenesis. Cytokines exert a robust effect on the progression of AML and affect survival outcomes. The dysregulation in the cytokine network may foster a pro-tumorigenic microenvironment, increasing leukemic cell proliferation, decreasing survival and driving drug resistance. The dominance of pro-inflammatory mediators such as IL-11β, TNF-α and IL-6 over anti-inflammatory mediators such as TGF-β and IL-10 has been implicated in tumor progression. Additionally, inflammatory cytokines have favored certain populations of hematopoietic stem and progenitor cells with mutated clonal hematopoiesis genes. This article summarizes current knowledge about inflammatory cytokines and signaling pathways in AML, their modes of action and the implications for immune tolerance and clonal hematopoiesis, with the aim of finding potential therapeutic interventions to improve clinical outcomes in AML patients.
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Affiliation(s)
- Nour Sabiha Naji
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
| | - Mrudula Sathish
- Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Theodoros Karantanos
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
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Yu F, Jiang H, Gu Y. Causal relationship between immune cells and acute myeloid leukemia: a two-sample Mendelian randomization study. Discov Oncol 2024; 15:675. [PMID: 39560825 DOI: 10.1007/s12672-024-01565-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 11/11/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Immune cells are crucial in the etiology of acute myeloid leukemia (AML). Given the genetic, epigenetic, and clonal complexities of AML, pinpointing factors linked to immunotherapy presents a formidable challenge. Moreover, investigations into the connection between immune cells and AML are still in their infancy, necessitating further studies to decode the intricate connections involved. MATERIALS AND METHODS Based on Mendelian independent distribution law, Mendelian randomisation (MR) is an analytical method mainly used in epidemiological aetiology inference. This bidirectional two-sample MR study aims to investigate the causal link between immune cell phenotypes and AML. Pooled phenotypic data from 3,757 individuals in a Sardinian cohort, encompassing 731 immune cell phenotypes, were utilized. Aggregate data on AML were sourced from the FinnGen project of the Finnish Biobank. We analyzed the sensitivity of the results and evaluated heterogeneity, employing Cochran's Q test in conjunction with MR-Egger and MR-Presso to assess pleiotropy levels. RESULTS 26 distinct immune cell types were identified that potentially linked causally with AML. Furthermore, our analysis indicated a bidirectional causal link between Resting Treg % CD4 Treg, BAFF-R on memory B cells and AML. CONCLUSION This investigation delineates the causal link between immune cell phenotypes and the pathogenesis of AML, thereby unveiling potential therapeutic avenues to modulate immune cell functions in AML patients. It aims to discover innovative therapeutic strategies that target immune evasion tactics to reinstate immune responses against leukemia.
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Affiliation(s)
- Fanhua Yu
- Shaoxing Keqiao District Hospital of Traditional Chinese Medicine, Shaoxing, China
| | - Hao Jiang
- Zhejiang Provincial People's Hospital, Hangzhou, China
| | - Yena Gu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, China.
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Li Y, Jia Z, Liu X, Zhao H, Cui G, Luo J, Kong X. Single-cell sequencing technology to characterize stem T-cell subpopulations in acute T-lymphoblastic leukemia and the role of stem T-cells in the disease process. Aging (Albany NY) 2024; 16:13117-13131. [PMID: 39422621 PMCID: PMC11552640 DOI: 10.18632/aging.206123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 07/17/2024] [Indexed: 10/19/2024]
Abstract
BACKGROUND Precursor T-cell acute lymphoblastic leukemia (Pre-T ALL) is a malignant neoplastic disease in which T-cells proliferate in the bone marrow. Single-cell sequencing technology could identify characteristic cell types, facilitating the study of the therapeutic mechanisms in Pre-T ALL. METHODS The single-cell sequencing data (scRNA-seq) of Pre-T ALL were obtained from public databases. Key immune cell subpopulations involved in the progression of Pre-T ALL were identified by clustering and annotating the cellular data using AUCell. Next, pseudo-temporal analysis was performed to identify the differentiation trajectories of immune cell subpopulations using Monocle. Copy number mutation landscape of cell subpopulations was characterized by inferCNV. Finally, cellphoneDB was used to analyze intercellular communication relationships. RESULTS A total of 10 cellular subpopulations were classified, with Pre-T ALL showing a higher proportion of NK/T cells. NK/T cells were further clustered into two subpopulations. Stem T cells showed a high expression of marker genes related to hematopoietic stem cells, Naive T cells had a high expression of CCR7, CCR7, RCAN3, and NK cells high-expressed KLRD1, TRDC. The cell proliferation was reduced and the activation of T cell was increased during the differentiation of stem T cells to Naive T cells. We observed interaction between stem T cells with dendritic cells such as CD74-COPA, CD74-MIF as well as co-inhibition-related interactions such as LGALS9-HAVCR2, TGFB1-TGFBR3. CONCLUSION Stem T cells were involved in the development of Pre-T-ALL through the regulatory effects of transcription factors (TFs) KLF2 and FOS and multiple ligand-receptor pairs.
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Affiliation(s)
- Yan Li
- Department of Hematology, Handan First Hospital, Handan, Hebei 056001, China
| | - Zhenwei Jia
- Department of Hematology, Handan First Hospital, Handan, Hebei 056001, China
| | - Xiaoyan Liu
- Department of Hematology, Handan First Hospital, Handan, Hebei 056001, China
| | - Hongbo Zhao
- Department of Hematology, Handan First Hospital, Handan, Hebei 056001, China
| | - Guirong Cui
- Department of Hematology, Handan First Hospital, Handan, Hebei 056001, China
| | - Jianmin Luo
- Department of Hematology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei 050000, China
| | - Xiaoyang Kong
- Department of Hematology, Handan First Hospital, Handan, Hebei 056001, China
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11
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Deo AS, Shrijana, S U S, Karun S, Bisaria K, Sarkar K. Participation of T cells in generating immune protection against cancers. Pathol Res Pract 2024; 262:155534. [PMID: 39180801 DOI: 10.1016/j.prp.2024.155534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 08/09/2024] [Accepted: 08/11/2024] [Indexed: 08/27/2024]
Abstract
T cells are essential to the immune system's reaction. The major job of the immune system is to identify and get rid of any abnormal or malignant cells in the body. White blood cells called T cells coordinate and carry out immunological responses, including identifying and eliminating cancer cells. It mostly consists of two types called helper T-cells and cytotoxic T-cells. Together, they create an efficient reaction against cancer. Both the primary T cell subtype - CD4+ and CD8+ Tcells have specific role to play in our immune system.CD4+ T cells are limited to MHC-II molecules and acts as helper cell by activating and enhancing other immune cells. On the other side CD8+ T cells are called the killer cells as they eradicate the abnormal and contaminated cells and are limited to MHC-I molecules. The malignant cells are destroyed when cytotoxic T cells come into direct contact with them. This happens via number of processes, including TCR recognition, the release of cytotoxic chemicals, and finally the activation of the immune system. T cell receptors on the surface of cytotoxic T cells allow them to identify tumour cells and these T cells release harmful chemicals like perforins and granzymes when they connect to malignant cells. T-cells that have been stimulated release cytokines such as gamma interferon. T-cells can also acquire memory responses that improve their capacity for recognition and response. Helper T-cells contribute to the development of an immune response. It entails coordination and activation as well as the enlistment of additional immune cells, including macrophages and natural killer cells, to assist in the eradication of cancer cells. Despite the fact that the cancer frequently creates defence systems to circumvent their immune response. Together, these activities support the immune surveillance and T-cell-mediated regulation of cancer cells. Treatments like chemotherapy, radiation, and surgery are main ways to treat cancer but immunotherapy has been emerging since last few decades. These immune specific treatments have shown huge positive result. CAR T cell therapy is a promising weapon to fight again blood cancer and it works by focusing on our immune system to fight and eliminate cancer.
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Affiliation(s)
- Anisha Singha Deo
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Shrijana
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Sruthika S U
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Shreya Karun
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Kashish Bisaria
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India
| | - Koustav Sarkar
- Department of Biotechnology, SRM Institute of Science and Technology, Kattankulathur, Tamil Nadu 603203, India.
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12
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Radpour R, Simillion C, Wang B, Abbas HA, Riether C, Ochsenbein AF. IL-9 secreted by leukemia stem cells induces Th1-skewed CD4+ T cells, which promote their expansion. Blood 2024; 144:888-903. [PMID: 38941612 DOI: 10.1182/blood.2024024000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2024] [Revised: 05/28/2024] [Accepted: 06/18/2024] [Indexed: 06/30/2024] Open
Abstract
ABSTRACT In acute myeloid leukemia (AML), leukemia stem cells (LSCs) and leukemia progenitor cells (LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating their expansion and differentiation. To study the interaction of CD4+ and CD8+ T cells in the BM with LSCs and LPCs, we analyzed their transcriptome and predicted cell-cell interactions by unbiased high-throughput correlation network analysis. We found that CD4+ T cells in the BM of patients with AML were activated and skewed toward T-helper (Th)1 polarization, whereas interleukin-9 (IL-9)-producing (Th9) CD4+ T cells were absent. In contrast to normal hematopoietic stem cells, LSCs produced IL-9, and the correlation modeling predicted IL9 in LSCs as a main hub gene that activates CD4+ T cells in AML. Functional validation revealed that IL-9 receptor signaling in CD4+ T cells leads to activation of the JAK-STAT pathway that induces the upregulation of KMT2A and KMT2C genes, resulting in methylation on histone H3 at lysine 4 to promote genome accessibility and transcriptional activation. This induced Th1-skewing, proliferation, and effector cytokine secretion, including interferon gamma (IFN-γ) and tumor necrosis factor α (TNF-α). IFN-γ and, to a lesser extent, TNF-α produced by activated CD4+ T cells induced the expansion of LSCs. In accordance with our findings, high IL9 expression in LSCs and high IL9R, TNF, and IFNG expression in BM-infiltrating CD4+ T cells correlated with worse overall survival in AML. Thus, IL-9 secreted by AML LSCs shapes a Th1-skewed immune environment that promotes their expansion by secreting IFN-γ and TNF-α.
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MESH Headings
- Interleukin-9/genetics
- Interleukin-9/metabolism
- Humans
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/metabolism
- Neoplastic Stem Cells/pathology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/immunology
- Th1 Cells/immunology
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/metabolism
- Cell Proliferation
- Myeloid-Lymphoid Leukemia Protein/genetics
- Myeloid-Lymphoid Leukemia Protein/metabolism
- Tumor Microenvironment/immunology
- Receptors, Interleukin-9/genetics
- Receptors, Interleukin-9/metabolism
- Interferon-gamma/metabolism
- Histone-Lysine N-Methyltransferase/genetics
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Affiliation(s)
- Ramin Radpour
- Department for BioMedical Research, Tumor Immunology, University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | | | - Bofei Wang
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX
| | - Hussein A Abbas
- Department of Leukemia, MD Anderson Cancer Center, Houston, TX
- Department of Genomic Medicine, MD Anderson Cancer Center, Houston, TX
| | - Carsten Riether
- Department for BioMedical Research, Tumor Immunology, University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Adrian F Ochsenbein
- Department for BioMedical Research, Tumor Immunology, University of Bern, Bern, Switzerland
- Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
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13
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Godefroy E, Chevallier P, Haspot F, Vignes C, Daguin V, Lambot S, Verdon M, De Seilhac M, Letailleur V, Jarry A, Pédron A, Guillaume T, Peterlin P, Garnier A, Vibet MA, Mougon M, Le Bourgeois A, Jullien M, Jotereau F, Altare F. Human gut microbiota-reactive DP8α Tregs prevent acute graft-versus-host disease in a CD73-dependent manner. JCI Insight 2024; 9:e179458. [PMID: 39088302 PMCID: PMC11457850 DOI: 10.1172/jci.insight.179458] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 07/25/2024] [Indexed: 08/03/2024] Open
Abstract
Graft-versus-host disease (GvHD) is a life-threatening complication frequently occurring following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Since gut microbiota and regulatory T cells (Tregs) are believed to play roles in GvHD prevention, we investigated whether DP8α Tregs, which we have previously described to harbor a T cell receptor specificity for the gut commensal Faecalibacterium prausnitzii, could protect against GvHD, thereby linking the microbiota and its effect on GvHD. We observed a decrease in CD73+ DP8α Treg frequency in allo-HSCT patients 1 month after transplantation, which was associated with acute GvHD (aGvHD) development at 1 month after transplantation, as compared with aGvHD-free patients, without being correlated to hematological disease relapse. Importantly, CD73 activity was shown to be critical for DP8α Treg suppressive function. Moreover, the frequency of host-reactive DP8α Tregs was also lower in aGvHD patients, as compared with aGvHD-free patients, which could embody a protective mechanism responsible for the maintenance of this cell subset in GvHD-free patients. We also showed that human DP8α Tregs protected mice against xenogeneic GvHD through limiting deleterious inflammation and preserving gut integrity. Altogether, these results demonstrated that human DP8α Tregs mediate aGvHD prevention in a CD73-dependent manner, likely through host reactivity, advocating for the use of these cells for the development of innovative therapeutic strategies to preclude aGvHD-related inflammation.
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Affiliation(s)
- Emmanuelle Godefroy
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- LabEx IGO, Nantes University, Nantes, France
| | - Patrice Chevallier
- CHU de Nantes, F-44000 Nantes, France
- INSERM UMR 1307, CRCI2NA IRS-UN, Nantes Université, Nantes, France
| | - Fabienne Haspot
- LabEx IGO, Nantes University, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France
| | - Caroline Vignes
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- LabEx IGO, Nantes University, Nantes, France
| | - Véronique Daguin
- LabEx IGO, Nantes University, Nantes, France
- Nantes Université, INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France
| | - Sylvia Lambot
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- LabEx IGO, Nantes University, Nantes, France
| | - Margaux Verdon
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- LabEx IGO, Nantes University, Nantes, France
| | - Margaux De Seilhac
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- LabEx IGO, Nantes University, Nantes, France
- Maat Pharma, Lyon, France
| | | | - Anne Jarry
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- LabEx IGO, Nantes University, Nantes, France
| | - Annabelle Pédron
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- Université Libre de Bruxelles, Institute for Medical Immunology, and ULB Center for Research in Immunology, Gosselies, Belgium
| | - Thierry Guillaume
- CHU de Nantes, F-44000 Nantes, France
- INSERM UMR 1307, CRCI2NA IRS-UN, Nantes Université, Nantes, France
| | - Pierre Peterlin
- CHU de Nantes, F-44000 Nantes, France
- INSERM UMR 1307, CRCI2NA IRS-UN, Nantes Université, Nantes, France
| | - Alice Garnier
- CHU de Nantes, F-44000 Nantes, France
- INSERM UMR 1307, CRCI2NA IRS-UN, Nantes Université, Nantes, France
| | - Marie-Anne Vibet
- Department of Biostatistics, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France
| | - Maxence Mougon
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- LabEx IGO, Nantes University, Nantes, France
| | - Amandine Le Bourgeois
- CHU de Nantes, F-44000 Nantes, France
- INSERM UMR 1307, CRCI2NA IRS-UN, Nantes Université, Nantes, France
| | - Maxime Jullien
- CHU de Nantes, F-44000 Nantes, France
- INSERM UMR 1307, CRCI2NA IRS-UN, Nantes Université, Nantes, France
| | - Francine Jotereau
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- LabEx IGO, Nantes University, Nantes, France
| | - Frédéric Altare
- Nantes Université, Univ Angers, INSERM, CNRS, Immunology and New Concepts in ImmunoTherapy, INCIT,UMR 1302, F-44000 Nantes, France
- LabEx IGO, Nantes University, Nantes, France
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14
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Qin L, Li B, Wang S, Tang Y, Fahira A, Kou Y, Li T, Hu Z, Huang Z. Construction of an immune-related prognostic signature and lncRNA-miRNA-mRNA ceRNA network in acute myeloid leukemia. J Leukoc Biol 2024; 116:146-165. [PMID: 38393298 DOI: 10.1093/jleuko/qiae041] [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: 08/17/2023] [Revised: 01/22/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024] Open
Abstract
The progression of acute myeloid leukemia (AML) is influenced by the immune microenvironment in the bone marrow and dysregulated intracellular competing endogenous RNA (ceRNA) networks. Our study utilized data from UCSC Xena, The Cancer Genome Atlas Program, the Gene Expression Omnibus, and the Immunology Database and Analysis Portal. Using Cox regression analysis, we identified an immune-related prognostic signature. Genomic analysis of prognostic messenger RNA (mRNA) was conducted through Gene Set Cancer Analysis (GSCA), and a prognostic ceRNA network was constructed using the Encyclopedia of RNA Interactomes. Correlations between signature mRNAs and immune cell infiltration, checkpoints, and drug sensitivity were assessed using R software, gene expression profiling interactive analysis (GEPIA), and CellMiner, respectively. Adhering to the ceRNA hypothesis, we established a potential long noncoding RNA (lncRNA)/microRNA (miRNA)/mRNA regulatory axis. Our findings pinpointed 9 immune-related prognostic mRNAs (KIR2DL1, CSRP1, APOBEC3G, CKLF, PLXNC1, PNOC, ANGPT1, IL1R2, and IL3RA). GSCA analysis revealed the impact of copy number variations and methylation on AML. The ceRNA network comprised 14 prognostic differentially expressed lncRNAs (DE-lncRNAs), 6 prognostic DE-miRNAs, and 3 prognostic immune-related DE-mRNAs. Correlation analyses linked these mRNAs' expression to 22 immune cell types and 6 immune checkpoints, with potential sensitivity to 27 antitumor drugs. Finally, we identified a potential LINC00963/hsa-miR-431-5p/CSRP1 axis. This study offers innovative insights for AML diagnosis and treatment through a novel immune-related signature and ceRNA axis. Identified novel biomarkers, including 2 mRNAs (CKLF, PNOC), 1 miRNA (hsa-miR-323a-3p), and 10 lncRNAs (SNHG25, LINC01857, AL390728.6, AC127024.5, Z83843.1, AP002884.1, AC007038.1, AC112512, AC020659.1, AC005921.3) present promising candidates as potential targets for precision medicine, contributing to the ongoing advancements in the field.
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Affiliation(s)
- Ling Qin
- Department of Hematology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Jianxi District, Luoyang 471003, China
| | - Boya Li
- Department of Hematology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Jianxi District, Luoyang 471003, China
| | - Shijie Wang
- Department of Hematology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Jianxi District, Luoyang 471003, China
| | - Yulai Tang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, No. 1 Xincheng Road, Songshan Lake District, Dongguan 523808, Guangdong, China
| | - Aamir Fahira
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, No. 1 Xincheng Road, Songshan Lake District, Dongguan 523808, Guangdong, China
| | - Yanqi Kou
- Department of Hematology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Jianxi District, Luoyang 471003, China
| | - Tong Li
- Department of Hematology, The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, No. 24 Jinghua Road, Jianxi District, Luoyang 471003, China
| | - Zhigang Hu
- School of Medical Technology and Engineering, Henan University of Science and Technology, No.263 Kaiyuan Avenue, Luolong District, Luoyang 471000, China
| | - Zunnan Huang
- Key Laboratory of Big Data Mining and Precision Drug Design of Guangdong Medical University, Key Laboratory of Computer-Aided Drug Design of Dongguan City, Key Laboratory for Research and Development of Natural Drugs of Guangdong Province, School of Pharmacy, Guangdong Medical University, No. 1 Xincheng Road, Songshan Lake District, Dongguan 523808, Guangdong, China
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15
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Mathioudaki A, Wang X, Sedloev D, Huth R, Kamal A, Hundemer M, Liu Y, Vasileiou S, Lulla P, Müller-Tidow C, Dreger P, Luft T, Sauer T, Schmitt M, Zaugg JB, Pabst C. The remission status of AML patients after allo-HCT is associated with a distinct single-cell bone marrow T-cell signature. Blood 2024; 143:1269-1281. [PMID: 38197505 PMCID: PMC10997908 DOI: 10.1182/blood.2023021815] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 11/14/2023] [Accepted: 11/28/2023] [Indexed: 01/11/2024] Open
Abstract
ABSTRACT Acute myeloid leukemia (AML) is a hematologic malignancy for which allogeneic hematopoietic cell transplantation (allo-HCT) often remains the only curative therapeutic approach. However, incapability of T cells to recognize and eliminate residual leukemia stem cells might lead to an insufficient graft-versus-leukemia (GVL) effect and relapse. Here, we performed single-cell RNA-sequencing (scRNA-seq) on bone marrow (BM) T lymphocytes and CD34+ cells of 6 patients with AML 100 days after allo-HCT to identify T-cell signatures associated with either imminent relapse (REL) or durable complete remission (CR). We observed a higher frequency of cytotoxic CD8+ effector and gamma delta (γδ) T cells in CR vs REL samples. Pseudotime and gene regulatory network analyses revealed that CR CD8+ T cells were more advanced in maturation and had a stronger cytotoxicity signature, whereas REL samples were characterized by inflammatory tumor necrosis factor/NF-κB signaling and an immunosuppressive milieu. We identified ADGRG1/GPR56 as a surface marker enriched in CR CD8+ T cells and confirmed in a CD33-directed chimeric antigen receptor T cell/AML coculture model that GPR56 becomes upregulated on T cells upon antigen encounter and elimination of AML cells. We show that GPR56 continuously increases at the protein level on CD8+ T cells after allo-HCT and confirm faster interferon gamma (IFN-γ) secretion upon re-exposure to matched, but not unmatched, recipient AML cells in the GPR56+ vs GPR56- CD8+ T-cell fraction. Together, our data provide a single-cell reference map of BM-derived T cells after allo-HCT and propose GPR56 expression dynamics as a surrogate for antigen encounter after allo-HCT.
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Affiliation(s)
- Anna Mathioudaki
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Xizhe Wang
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - David Sedloev
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Richard Huth
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Aryan Kamal
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Michael Hundemer
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Yi Liu
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Spyridoula Vasileiou
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital-Texas Children's Hospital, Houston, TX
| | - Premal Lulla
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital-Texas Children's Hospital, Houston, TX
| | - Carsten Müller-Tidow
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Peter Dreger
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Thomas Luft
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Tim Sauer
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Michael Schmitt
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
| | - Judith B. Zaugg
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Caroline Pabst
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany
- Department of Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
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16
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Li F, Miao J, Liu R, Zhang R, He A. Pan-cancer analysis of DDIT4 identifying its prognostic value and function in acute myeloid leukemia. J Cancer Res Clin Oncol 2024; 150:144. [PMID: 38507057 PMCID: PMC10954950 DOI: 10.1007/s00432-024-05676-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 03/01/2024] [Indexed: 03/22/2024]
Abstract
BACKGROUND Acute myeloid leukemia (AML) is a hematological malignancy derived from the accumulation of abnormal proliferation of infantile leukocytes in the hematopoietic system. DNA-damage-inducible transcript 4 (DDIT4) acting as a negative regulator of rapamycin inhibitor is involved in various cellular functions. Many studies have suggested that DDIT4 plays a key role in tumorigenesis. However, the role of DDIT4 in AML has been poorly studied. METHOD In this study, we analyzed the expression of DDIT4 in AML patients using The Cancer Genome Atlas and real-time polymerase chain reaction. The Chi-square test was used to assess the correlation between DDIT4 and clinical characters in AML patients. Loss-of-function experiments were implemented to investigate the role of DDIT4 in AML carcinogenesis. The R package was applied to evaluate the correlation between DDIT4 expression and immune cells. RESULTS Results showed that the expression of DDIT4 was associated with Age, Cytogenetic risk, Cytogenetics and OS event. Moreover, high expression of DDIT4 led to a terrible prognosis. KEGG analysis showed that differently expressed genes (DEGs) were involved in the PI3-Akt signaling pathway. GSEA enrichment analysis displayed DEGs were correlated with apoptosis. Functional experiments presented that knocking down DDIT4 suppressed cell cycle transition/proliferation and facilitated apoptosis. In addition, DDIT4 is associated with immune infiltration. CONCLUSION Our research verified that DDIT4 can be used as a prognostic marker and a potential therapeutic target for AML.
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Affiliation(s)
- Fangmei Li
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 Xiwu Road, Lianhu District, Xi'an City, 710004, China
| | - Jiyu Miao
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 Xiwu Road, Lianhu District, Xi'an City, 710004, China
| | - Rui Liu
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 Xiwu Road, Lianhu District, Xi'an City, 710004, China
| | - Ru Zhang
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 Xiwu Road, Lianhu District, Xi'an City, 710004, China
| | - Aili He
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, NO.157 Xiwu Road, Lianhu District, Xi'an City, 710004, China.
- Xi'an Key Laboratory of Diagnosis and Treatment of Hematological Diseases, Xi'an, China.
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17
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Azizidoost S, Nasrolahi A, Sheykhi-Sabzehpoush M, Anbiyaiee A, Khoshnam SE, Farzaneh M, Uddin S. Signaling pathways governing the behaviors of leukemia stem cells. Genes Dis 2024; 11:830-846. [PMID: 37692500 PMCID: PMC10491880 DOI: 10.1016/j.gendis.2023.01.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 01/02/2023] [Indexed: 08/28/2023] Open
Abstract
Leukemia is a malignancy in the blood that develops from the lymphatic system and bone marrow. Although various treatment options have been used for different types of leukemia, understanding the molecular pathways involved in the development and progression of leukemia is necessary. Recent studies showed that leukemia stem cells (LSCs) play essential roles in the pathogenesis of leukemia by targeting several signaling pathways, including Notch, Wnt, Hedgehog, and STAT3. LSCs are highly proliferative cells that stimulate tumor initiation, migration, EMT, and drug resistance. This review summarizes cellular pathways that stimulate and prevent LSCs' self-renewal, metastasis, and tumorigenesis.
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Affiliation(s)
- Shirin Azizidoost
- Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Ava Nasrolahi
- Infectious Ophthalmologic Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Mohadeseh Sheykhi-Sabzehpoush
- Department of Laboratory, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran 2193672411, Iran
| | - Amir Anbiyaiee
- Department of Surgery, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Seyed Esmaeil Khoshnam
- Persian Gulf Physiology Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6193673111, Iran
| | - Shahab Uddin
- Translational Research Institute and Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha 3050, Qatar
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18
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Hu X, Cao D, Zhou Z, Wang Z, Zeng J, Hong WX. Single-cell transcriptomic profiling reveals immune cell heterogeneity in acute myeloid leukaemia peripheral blood mononuclear cells after chemotherapy. Cell Oncol (Dordr) 2024; 47:97-112. [PMID: 37615858 PMCID: PMC10899424 DOI: 10.1007/s13402-023-00853-2] [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: 07/31/2023] [Indexed: 08/25/2023] Open
Abstract
PURPOSE Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the rapid clonal expansion of abnormally differentiated myeloid progenitor cells residing in a complex microenvironment. However, the immune cell types, status, and genome profile of the peripheral blood mononuclear cell (PBMC) microenvironment in AML patients after chemotherapy are poorly understood. In order to explore the immune microenvironment of AML patients after chemotherapy, we conducted this study for providing insights into precision medicine and immunotherapy of AML. METHODS In this study, we used single-cell RNA sequencing (scRNA-seq) to analyse the PBMC microenvironment from five AML patients treated with different chemotherapy regimens and six healthy donors. We compared the cell compositions in AML patients and healthy donors, and performed gene set enrichment analysis (GSEA), CellPhoneDB, and copy number variation (CNV) analysis. RESULTS Using scRNA-seq technology, 91,772 high quality cells of 44,950 PBMCs from AML patients and 46,822 PBMCs from healthy donors were classified as 14 major cell clusters. Our study revealed the sub-cluster diversity of T cells, natural killer (NK) cells, monocytes, dendritic cells (DCs), and haematopoietic stem cell progenitors (HSC-Prog) in AML patients under chemotherapy. NK cells and monocyte-DCs showed significant changes in transcription factor expression and chromosome copy number variation (CNV). We also observed significant heterogeneity in CNV and intercellular interaction networks in HSC-Prog cells. CONCLUSION Our results elucidated the PBMC single-cell landscape and provided insights into precision medicine and immunotherapy for treating AML.
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Affiliation(s)
- Xuqiao Hu
- Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen, China.
- Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China.
| | - Dongyan Cao
- Department of Biliary-Pancreatic Surgery, the Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Zhenru Zhou
- Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen, China
- Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China
| | - Zhaoyang Wang
- Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen, China
- Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China
| | - Jieying Zeng
- Second Clinical Medical College of Jinan University, First Affiliated Hospital of Southern University of Science and Technology (Shenzhen People's Hospital), Shenzhen, China
| | - Wen-Xu Hong
- Shenzhen Center for Chronic Disease Control and Prevention, Shenzhen Institute of Dermatology, Shenzhen, China.
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19
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Chen H, Wang X, Wang Y, Chang X. What happens to regulatory T cells in multiple myeloma. Cell Death Discov 2023; 9:468. [PMID: 38129374 PMCID: PMC10739837 DOI: 10.1038/s41420-023-01765-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 12/03/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023] Open
Abstract
Abnormal tumor microenvironment and immune escape in multiple myeloma (MM) are associated with regulatory T cells (Tregs), which play an important role in maintaining self-tolerance and regulating the overall immune response to infection or tumor cells. In patients with MM, there are abnormalities in the number, function and distribution of Tregs, and these abnormalities may be related to the disease stage, risk grade and prognosis of patients. During the treatment, Tregs have different responses to various treatment regiments, thus affecting the therapeutic effect of MM. It is also possible to predict the therapeutic response by observing the changes of Tregs. In addition to the above, we reviewed the application of Tregs in the treatment of MM. In conclusion, there is still much room for research on the mechanism and application of Tregs in MM.
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Affiliation(s)
- Huixian Chen
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Department of Hematology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Xueling Wang
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
- Department of Gastroenterology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China
| | - Yan Wang
- Department of Pediatrics, Qilu Hospital of Shandong University, Jinan, 250012, China
| | - Xiaotian Chang
- Medical Research Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China.
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20
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Pospiech M, Tamizharasan M, Wei YC, Kumar AMS, Lou M, Milstein J, Alachkar H. Features of the TCR repertoire associate with patients' clinical and molecular characteristics in acute myeloid leukemia. Front Immunol 2023; 14:1236514. [PMID: 37928542 PMCID: PMC10620936 DOI: 10.3389/fimmu.2023.1236514] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 09/07/2023] [Indexed: 11/07/2023] Open
Abstract
Background Allogeneic hematopoietic stem cell transplant remains the most effective strategy for patients with high-risk acute myeloid leukemia (AML). Leukemia-specific neoantigens presented by the major histocompatibility complexes (MHCs) are recognized by the T cell receptors (TCR) triggering the graft-versus-leukemia effect. A unique TCR signature is generated by a complex V(D)J rearrangement process to form TCR capable of binding to the peptide-MHC. The generated TCR repertoire undergoes dynamic changes with disease progression and treatment. Method Here we applied two different computational tools (TRUST4 and MIXCR) to extract the TCR sequences from RNA-seq data from The Cancer Genome Atlas (TCGA) and examine the association between features of the TCR repertoire in adult patients with AML and their clinical and molecular characteristics. Results We found that only ~30% of identified TCR CDR3s were shared by the two computational tools. Yet, patterns of TCR associations with patients' clinical and molecular characteristics based on data obtained from either tool were similar. The numbers of unique TCR clones were highly correlated with patients' white blood cell counts, bone marrow blast percentage, and peripheral blood blast percentage. Multivariable regressions of TCRA and TCRB median normalized number of unique clones with mutational status of AML patients using TRUST4 showed significant association of TCRA or TCRB with WT1 mutations, WBC count, %BM blast, and sex (adjusted in TCRB model). We observed a correlation between TCRA/B number of unique clones and the expression of T cells inhibitory signal genes (TIGIT, LAG3, CTLA-4) and foxp3, but not IL2RA, CD69 and TNFRSF9 suggestive of exhausted T cell phenotypes in AML. Conclusion Benchmarking of computational tools is needed to increase the accuracy of the identified clones. The utilization of RNA-seq data enables identification of highly abundant TCRs and correlating these clones with patients' clinical and molecular characteristics. This study further supports the value of high-resolution TCR-Seq analyses to characterize the TCR repertoire in patients.
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Affiliation(s)
- Mateusz Pospiech
- Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Mukund Tamizharasan
- Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Department of Computer Science, University of Southern California, Los Angeles, CA, United States
| | - Yu-Chun Wei
- Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Advaith Maya Sanjeev Kumar
- Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Department of Computer Science, University of Southern California, Los Angeles, CA, United States
| | - Mimi Lou
- Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
| | - Joshua Milstein
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Houda Alachkar
- Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, United States
- Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States
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21
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Wang N. Analysis of prognostic biomarker models and immune microenvironment in acute myeloid leukemia by integrative bioinformatics. J Cancer Res Clin Oncol 2023; 149:9609-9619. [PMID: 37222809 DOI: 10.1007/s00432-023-04871-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 05/19/2023] [Indexed: 05/25/2023]
Abstract
BACKGROUND Acute myeloid leukemia (AML) is a hematological cancer driven on by aberrant myeloid precursor cell proliferation and differentiation. A prognostic model was created in this study to direct therapeutic care. METHODS Differentially expressed genes (DEGs) were investigated using the RNA-seq data from the TCGA-LAML and GTEx. Weighted Gene Coexpression Network Analysis (WGCNA) examines the genes involved in cancer. Find the intersection genes and construct the PPI network to discover hub genes and remove prognosis-related genes. A nomogram was produced for predicting the prognosis of AML patients using the risk prognosis model that was constructed using COX and Lasso regression analysis. GO, KEGG, and ssGSEA analysis were used to look into its biological function. TIDE score predicts immunotherapy response. RESULTS Differentially expressed gene analysis revealed 1004 genes, WGCNA analysis revealed 19,575 tumor-related genes, and 941 intersection genes in total. Twelve prognostic genes were found using the PPI network and prognostic analysis. To build a risk rating model, RPS3A and PSMA2 were examined using COX and Lasso regression analysis. The risk score was used to divide the patients into two groups, and Kaplan-Meier analysis indicated that the two groups had different overall survival rates. Univariate and multivariate COX studies demonstrated that risk score is an independent prognostic factor. According to the TIDE study, the immunotherapy response was better in the low-risk group than in the high-risk group. CONCLUSIONS We eventually selected out two molecules to construct prediction models that might be used as biomarkers for predicting AML immunotherapy and prognosis.
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Affiliation(s)
- Naihong Wang
- Lanzhou University Second Hospital, Gansu, 730000, China.
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22
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Damiani D, Tiribelli M. Checkpoint Inhibitors in Acute Myeloid Leukemia. Biomedicines 2023; 11:1724. [PMID: 37371818 PMCID: PMC10295997 DOI: 10.3390/biomedicines11061724] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Revised: 06/09/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
The prognosis of acute myeloid leukemia (AML) remains unsatisfactory. Among the reasons for the poor response to therapy and high incidence of relapse, there is tumor cell immune escape, as AML blasts can negatively influence various components of the immune system, mostly weakening T-cells. Since leukemic cells can dysregulate immune checkpoints (ICs), receptor-based signal transductors that lead to the negative regulation of T-cells and, eventually, to immune surveillance escape, the inhibition of ICs is a promising therapeutic strategy and has led to the development of so-called immune checkpoint inhibitors (ICIs). ICIs, in combination with conventional chemotherapy, hypomethylating agents or targeted therapies, are being increasingly tested in cases of AML, but the results reported are often conflicting. Here, we review the main issues concerning the immune system in AML, the main pathways leading to immune escape and the results obtained from clinical trials of ICIs, alone or in combination, in newly diagnosed or relapsed/refractory AML.
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Affiliation(s)
- Daniela Damiani
- Division of Hematology and Stem Cell Transplantation, Udine Hospital, 33100 Udine, Italy;
- Department of Medicine, Udine University, 33100 Udine, Italy
| | - Mario Tiribelli
- Division of Hematology and Stem Cell Transplantation, Udine Hospital, 33100 Udine, Italy;
- Department of Medicine, Udine University, 33100 Udine, Italy
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23
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Ma M, Xu L, Cui W, Huang Y, Chi G. FIBP is a prognostic biomarker and correlated with clinicalpathological characteristics and immune infiltrates in acute myeloid leukemia. Discov Oncol 2023; 14:97. [PMID: 37310595 DOI: 10.1007/s12672-023-00723-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/08/2023] [Indexed: 06/14/2023] Open
Abstract
Acute myeloid leukemia (AML) is one of the most common hematological malignancy that has a high recurrence rate. FIBP was reported to be highly expressed in multiple tumor types. However, its expression and role in acute myeloid leukemia remains largely unknown. The aim of this study was to clarify the role and value of FIBP in the diagnosis and prognosis, and to analyze its correlation with immune infiltration in acute myeloid leukemia by The Cancer Genome Atlas (TCGA) dataset. FIBP was highly expressed in AML samples compared to normal samples. The differentially expressed genes were identified between high and low expression of FIBP. The high FIBP expression group had poorer overall survival. FIBP was closely correlated with CD4, IL-10 and IL-2. The enrichment analysis indicated DEGs were mainly related to leukocyte migration, leukocyte cell-cell adhesion, myeloid leukocyte differentiation, endothelial cell proliferation and T cell tolerance induction. FIBP expression has significant correlation with infiltrating levels of various immune cells. FIBP could be a potential targeted therapy and prognostic biomarker associated with immune infiltrates for AML.
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Affiliation(s)
- Muya Ma
- Department of Hematology, Changzhi People's Hospital, The Affiliated Hospital of Changzhi Medical College, Changzhi, 046000, Shanxi, China
| | - Lingling Xu
- Department of Hematology, Yantai Yuhuangding Hospital, The Affiliated Hospital of Qingdao University, Shandong, 264000, Yantai, China
| | - Wenhua Cui
- Department of Hematology, Changzhi People's Hospital, The Affiliated Hospital of Changzhi Medical College, Changzhi, 046000, Shanxi, China
| | - Yan Huang
- Department of Biochemistry, Changzhi Medical College, Changazhi, 046000, Shanxi, China
| | - Gang Chi
- Department of Biochemistry, Changzhi Medical College, Changazhi, 046000, Shanxi, China.
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24
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Kotsiafti A, Giannakas K, Christoforou P, Liapis K. Progress toward Better Treatment of Therapy-Related AML. Cancers (Basel) 2023; 15:cancers15061658. [PMID: 36980546 PMCID: PMC10046015 DOI: 10.3390/cancers15061658] [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: 01/29/2023] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/30/2023] Open
Abstract
Therapy-related acute myeloid leukemia (t-AML) comprises 10-20% of all newly diagnosed cases of AML and is related to previous use of chemotherapy or ionizing radiotherapy for an unrelated malignant non-myeloid disorder or autoimmune disease. Classic examples include alkylating agents and topoisomerase II inhibitors, whereas newer targeted therapies such as poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors have emerged as causative agents. Typically, t-AML is characterized by adverse karyotypic abnormalities and molecular lesions that confer a poor prognosis. Nevertheless, there are also cases of t-AML without poor-risk features. The management of these patients remains controversial. We describe the causes and pathophysiology of t-AML, putting emphasis on its mutational heterogeneity, and present recent advances in its treatment including CPX-351, hypomethylating agent plus venetoclax combination, and novel, molecularly targeted agents that promise to improve the cure rates. Evidence supporting personalized medicine for patients with t-AML is presented, as well as the authors' clinical recommendations.
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Affiliation(s)
| | | | - Panagiotis Christoforou
- Pathophysiology Department, National and Kapodistrian University of Athens, 157 72 Athens, Greece
| | - Konstantinos Liapis
- Dragana Campus, Democritus University of Thrace Medical School, 681 00 Alexandroupolis, Greece
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25
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Hino C, Xu Y, Xiao J, Baylink DJ, Reeves ME, Cao H. The potential role of the thymus in immunotherapies for acute myeloid leukemia. Front Immunol 2023; 14:1102517. [PMID: 36814919 PMCID: PMC9940763 DOI: 10.3389/fimmu.2023.1102517] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Accepted: 01/20/2023] [Indexed: 02/09/2023] Open
Abstract
Understanding the factors which shape T-lymphocyte immunity is critical for the development and application of future immunotherapeutic strategies in treating hematological malignancies. The thymus, a specialized central lymphoid organ, plays important roles in generating a diverse T lymphocyte repertoire during the infantile and juvenile stages of humans. However, age-associated thymic involution and diseases or treatment associated injury result in a decline in its continuous role in the maintenance of T cell-mediated anti-tumor/virus immunity. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy that mainly affects older adults, and the disease's progression is known to consist of an impaired immune surveillance including a reduction in naïve T cell output, a restriction in T cell receptor repertoire, and an increase in frequencies of regulatory T cells. As one of the most successful immunotherapies thus far developed for malignancy, T-cell-based adoptive cell therapies could be essential for the development of a durable effective treatment to eliminate residue leukemic cells (blasts) and prevent AML relapse. Thus, a detailed cellular and molecular landscape of how the adult thymus functions within the context of the AML microenvironment will provide new insights into both the immune-related pathogenesis and the regeneration of a functional immune system against leukemia in AML patients. Herein, we review the available evidence supporting the potential correlation between thymic dysfunction and T-lymphocyte impairment with the ontogeny of AML (II-VI). We then discuss how the thymus could impact current and future therapeutic approaches in AML (VII). Finally, we review various strategies to rejuvenate thymic function to improve the precision and efficacy of cancer immunotherapy (VIII).
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Affiliation(s)
- Christopher Hino
- Department of Internal Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Yi Xu
- Division of Hematology and Oncology, Department of Medicine, Loma Linda University, Loma Linda, CA, United States.,Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, United States.,Loma Linda University Cancer Center, Loma Linda, CA, United States
| | - Jeffrey Xiao
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - David J Baylink
- Division of Regenerative Medicine, Department of Medicine, Loma Linda University, Loma Linda, CA, United States
| | - Mark E Reeves
- Division of Hematology and Oncology, Department of Medicine, Loma Linda University, Loma Linda, CA, United States.,Loma Linda University Cancer Center, Loma Linda, CA, United States
| | - Huynh Cao
- Division of Hematology and Oncology, Department of Medicine, Loma Linda University, Loma Linda, CA, United States.,Loma Linda University Cancer Center, Loma Linda, CA, United States
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26
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Sun H, Ren Y, Zhou X, Chen Q, Liu Y, Zhu C, Ruan Y, Ruan H, Tong H, Ying S, Lin P. DUSP1 Signaling Pathway Regulates Cytarabine Sensitivity in Acute Myeloid Leukemia. Technol Cancer Res Treat 2023; 22:15330338231207765. [PMID: 37872685 PMCID: PMC10594969 DOI: 10.1177/15330338231207765] [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: 06/12/2023] [Revised: 07/30/2023] [Accepted: 08/23/2023] [Indexed: 10/25/2023] Open
Abstract
Objectives: Dual specificity phosphatase 1 (DUSP1) is high-expressed in various cancers and plays an important role in the cellular response to agents that damage DNA. We aimed to investigate the expressions and mechanisms of DUSP1 signaling pathway regulating cytarabine (Ara-C) resistance in acute myeloid leukemia (AML). Methods: Immunohistochemistry was performed on bone marrow biopsy specimens from AML and controls to explore the expression of DUSP1. Western blot and Q-PCR were used to detect the protein and mRNA expression levels. MTT assay was used to detect the proliferation of cells. Cell apoptosis was detected by flow cytometry. The immune protein-protein interaction (PPI) network of DUSP1 was analyzed in the platform of Pathway Commons, and immune infiltration analysis was used to study the immune microenvironment of AML. Results: We found that the expression levels of DUSP1 in AML patients exceeded that in controls. Survival analysis in public datasets showed that AML patients with higher levels of DUSP1 had poor clinical outcomes. Further public data analysis indicated that DUSP1 was overexpressed in NRAS mutated AML. DUSP1 knockdown by siRNA could sensitize AML cells to Ara-C treatments. The phosphorylation level of mitogen-activated protein kinase (MAPK) pathway was significantly elevated in DUSP1 down-regulated NRAS G13D mutated AML cells. The PPI analysis showed DUSP1 correlated with immune gene CREB1 and CXCL8 in NRAS mutated AML. We also revealed a correlation between tumor-infiltrating immune cells in RAS mutated AML microenvironment. Conclusion: Our findings suggest that DUSP1 signaling pathways may regulate Ara-C sensitivity in AML.
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Affiliation(s)
- Huali Sun
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Yanling Ren
- Myelodysplastic Syndrome Center, Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Xinping Zhou
- Myelodysplastic Syndrome Center, Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Qi Chen
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Yanmei Liu
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Chumeng Zhu
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Yanyun Ruan
- Precision Medicine Center, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Hongli Ruan
- Department of Emergency Medicine, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Hongyan Tong
- Myelodysplastic Syndrome Center, Department of Hematology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Shenpeng Ying
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
| | - Peipei Lin
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, Zhejiang, China
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27
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Ren Z, Huang X, Lv Q, Lei Y, Shi H, Wang F, Wang M. High expression of B4GALT1 is associated with poor prognosis in acute myeloid leukemia. Front Genet 2022; 13:882004. [PMID: 36568388 PMCID: PMC9780537 DOI: 10.3389/fgene.2022.882004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 11/28/2022] [Indexed: 12/13/2022] Open
Abstract
Acute myeloid leukemia is the most prevalent type of leukemia in adults and is prone to relapse and chemoresistance, with a low long-term survival rate. Therefore, the identification of quality biomarkers constitutes an urgent unmet need. High expression of beta-1,4-galactosyltransferase 1 (B4GALT1) has been observed in several cancer types; however, its function in acute myeloid leukemia has rarely been studied. Therefore, our study obtained gene expression data from The Cancer Genome Atlas (TCGA) database to analyze the relationship between B4GALT1 and LAML. We compared the expression of B4GALT1 in LAML and healthy samples using the Wilcoxon rank-sum test. Furthermore, the association between B4GALT1 and survival rates was investigated using Kaplan-Meier analysis and Cox regression. The nomogram obtained by Cox analysis predicts the effect of B4GALT1 on the prognosis. To assess B4GALT1-related genes' enrichment pathway and function and the correlation between B4GALT1 and immune features, GO/KEGG, protein-protein interaction network, and single sample gene set enrichment analysis were used. In addition, B4GALT1-specific siRNAs were used to verify the effect of B4GALT1 on apoptosis. The results showed that B4GALT1 is overexpressed in LAML and has some reference value in the diagnostic and prognostic assessment of LAML. Moreover, functional enrichment showed that B4GALT1 and its 63 associated genes were closely associated with the negative regulation of the apoptotic signaling pathway. Silencing B4GALT1 significantly promoted apoptosis. In addition, B4GALT1 expression was positively correlated with the infiltration levels of macrophages, regulatory T-cell (Tregs), and Th17 cells; in contrast, B4GALT1 expression was negatively correlated with the infiltration levels of T helper cells, Mast cells, and NK cells. In conclusion, our study shows that B4GALT1 may play a vital role in the occurrence of LAML.
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Affiliation(s)
- Zhihong Ren
- School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Xiaoyu Huang
- Henan Key Laboratory of Immunology and Targeted Drug, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Qing Lv
- School of Nursing and Health, Hennan University, Kaifeng, China
| | - Yiming Lei
- School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China
| | - Haiqiang Shi
- School of Public Health, Xinxiang Medical University, Xinxiang, China
| | - Fanping Wang
- School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China,*Correspondence: Fanping Wang, ; Mingyong Wang,
| | - Mingyong Wang
- School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China,Xinxiang Key Laboratory of Immunoregulation and Molecular Diagnostics, Xinxiang Medical University, Xinxiang, China,*Correspondence: Fanping Wang, ; Mingyong Wang,
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28
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Huang K, Xie L, Wang F. A Novel Defined Pyroptosis-Related Gene Signature for the Prognosis of Acute Myeloid Leukemia. Genes (Basel) 2022; 13:2281. [PMID: 36553549 PMCID: PMC9778227 DOI: 10.3390/genes13122281] [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: 10/11/2022] [Revised: 11/22/2022] [Accepted: 11/26/2022] [Indexed: 12/12/2022] Open
Abstract
Pyroptosis is an inflammatory form of programmed necrotic cell death, but its potential prognostic value in acute myeloid leukemia (AML) remains unclear. On the basis of available AML data from TCGA and TARGET databases, a 10-gene signature model was constructed to effectively predict AML prognosis by performing LASSO Cox regression analysis, which showed that patients with a low-risk score had a significantly better prognosis than that of the high-risk group, and receiver operator characteristic (ROC) analysis achieved superior performance in the prognostic model. The model was further well-verified in an external GEO cohort. Multivariable Cox regression analysis showed that, in addition to age, the risk score was an independent poor survival factor for AML patients, and a nomogram model was constructed with high accuracy. Moreover, the high-risk group generally had higher cytolytic activity and increased levels of infiltrating immune cells, including tumor-infiltrating lymphocytes (TILs) and regulatory T cells (Tregs), which could be related to the expression of immune checkpoint genes. Additionally, low-risk AML patients may have a better response from traditional chemotherapeutic drugs. In conclusion, a pyroptosis-related gene signature can independently predict the prognosis of AML patients with sufficient predictive power, and pyroptosis plays an important role in the immune microenvironment of AML, which may be used to develop a new effective therapeutic method for AML in the future.
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Affiliation(s)
- Kecheng Huang
- Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Linka Xie
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Fan Wang
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
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29
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Rahmani S, Yazdanpanah N, Rezaei N. Natural killer cells and acute myeloid leukemia: promises and challenges. Cancer Immunol Immunother 2022; 71:2849-2867. [PMID: 35639116 PMCID: PMC10991240 DOI: 10.1007/s00262-022-03217-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 04/26/2022] [Indexed: 10/18/2022]
Abstract
Acute myeloid leukemia (AML) is considered as one of the most malignant conditions of the bone marrow. Over the past few decades, despite substantial progresses in the management of AML, relapse remission remains a major problem. Natural killer cells (NK cells) are known as a unique component of the innate immune system. Due to swift tumor detection, distinct cytotoxic action, and extensive immune interaction, NK cells have been used in various cancer settings for decades. It has been a growing knowledge of therapeutic magnitudes ranging from adoptive NK cell transfer to chimeric antigen receptor NK cells, aiming to achieve better therapeutic responses in patients with AML. In this article, the potentials of NK cells for treatment of AML are highlighted, and challenges for such therapeutic methods are discussed. In addition, the clinical application of NK cells, mainly in patients with AML, is pictured according to the existing evidence.
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Affiliation(s)
- Shayan Rahmani
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niloufar Yazdanpanah
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center Hospital, Tehran University of Medical Sciences, Dr. Qarib St, Keshavarz Blvd, Tehran, 14194, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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30
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Sun K, Xu Y, Zhang L, Niravath P, Darcourt J, Patel T, Teh BS, Farach AM, Guerrero C, Mathur S, Sultenfuss MA, Gupta N, Schwartz MR, Haley SL, Nair S, Li X, Nguyen TTA, Butner JD, Ensor J, Mejia JA, Mei Z, Butler EB, Chen SH, Bernicker EH, Chang JC. A Phase 2 Trial of Enhancing Immune Checkpoint Blockade by Stereotactic Radiation and In Situ Virus Gene Therapy in Metastatic Triple-Negative Breast Cancer. Clin Cancer Res 2022; 28:4392-4401. [PMID: 35877117 PMCID: PMC9561553 DOI: 10.1158/1078-0432.ccr-22-0622] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/06/2022] [Accepted: 07/21/2022] [Indexed: 01/07/2023]
Abstract
PURPOSE A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. PATIENTS AND METHODS In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. RESULTS Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. CONCLUSIONS The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.
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Affiliation(s)
- Kai Sun
- Houston Methodist Neal Cancer Center, Houston, Texas
| | - Yitian Xu
- Houston Methodist Research Institute, Center for Immunotherapy Research, Houston, Texas
| | - Licheng Zhang
- Houston Methodist Research Institute, Center for Immunotherapy Research, Houston, Texas
| | | | | | - Tejal Patel
- Houston Methodist Neal Cancer Center, Houston, Texas
| | - Bin S. Teh
- Department of Radiation Oncology, Houston Methodist Hospital, Houston, Texas
| | - Andrew M. Farach
- Department of Radiation Oncology, Houston Methodist Hospital, Houston, Texas
| | | | - Sunil Mathur
- Houston Methodist Neal Cancer Center, Houston, Texas
| | | | - Nakul Gupta
- Department of Radiology, Houston Methodist Hospital, Houston, Texas
| | - Mary R. Schwartz
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas
| | - Susan L. Haley
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas
| | - Sindhu Nair
- Houston Methodist Neal Cancer Center, Houston, Texas
| | - Xiaoxian Li
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia
| | - Thi Truc Anh Nguyen
- Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia
| | - Joseph D. Butner
- Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, Texas
| | - Joe Ensor
- Houston Methodist Neal Cancer Center, Houston, Texas
| | | | - Zhuyong Mei
- Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas
| | - E. Brian Butler
- Department of Radiation Oncology, Houston Methodist Hospital, Houston, Texas
| | - Shu-hsia Chen
- Houston Methodist Research Institute, Center for Immunotherapy Research, Houston, Texas
| | | | - Jenny C. Chang
- Houston Methodist Neal Cancer Center, Houston, Texas.,Corresponding Author: Jenny C. Chang, Houston Methodist Research Institute, 6445 Main Street, Floor 24, Houston, TX 77030. Phone: 713-441-9948; Fax: 713-441-8791; E-mail:
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Li P, Li J, Wen F, Cao Y, Luo Z, Zuo J, Wu F, Li Z, Li W, Wang F. A novel cuproptosis-related LncRNA signature: Prognostic and therapeutic value for acute myeloid leukemia. Front Oncol 2022; 12:966920. [PMID: 36276132 PMCID: PMC9585311 DOI: 10.3389/fonc.2022.966920] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Accepted: 09/23/2022] [Indexed: 11/24/2022] Open
Abstract
Background Cuproptosis is a type of programmed cell death that is involved in multiple physiological and pathological processes, including cancer. We constructed a prognostic cuproptosis-related long non-coding RNA (lncRNA) signature for acute myeloid leukemia (AML). Methods RNA-seq and clinical data for AML patients were acquired from The Cancer Genome Atlas (TCGA) database. The cuproptosis-related prognostic lncRNAs were identified by co-expression and univariate Cox regression analysis. The least absolute shrinkage and selection operator (LASSO) was performed to construct a cuproptosis-related lncRNA signature, after which the AML patients were classified into two risk groups based on the risk model. Kaplan-Meier, ROC, univariate and multivariate Cox regression, nomogram, and calibration curves analyses were used to evaluate the prognostic value of the model. Then, expression levels of the lncRNAs in the signature were investigated in AML samples by quantitative polymerase chain reaction (qPCR). KEGG functional analysis, single-sample GSEA (ssGSEA), and the ESTIMATE algorithm were used to analyze the mechanisms and immune status between the different risk groups. The sensitivities for potential therapeutic drugs for AML were also investigated. Results Five hundred and three lncRNAs related to 19 CRGs in AML samples from the TCGA database were obtained, and 21 differentially expressed lncRNAs were identified based on the 2-year overall survival (OS) outcomes of AML patients. A 4-cuproptosis-related lncRNA signature for survival was constructed by LASSO Cox regression. High-risk AML patients exhibited worse outcomes. Univariate and multivariate Cox regression analyses demonstrated the independent prognostic value of the model. ROC, nomogram, and calibration curves analyses revealed the predictive power of the signature. KEGG pathway and ssGSEA analyses showed that the high-risk group had higher immune activities. Lastly, AML patients from different risk groups showed differential responses to various agents. Conclusion A cuproptosis-related lncRNA signature was established to predict the prognosis and inform on potential therapeutic strategies for AML patients.
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Affiliation(s)
- Pian Li
- The First Affiliated Hospital, Department of Oncology Radiotherapy, Hengyang Medical School, University of South China, Hengyang, China
| | - Junjun Li
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, Hengyang, China
| | - Feng Wen
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, Hengyang, China
| | - Yixiong Cao
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, Hengyang, China
| | - Zeyu Luo
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, Hengyang, China
| | - Juan Zuo
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, Hengyang, China
| | - Fei Wu
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, Hengyang, China
| | - Zhiqin Li
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, Hengyang, China
| | - Wenlu Li
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, Hengyang, China
| | - Fujue Wang
- The First Affiliated Hospital, Department of Hematology, Hengyang Medical School, University of South China, Hengyang, China
- Department of Hematology, West China Hospital of Sichuan University, Chengdu, China
- *Correspondence: Fujue Wang,
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Mohty R, Al Hamed R, Bazarbachi A, Brissot E, Nagler A, Zeidan A, Mohty M. Treatment of myelodysplastic syndromes in the era of precision medicine and immunomodulatory drugs: a focus on higher-risk disease. J Hematol Oncol 2022; 15:124. [PMID: 36045390 PMCID: PMC9429775 DOI: 10.1186/s13045-022-01346-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 08/22/2022] [Indexed: 11/22/2022] Open
Abstract
Myelodysplastic syndromes (MDS) are a heterogeneous clonal disease of myeloid neoplasms characterized by ineffective hematopoiesis, variable degree of cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). Molecular and genetic characterization of MDS has led to a better understanding of the disease pathophysiology and is leading to the development of novel therapies. Targeted and immune therapies have shown promising results in different hematologic malignancies. However, their potential use in MDS is yet to be fully defined. Here, we review the most recent advances in therapeutic approaches in MDS, focusing on higher-risk disease. Allogeneic hematopoietic cell transplantation is beyond the scope of this article.
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Affiliation(s)
- Razan Mohty
- Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL, USA
| | - Rama Al Hamed
- Department of Internal Medicine, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA
| | - Ali Bazarbachi
- Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Eolia Brissot
- Department of Clinical Hematology and Cellular Therapy, Saint-Antoine Hospital, AP-HP, Sorbonne University, and INSERM, Saint-Antoine Research Centre, 75012, Paris, France
| | - Arnon Nagler
- Hematology and Bone Marrow Transplant Unit, Chaim Sheba Medical Center, Tel Hashomer, Israel
| | - Amer Zeidan
- Division of Hematology/Oncology, Department of Internal Medicine, Yale School of Medicine, Yale University, New Haven, CT, USA
| | - Mohamad Mohty
- Department of Clinical Hematology and Cellular Therapy, Saint-Antoine Hospital, AP-HP, Sorbonne University, and INSERM, Saint-Antoine Research Centre, 75012, Paris, France.
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Guo X, Zhou X. Risk stratification of acute myeloid leukemia: Assessment using a novel prediction model based on ferroptosis-immune related genes. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2022; 19:11821-11839. [PMID: 36653976 DOI: 10.3934/mbe.2022551] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Abstract
In acute myeloid leukemia (AML), the link between ferroptosis and the immune microenvironment has profound clinical significance. The objective of this study was to investigate the role of ferroptosis-immune related genes (FIRGs) in predicting the prognosis and therapeutic sensitivity in patients with AML. Using The Cancer Genome Atlas dataset, single sample gene set enrichment analysis was performed to calculate the ferroptosis score of AML samples. To search for FIRGs, differentially expressed genes between the high- and low-ferroptosis score groups were identified and then cross-screened with immune related genes. Univariate Cox and LASSO regression analyses were performed on the FIRGs to establish a prognostic risk score model with five signature FIRGs (BMP2, CCL3, EBI3, ELANE, and S100A6). The prognostic risk score model was then used to divide the patients into high- and low-risk groups. For external validation, two Gene Expression Omnibus cohorts were employed. Overall survival was poorer in the high-risk group than in the low-risk group. The novel risk score model was an independent prognostic factor for overall survival in patients with AML. Infiltrating immune cells were also linked to high-risk scores. Treatment targeting programmed cell death protein 1 may be more effective in high-risk patients. This FIRG-based prognostic risk model may aid in optimizing prognostic risk stratification and treatment of AML.
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Affiliation(s)
- Xing Guo
- Department of Hematology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China
| | - Xiaogang Zhou
- Department of Hematology, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing 210000, China
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Ding H, Feng Y, Xu J, Lin Z, Huang J, Wang F, Luo H, Gao Y, Zhai X, Wang X, Zhang L, Niu T, Zheng Y. A novel immune prognostic model of non-M3 acute myeloid leukemia. Am J Transl Res 2022; 14:5308-5325. [PMID: 36105048 PMCID: PMC9452334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 07/03/2022] [Indexed: 06/15/2023]
Abstract
Acute myeloid leukemia (AML) is a common hematological malignancy in adults. AML patients exhibit clinical heterogeneity with complications of molecular basis. The leukemogenesis of AML involves immune escape, and the immunosuppression status of the patient might have great impact on AML treatment outcome. In this study, we established an immune prognostic model of AML using bioinformatics tools. With the data in the TCGA and GTEx datasets, we analyzed differentially expressed genes (DEGs) in non-M3 AML and identified 420 immune-related DEGs. Among which, 49 genes' expression was found to be related to AML prognosis based on univariate Cox regression analysis. Next, we established a prognostic model with these 49 genes in AML by LASSO regression and multivariate Cox regression analyses. In our model, the expressions of 5 immune genes, MIF, DEF6, OSM, MPO, AVPR1B, were used to stratify non-M3 AML patients' treatment outcome. A patient's risk score could be calculated as Risk Score=0.40081 × MIF (MIF expression) - 0.15201 × MPO + 0.78073 × DEF6 - 0.45192 × AVPR1B + 0.25912 × OSM. The area under the curve of the risk score signature was 0.8, 0.8, and 0.96 at 1 year, 3 years, and 5 years, respectively. The prognostic model was then validated internally by TCGA data and externally by GEO data. At last, the result of single-sample gene-set enrichment analysis demonstrated that compared with healthy samples, the abundance of non-turmeric immune cells was significantly repressed in AML. To summarize, we presented an immune-related 5-gene signature prognostic model in AML.
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Affiliation(s)
- Hong Ding
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Yu Feng
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Juan Xu
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Zhimei Lin
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
- Department of Hematology, The Affiliated Hospital of Chengdu UniversityChengdu 610081, Sichuan, China
| | - Jingcao Huang
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Fangfang Wang
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Hongmei Luo
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Yuhan Gao
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Xinyu Zhai
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Xin Wang
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Li Zhang
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Ting Niu
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
| | - Yuhuan Zheng
- Department of Hematology, West China Hospital, Sichuan UniversityChengdu 610041, Sichuan, China
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Tao Y, Wei L, You H. Ferroptosis-related gene signature predicts the clinical outcome in pediatric acute myeloid leukemia patients and refines the 2017 ELN classification system. Front Mol Biosci 2022; 9:954524. [PMID: 36032681 PMCID: PMC9403410 DOI: 10.3389/fmolb.2022.954524] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 07/08/2022] [Indexed: 11/16/2022] Open
Abstract
Background: The prognostic roles of ferroptosis-related mRNAs (FG) and lncRNAs (FL) in pediatric acute myeloid leukemia (P-AML) patients remain unclear. Methods: RNA-seq and clinical data of P-AML patients were downloaded from the TARGET project. Cox and LASSO regression analyses were performed to identify FG, FL, and FGL (combination of FG and FL) prognostic models, and their performances were compared. Tumor microenvironment, functional enrichment, mutation landscape, and anticancer drug sensitivity were analyzed. Results: An FGL model of 22 ferroptosis-related signatures was identified as an independent parameter, and it showed performance better than FG, FL, and four additional public prognostic models. The FGL model divided patients in the discovery cohort (N = 145), validation cohort (N = 111), combination cohort (N = 256), and intermediate-risk group (N = 103) defined by the 2017 European LeukemiaNet (ELN) classification system into two groups with distinct survival. The high-risk group was enriched in apoptosis, hypoxia, TNFA signaling via NFKB, reactive oxygen species pathway, oxidative phosphorylation, and p53 pathway and associated with low immunity, while patients in the low-risk group may benefit from anti-TIM3 antibodies. In addition, patients within the FGL high-risk group might benefit from treatment using SB505124_1194 and JAK_8517_1739. Conclusion: Our established FGL model may refine and provide a reference for clinical prognosis judgment and immunotherapies for P-AML patients.
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Affiliation(s)
- Yu Tao
- Department of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
| | - Li Wei
- NHC Key Laboratory of Birth Defects and Reproductive Health, Chongqing Population and Family Planning Science and Technology Research Institute, Chongqing, China
| | - Hua You
- Department of Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China
- *Correspondence: Hua You,
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Leukemia derived dendritic cell (DC leu) mediated immune response goes along with reduced (leukemia-specific) regulatory T-cells. Immunobiology 2022; 227:152237. [PMID: 35749805 DOI: 10.1016/j.imbio.2022.152237] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 05/18/2022] [Accepted: 06/07/2022] [Indexed: 12/17/2022]
Abstract
The blastmodulatory Kit-M, composed of granulocyte-macrophage colony-stimulating-factor (GM-CSF) and Prostaglandin E1 (PGE1), is known to convert myeloid leukaemic blasts (from AML patients) into leukaemia derived dendritic cells (DCleu), which activate immunoreactive cells to gain antileukemic/leukaemia-specific activity. In this study we had a special focus on the influence of Kit-M treated, DC/DCleu containing patients'whole blood (WB, n = 16) on the provision of immunosuppressive regulatory T-cells. We could confirm that Kit-M significantly increased frequencies of (mature) dendritic cells (DC) and DCleu from leukemic whole blood (WB) without induction of blast proliferation. After mixed lymphocyte culture (MLC) with patients' T-cells we confirmed that DCleu mediated leukemia-specific responses- going along with activated and leukemia-specific T- and NK-cells in an intracellular cytokine staining assay (ICS) and a degranulation assay (Deg)- resulted in an increased anti-leukemic cytotoxicity (Cytotoxicity Fluorolysis Assay = CTX). We could demonstrate that (leukemia-specific) CD4+ and CD8+ regulatory T-cell population (Treg) decreased significantly after MLC compared to controls. We found significant positive correlations of leukemia-specific CD3+CD4+ cells with frequencies of (mature) DCleu. Achieved anti-leukemic cytotoxicity correlated significantly positive with leukemia-specific CD3+CD8+ cells and significantly negatively with (leukemia-specific) Treg. In summary we demonstrate that immunesuppressive (leukemia-specific) regulatory T-cells are significantly downregulated after Kit-M triggered MLC- going along with a (reinstalled) antileukemic reactivity of the immune system (as demonstrated with functional assays ICS, Deg, CTX).
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37
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Xu Q, Guo T. Somatic mutation-associated risk index based on lncRNA expression for predicting prognosis in acute myeloid leukemia. Hematology 2022; 27:659-671. [PMID: 35666642 DOI: 10.1080/16078454.2022.2056677] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Objectives: Genomic instability has several implications for acute myeloid leukemia (AML) prognosis. This article aims to construct a somatic mutation-associated risk index (SMRI) of genomic instability for AML to predict prognosis and explore the potential determinants of AML prognosis.Methods: We obtained differentially expressed lncRNAs from genomic instability subtypes and selected six lncRNAs to construct the SMRI through multivariate Cox regression analysis. The median SMRI classified patients into high and low SMRI groups. Kaplan-Meier survival analysis was used to clarify the prognostic differences of SMRI subtypes. Receiver operating characteristic curve analysis was performed to elucidate the value of SMRI as a prognostic indicator. Gene set variation analysis, tumor mutation burden (TMB) analysis, immune infiltration, and immune checkpoint expression analysis were performed to investigate possible causes for the differences in prognosis of SMRI subtypes.Results: The high SMRI group exhibited a poor prognosis, which was characterized by elevated levels of TMB, mutation counts (TP53, NPM1, DNMT3A, and FLT3-TKD), CD8+ T cell infiltration, and immune checkpoint (PD-1, PD-L2, CTLA4, LAG3) expression. The SMRI was still associated with prognosis, even after adjustment for age, sex, cytogenetic risk, DNMT3A status, FLT3 status, and NPM1 status. Gene set variation analysis showed that AML with FLT3-ITD mutation, CEBPA mutation, and LSCs (leukemia stem cells) were enriched in the high SMRI group.Conclusion: Our research suggests that the SMRI derived from genomic instability subtypes is a useful biomarker for predicting prognosis and may be beneficial for improving the clinical outcome of patients with AML.
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Affiliation(s)
- Qiang Xu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Tao Guo
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.,Collaborative Innovation Center of Hematology, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Xu Z, Jin Y, Zhang X, Xia P, Wen X, Ma J, Lin J, Qian J. Pan-cancer analysis identifies CD300 molecules as potential immune regulators and promising therapeutic targets in acute myeloid leukemia. Cancer Med 2022; 12:789-807. [PMID: 35642341 PMCID: PMC9844665 DOI: 10.1002/cam4.4905] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 02/10/2022] [Accepted: 05/24/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND CD300s are a group of proteins playing vital roles in immune responses. However, much is yet to be elucidated regarding the expression patterns and clinical significances of CD300s in cancers. METHODS In this study, we comprehensively investigated CD300s in a pan-cancer manner using multi-omic data from The Cancer Genome Atlas. We also studied the relationship between CD300s and the immune landscape of AML. RESULTS We found that CD300A-CD300LF were generally overexpressed in tumors (especially AML), whereas CD300LG was more often downregulated. In AML, transactivation of CD300A was not mediated by genetic alterations but by histone modification. Survival analyses revealed that high CD300A-CD300LF expression predicted poor outcome in AML patients; the prognostic value of CD300A was validated in seven independent datasets and a meta dataset including 1115 AML patients. Furthermore, we demonstrated that CD300A expression could add prognostic value in refining existing risk models in AML. Importantly, CD300A-CD300LF expression was closely associated with T-cell dysfunction score and could predict response to AML immunotherapy. Also, CD300A was found to be positively associated with HLA genes and critical immune checkpoints in AML, such as VISTA, CD86, CD200R1, Tim-3, and the LILRB family genes. CONCLUSIONS Our study demonstrated CD300s as potential prognostic biomarker and an ideal immunotherapy target in AML, which warrants future functional and clinical studies.
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Affiliation(s)
- Zi‐jun Xu
- Laboratory CenterAffiliated People's Hospital of Jiangsu UniversityZhenjiangJiangsuPeople's Republic of China,Zhenjiang Clinical Research Center of HematologyZhenjiangJiangsuPeople's Republic of China,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang CityZhenjiangJiangsuPeople's Republic of China
| | - Ye Jin
- Zhenjiang Clinical Research Center of HematologyZhenjiangJiangsuPeople's Republic of China,Department of HematologyAffiliated People's Hospital of Jiangsu UniversityZhenjiangJiangsuPeople's Republic of China
| | - Xin‐long Zhang
- Department of HematologyThe People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong UniversityDanyangJiangsuPeople's Republic of China
| | - Pei‐hui Xia
- Laboratory CenterAffiliated People's Hospital of Jiangsu UniversityZhenjiangJiangsuPeople's Republic of China,Zhenjiang Clinical Research Center of HematologyZhenjiangJiangsuPeople's Republic of China,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang CityZhenjiangJiangsuPeople's Republic of China
| | - Xiang‐mei Wen
- Laboratory CenterAffiliated People's Hospital of Jiangsu UniversityZhenjiangJiangsuPeople's Republic of China,Zhenjiang Clinical Research Center of HematologyZhenjiangJiangsuPeople's Republic of China,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang CityZhenjiangJiangsuPeople's Republic of China
| | - Ji‐chun Ma
- Laboratory CenterAffiliated People's Hospital of Jiangsu UniversityZhenjiangJiangsuPeople's Republic of China,Zhenjiang Clinical Research Center of HematologyZhenjiangJiangsuPeople's Republic of China,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang CityZhenjiangJiangsuPeople's Republic of China
| | - Jiang Lin
- Laboratory CenterAffiliated People's Hospital of Jiangsu UniversityZhenjiangJiangsuPeople's Republic of China,Zhenjiang Clinical Research Center of HematologyZhenjiangJiangsuPeople's Republic of China,The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang CityZhenjiangJiangsuPeople's Republic of China
| | - Jun Qian
- Zhenjiang Clinical Research Center of HematologyZhenjiangJiangsuPeople's Republic of China,Department of HematologyThe People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong UniversityDanyangJiangsuPeople's Republic of China
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Pompura SL, Hafler DA, Dominguez-Villar M. Fatty Acid Metabolism and T Cells in Multiple Sclerosis. Front Immunol 2022; 13:869197. [PMID: 35603182 PMCID: PMC9116144 DOI: 10.3389/fimmu.2022.869197] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/30/2022] [Indexed: 11/25/2022] Open
Abstract
Cellular metabolic remodeling is intrinsically linked to the development, activation, differentiation, function, and survival of T cells. T cells transition from a catabolic, naïve state to an anabolic effector state upon T cell activation. Subsequently, specialization of T cells into T helper (Th) subsets, including regulatory T cells (Treg), requires fine-tuning of metabolic programs that better support and optimize T cell functions for that particular environment. Increasingly, studies have shown that changes in nutrient availability at both the cellular and organismal level during disease states can alter T cell function, highlighting the importance of better characterizing metabolic-immune axes in both physiological and disease settings. In support of these data, a growing body of evidence is emerging that shows specific lipid species are capable of altering the inflammatory functional phenotypes of T cells. In this review we summarize the metabolic programs shown to support naïve and effector T cells, and those driving Th subsets. We then discuss changes to lipid profiles in patients with multiple sclerosis, and focus on how the presence of specific lipid species can alter cellular metabolism and function of T cells.
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Affiliation(s)
- Saige L. Pompura
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, United States
| | - David A. Hafler
- Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT, United States
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40
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Menter T, Tzankov A. Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches. Front Immunol 2022; 13:811144. [PMID: 35273598 PMCID: PMC8901718 DOI: 10.3389/fimmu.2022.811144] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 02/03/2022] [Indexed: 12/19/2022] Open
Abstract
Acute myeloid leukemias (AML) comprise a wide array of different entities, which have in common a rapid expansion of myeloid blast cells leading to displacement of normal hematopoietic cells and also disruption of the microenvironment in the bone marrow niches. Based on an insight into the complex cellular interactions in the bone marrow niches in non-neoplastic conditions in general, this review delineates the complex relationship between leukemic cells and reactive cells of the tumor microenvironment (TME) in AML. A special focus is directed on niche cells and various T-cell subsets as these also provide a potential therapeutic rationale considering e.g. immunomodulation. The TME of AML on the one hand plays a vital role for sustaining and promoting leukemogenesis but - on the other hand - it also has adverse effects on abnormal blasts developing into overt leukemia hindering their proliferation and potentially removing such cells. Thus, leukemic cells need to and develop strategies in order to manipulate the TME. Interference with those strategies might be of particular therapeutic potential since mechanisms of resistance related to tumor cell plasticity do not apply to it.
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Affiliation(s)
- Thomas Menter
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
| | - Alexandar Tzankov
- Pathology, Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
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41
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Corradi G, Bassani B, Simonetti G, Sangaletti S, Vadakekolathu J, Fontana MC, Pazzaglia M, Gulino A, Tripodo C, Cristiano G, Bandini L, Ottaviani E, Ocadlikova D, Piccioli M, Martinelli G, Colombo MP, Rutella S, Cavo M, Ciciarello M, Curti A. Release of IFN-γ by acute myeloid leukemia cells remodels bone marrow immune microenvironment by inducing regulatory T cells. Clin Cancer Res 2022; 28:3141-3155. [PMID: 35349670 DOI: 10.1158/1078-0432.ccr-21-3594] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 02/10/2022] [Accepted: 03/25/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Tregs) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFN-γ released by AML cells in BM Tregs induction and its impact on AML prognosis. EXPERIMENTAL DESIGN BM aspirates from AML patients were subdivided according to IFNG expression. Gene expression profiles in INFGhigh and IFNGlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFN-g release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell co-cultures. In mice, AML cells silenced for IFN-γ expression were injected intrabone. RESULTS IFNGhigh AMLsamples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. By contrast, in AML patients, high IFNG expression associated with poor overall survival. Notably, IFN-g release by AML cells positively correlated with a higher BM suppressive Tregs' frequency. In co-culture experiments, IFNGhigh AML cells modified MSC transcriptome by up-regulating IFN-γ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFN-γ release by AML cells on MSC-derived Treg induction. Invivo, the genetic ablation of IFN-γ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment. CONCLUSIONS IFN-g release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunological landscape toward Treg induction, contributing to an immunotolerant microenvironment.
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Affiliation(s)
- Giulia Corradi
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Universit� di Bologna, Bologna, Italy, Bologna, Italy
| | | | - Giorgia Simonetti
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST), Meldola, FC, Italy
| | | | | | | | | | | | | | - Gianluca Cristiano
- Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Universit� di Bologna, Bologna, Italy
| | - Lorenza Bandini
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia, Italy
| | | | | | - Milena Piccioli
- 8Haematopathology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy, Italy
| | - Giovanni Martinelli
- IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST), Meldola (FC), Italy
| | | | - Sergio Rutella
- Nottingham Trent University, Nottingham, NA, United Kingdom
| | - Michele Cavo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia, Bologna, Italy
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42
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Saad AA. Targeting cancer-associated glycans as a therapeutic strategy in leukemia. ALL LIFE 2022. [DOI: 10.1080/26895293.2022.2049901] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
Affiliation(s)
- Ashraf Abdullah Saad
- Unit of Pediatric Hematologic Oncology and BMT, Sultan Qaboos University Hospital, Muscat, Oman
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43
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Ayyadurai VAS, Deonikar P, McLure KG, Sakamoto KM. Molecular Systems Architecture of Interactome in the Acute Myeloid Leukemia Microenvironment. Cancers (Basel) 2022; 14:756. [PMID: 35159023 PMCID: PMC8833542 DOI: 10.3390/cancers14030756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Accepted: 01/29/2022] [Indexed: 12/12/2022] Open
Abstract
A molecular systems architecture is presented for acute myeloid leukemia (AML) to provide a framework for organizing the complexity of biomolecular interactions. AML is a multifactorial disease resulting from impaired differentiation and increased proliferation of hematopoietic precursor cells involving genetic mutations, signaling pathways related to the cancer cell genetics, and molecular interactions between the cancer cell and the tumor microenvironment, including endothelial cells, fibroblasts, myeloid-derived suppressor cells, bone marrow stromal cells, and immune cells (e.g., T-regs, T-helper 1 cells, T-helper 17 cells, T-effector cells, natural killer cells, and dendritic cells). This molecular systems architecture provides a layered understanding of intra- and inter-cellular interactions in the AML cancer cell and the cells in the stromal microenvironment. The molecular systems architecture may be utilized for target identification and the discovery of single and combination therapeutics and strategies to treat AML.
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Affiliation(s)
- V. A. Shiva Ayyadurai
- Systems Biology Group, International Center for Integrative Systems, Cambridge, MA 02138, USA;
| | - Prabhakar Deonikar
- Systems Biology Group, International Center for Integrative Systems, Cambridge, MA 02138, USA;
| | | | - Kathleen M. Sakamoto
- Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA 94305, USA;
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44
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Xu Y, Mou J, Wang Y, Zhou W, Rao Q, Xing H, Tian Z, Tang K, Wang M, Wang J. Regulatory T cells promote the stemness of leukemia stem cells through IL10 cytokine-related signaling pathway. Leukemia 2022; 36:403-415. [PMID: 34381181 DOI: 10.1038/s41375-021-01375-2] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 07/28/2021] [Indexed: 02/06/2023]
Abstract
Regulatory T cells (Tregs) could maintain the characteristics of stem cells and inhibit the differentiation of normal hematopoietic stem/progenitor cells. Recent studies have shown that Tregs, as an important component of acute myeloid leukemia (AML) microenvironments, can help AML cells to evade immune surveillance. However, their function in directly regulating the stemness of AML cells remains elusive. In this study, the increased stemness of AML cells promoted by Tregs was verified in vitro and in vivo. The cytokines released by Tregs were explored, the highly expressed anti-inflammatory cytokine IL10 was found, which could promote the stemness of AML cells through the activation of PI3K/AKT signal pathway. Moreover, disrupting the IL10/IL10R/PI3K/AKT signal in AML/ETO c-kitmut (A/Ec) leukemia mice could prolong the mice survival and reduce the stemness of A/Ec leukemia cells. Finally, it was confirmed in patient samples that the proportion of Tregs to leukemia stem cells (LSCs) was positively correlated, and in CD34+ primary AML cells, the activation of PI3K/AKT was stronger in patients with high Tregs' infiltration. After rhIL10 treatment, primary AML cells showed increased activation of PI3K/AKT signaling. Therefore, blocking the interaction between Tregs and AML cells may be a new approach to target LSCs in AML treatment.
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MESH Headings
- Cell Differentiation
- Cell Proliferation
- Humans
- Interleukin-10/genetics
- Interleukin-10/metabolism
- Leukemia, Myeloid, Acute/immunology
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/pathology
- Neoplastic Stem Cells/metabolism
- Neoplastic Stem Cells/pathology
- Phosphatidylinositol 3-Kinases/genetics
- Phosphatidylinositol 3-Kinases/metabolism
- Proto-Oncogene Proteins c-akt/genetics
- Proto-Oncogene Proteins c-akt/metabolism
- Receptors, Interleukin-10/genetics
- Receptors, Interleukin-10/metabolism
- Signal Transduction
- T-Lymphocytes, Regulatory/immunology
- Tumor Cells, Cultured
- Tumor Microenvironment
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Affiliation(s)
- Yingxi Xu
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Junli Mou
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Ying Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Wei Zhou
- School of Medicine, Nankai University, Tianjin, China
| | - Qing Rao
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Haiyan Xing
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Zheng Tian
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Kejing Tang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
- Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Min Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
| | - Jianxiang Wang
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- Tianjin Key Laboratory of Cell Therapy for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
- National Clinical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
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45
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Hao F, Sholy C, Wang C, Cao M, Kang X. The Role of T Cell Immunotherapy in Acute Myeloid Leukemia. Cells 2021; 10:cells10123376. [PMID: 34943884 PMCID: PMC8699747 DOI: 10.3390/cells10123376] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 11/26/2021] [Accepted: 11/29/2021] [Indexed: 02/07/2023] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease associated with various alterations in T cell phenotype and function leading to an abnormal cell population, ultimately leading to immune exhaustion. However, restoration of T cell function allows for the execution of cytotoxic mechanisms against leukemic cells in AML patients. Therefore, long-term disease control, which requires multiple therapeutic approaches, includes those aimed at the re-establishment of cytotoxic T cell activity. AML treatments that harness the power of T lymphocytes against tumor cells have rapidly evolved over the last 3 to 5 years through various stages of preclinical and clinical development. These include tissue-infiltrated lymphocytes (TILs), bispecific antibodies, immune checkpoint inhibitors (ICIs), chimeric antigen receptor T (CAR-T) cell therapy, and tumor-specific T cell receptor gene-transduced T (TCR-T) cells. In this review, these T cell-based immunotherapies and the potential of TILs as a novel antileukemic therapy will be discussed.
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46
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Rollison DE, Messina JL, Cherpelis BS, Fenske NA, Schell MJ, Adeegbe DO, Zhao Y, Amorrortu RP, Akuffo AA, Hesterberg RS, Epling-Burnette PK. Circulating Immunosuppressive Regulatory T Cells Predict Risk of Incident Cutaneous Squamous Cell Carcinoma. Front Med (Lausanne) 2021; 8:735585. [PMID: 34796183 PMCID: PMC8593034 DOI: 10.3389/fmed.2021.735585] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/04/2021] [Indexed: 11/13/2022] Open
Abstract
Ultraviolet radiation exposure (UVR) is a risk factor for cutaneous squamous cell carcinoma (cuSCC) and has been shown to be positively associated with circulating immunosuppressive regulatory T cells ("Tregs"). However, the risk of cuSCC in association with circulating Tregs has not been studied. The aim of this study was to determine whether circulating Treg levels are associated with cuSCC development, particularly in the context of high UVR. Blood and spectrophotometer-based UVR measurements were obtained on 327 immunocompetent individuals undergoing routine skin cancer screenings at baseline and followed for up to 4 years for incident cuSCC development within a prospective cohort study. Proportions of phenotypically distinct Tregs, especially CCR4hi and CLA+ cells which are associated with activation and homing, respectively, were measured by flow cytometry. Tregs in cuSCC tumors were assessed using immunohistochemistry and graded for solar elastosis, a measure of cumulative UVR damage. Of several Treg phenotypes examined, higher levels of circulating CCR4hi Tregs at baseline were significantly associated with increased risk of subsequent cuSCC; those with higher levels of both CCR4hi and UVR were four times more likely to develop cuSCC compared to those with lower levels of both (Hazard Ratio = 4.11, 95% CI = 1.22-13.90). Within cuSCC tumors, CCR4hi Tregs were positively associated with solar elastosis. Results show that a higher proportion of CCR4hi peripheral Tregs predicts incident cuSCC up to 4 years, especially among highly UV-exposed individuals. Research of the underpinning biology of Tregs in UVR-associated skin damage may possibly reveal novel opportunities for screening, prevention, and treatment.
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Affiliation(s)
- Dana E Rollison
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, United States
| | - Jane L Messina
- Departments of Pathology and Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, United States
| | - Basil S Cherpelis
- Department of Dermatology and Cutaneous Surgery, University of South Florida College of Medicine, Tampa, FL, United States
| | - Neil A Fenske
- Department of Dermatology and Cutaneous Surgery, University of South Florida College of Medicine, Tampa, FL, United States
| | - Michael J Schell
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL, United States
| | - Dennis O Adeegbe
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
| | - Yayi Zhao
- Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, United States
| | | | - Afua A Akuffo
- Department of Immunology, Moffitt Cancer Center, Tampa, FL, United States
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47
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Mirfakhraie R, Noorazar L, Mohammadian M, Hajifathali A, Gholizadeh M, Salimi M, Sankanian G, Roshandel E, Mehdizadeh M. Treatment Failure in Acute Myeloid Leukemia: Focus on the Role of Extracellular Vesicles. Leuk Res 2021; 112:106751. [PMID: 34808592 DOI: 10.1016/j.leukres.2021.106751] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 11/11/2021] [Accepted: 11/15/2021] [Indexed: 12/12/2022]
Abstract
Acute myeloblastic leukemia (AML) is one of the most common types of blood malignancies that results in an AML-associated high mortality rate each year. Several causes have been reported as prognostic factors for AML in children and adults, the most important of which are cytogenetic abnormalities and environmental risk factors. Following the discovery of numerous drugs for AML treatment, leukemic cells sought a way to escape from the cytotoxic effects of chemotherapy drugs, leading to treatment failure. Nowadays, comprehensive studies have looked at the role of extracellular vesicles (EVs) secreted by AML blasts and how the microenvironment of the tumor changes in favor of cancer progression and survival to discover the mechanisms of treatment failure to choose the well-advised treatment. Reports show that malignant cells secrete EVs that transmit messages to adjacent cells and the tumor's microenvironment. By secreting EVs, containing immune-inhibiting cytokines, AML cells inactivate the immune system against malignant cells, thus ensuring their survival. Also, increased secretion of EVs in various malignancies indicates an unfavorable prognostic factor and the possibility of drug resistance. In this study, we briefly reviewed the challenges of treating AML with a glance at the EVs' role in this process. It is hoped that with a deeper understanding of EVs, new therapies will be developed to eliminate the relapse of leukemic cells.
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Affiliation(s)
- Reza Mirfakhraie
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Leila Noorazar
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mozhdeh Mohammadian
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Abbas Hajifathali
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Majid Gholizadeh
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Maryam Salimi
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Ghazaleh Sankanian
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Elham Roshandel
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mahshid Mehdizadeh
- Hematopoietic Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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48
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Zeidner JF, Vincent BG, Ivanova A, Moore D, McKinnon KP, Wilkinson AD, Mukhopadhyay R, Mazziotta F, Knaus HA, Foster MC, Coombs CC, Jamieson K, Van Deventer H, Webster JA, Prince GT, DeZern AE, Smith BD, Levis MJ, Montgomery ND, Luznik L, Serody JS, Gojo I. Phase II Trial of Pembrolizumab after High-Dose Cytarabine in Relapsed/Refractory Acute Myeloid Leukemia. Blood Cancer Discov 2021; 2:616-629. [PMID: 34778801 DOI: 10.1158/2643-3230.bcd-21-0070] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/12/2021] [Accepted: 08/25/2021] [Indexed: 12/17/2022] Open
Abstract
Immune suppression, exhaustion, and senescence are frequently seen throughout disease progression in acute myeloid leukemia (AML). We conducted a phase II study of high-dose cytarabine followed by pembrolizumab 200 mg i.v. on day 14 to examine whether PD-1 inhibition improves clinical responses in relapsed/refractory (R/R) AML. Overall responders could receive pembrolizumab maintenance up to 2 years. Among 37 patients enrolled, the overall response rate, composite complete remission (CRc) rate (primary endpoint), and median overall survival (OS) were 46%, 38%, and 11.1 months, respectively. Patients with refractory/early relapse and those receiving treatment as first salvage had encouraging outcomes (median OS, 13.2 and 11.3 months, respectively). Grade ≥3 immune-related adverse events were rare (14%) and self-limiting. Patients who achieved CRc had a higher frequency of progenitor exhausted CD8+ T cells expressing TCF-1 in the bone marrow prior to treatment. A multifaceted correlative approach of genomic, transcriptomic, and immunophenotypic profiling offers insights on molecular correlates of response and resistance to pembrolizumab. Significance Immune-checkpoint blockade with pembrolizumab was tolerable and feasible after high-dose cytarabine in R/R AML, with encouraging clinical activity, particularly in refractory AML and those receiving treatment as first salvage regimen. Further study of pembrolizumab and other immune-checkpoint blockade strategies after cytotoxic chemotherapy is warranted in AML.See related commentary by Wei et al., p. 551. This article is highlighted in the In This Issue feature, p. 549.
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Affiliation(s)
- Joshua F Zeidner
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.,Division of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Benjamin G Vincent
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.,Division of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina.,University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina.,Program in Computational Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Anastasia Ivanova
- University of North Carolina School of Medicine, Department of Biostatistics, Chapel Hill, North Carolina
| | - Dominic Moore
- University of North Carolina School of Medicine, Department of Biostatistics, Chapel Hill, North Carolina
| | - Karen P McKinnon
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.,University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina
| | - Alec D Wilkinson
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina
| | - Rupkatha Mukhopadhyay
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Francesco Mazziotta
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,University of Siena, Department of Medical Biotechnologies, Siena, Italy
| | - Hanna A Knaus
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland
| | - Matthew C Foster
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.,Division of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Catherine C Coombs
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.,Division of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Katarzyna Jamieson
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.,Division of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Hendrik Van Deventer
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.,Division of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Jonathan A Webster
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,Department of Oncology, Division of Hematological Malignancies, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Gabrielle T Prince
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,Department of Oncology, Division of Hematological Malignancies, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Amy E DeZern
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,Department of Oncology, Division of Hematological Malignancies, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - B Douglas Smith
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,Department of Oncology, Division of Hematological Malignancies, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Mark J Levis
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,Department of Oncology, Division of Hematological Malignancies, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Nathan D Montgomery
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.,Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Leo Luznik
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,Department of Oncology, Division of Hematological Malignancies, Johns Hopkins School of Medicine, Baltimore, Maryland
| | - Jonathan S Serody
- University of North Carolina School of Medicine, Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.,Division of Hematology, Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina.,University of North Carolina, Department of Microbiology and Immunology, Chapel Hill, North Carolina.,Program in Computational Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Ivana Gojo
- Johns Hopkins School of Medicine, Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.,University of Siena, Department of Medical Biotechnologies, Siena, Italy
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49
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Jimbu L, Mesaros O, Neaga A, Nanut AM, Tomuleasa C, Dima D, Bocsan C, Zdrenghea M. The Potential Advantage of Targeting Both PD-L1/PD-L2/PD-1 and IL-10-IL-10R Pathways in Acute Myeloid Leukemia. Pharmaceuticals (Basel) 2021; 14:1105. [PMID: 34832887 PMCID: PMC8620891 DOI: 10.3390/ph14111105] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/17/2021] [Accepted: 10/25/2021] [Indexed: 12/30/2022] Open
Abstract
Tumor cells promote the suppression of host anti-tumor type 1 T cell responses by various mechanisms, including the upregulation of surface inhibitory molecules such as programmed death ligand (PD-L)-1, and the production of immunosuppressive cytokines such as interleukin-10 (IL-10). There are over 2000 trials investigating PD-L1 and/or its receptor programmed-death 1 (PD-1) blockade in cancer, leading to the approval of PD-1 or PD-L1 inhibitors in several types of solid cancers and in hematological malignancies. The available data suggest that the molecule PD-L1 on antigen-presenting cells suppresses type 1 T cell immune responses such as cytotoxicity, and that the cytokine IL-10, in addition to downregulating immune responses, increases the expression of inhibitory molecule PD-L1. We hypothesize that the manipulation of both the co-inhibitory network (with anti-PD-L1 blocking antibodies) and suppressor network (with anti-IL-10 blocking antibodies) is an attractive immunotherapeutic intervention for acute myeloid leukemia (AML) patients ineligible for standard treatment with chemotherapy and hematopoietic stem cell transplantation, and with less severe adverse reactions. The proposed combination of these two immunotherapies represents a new approach that can be readily translated into the clinic to improve the therapeutic efficacy of AML disease treatment.
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Affiliation(s)
- Laura Jimbu
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania;
| | - Oana Mesaros
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
- “Octavian Fodor” Regional Institute of Gastroenterology and Hepatology, 19-21 Croitorilor Str., 400162 Cluj-Napoca, Romania
| | - Alexandra Neaga
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
| | - Ana Maria Nanut
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
| | - Ciprian Tomuleasa
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania;
| | - Delia Dima
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania;
| | - Corina Bocsan
- Department of Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania;
| | - Mihnea Zdrenghea
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, 8 Babes Str., 400012 Cluj-Napoca, Romania; (O.M.); (A.N.); (A.M.N.); (C.T.); (M.Z.)
- Department of Hematology, Ion Chiricuta Oncology Institute, 34-36 Republicii Str., 400015 Cluj-Napoca, Romania;
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Staub RB, Marcondes NA, Rotta LN. CD200 expression in hematopoietic neoplasms: Beyond a marker for diagnosis of B-cell neoplasms. Crit Rev Oncol Hematol 2021; 167:103509. [PMID: 34688895 DOI: 10.1016/j.critrevonc.2021.103509] [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: 04/25/2021] [Revised: 08/31/2021] [Accepted: 10/10/2021] [Indexed: 10/20/2022] Open
Abstract
CD200 (OX-2) is expressed in myeloid cells, B cells, subsets of T cells and on other normal and neoplastic non-hematopoietic cells. It interacts with CD200R and has a suppressive effect on T cells immune mediated response. We aimed to review CD200 expression and its role in the immune evasion of non-B cell hematopoietic neoplasms. In acute myeloid leukemia, CD200 seems to be related to the worst outcome, even in diseases of good prognosis, possibly due to an immunosuppressive effect. In plasma cell myeloma studies, while some have associated CD200 expression with worst prognosis possibly due to its suppressive effect on monocyte and T cell-mediated immune response, in others CD200 appeared to be a marker of a better outcome, or even showed no impact in event-free survival (EFS). Few studies have evaluated CD200 expression in T cell neoplasms; however, it appears to be a good immunophenotypic marker for angioimmunoblastic T cell lymphoma. In conclusion, CD200 appears to be involved in the immune evasion of malignant cells, which could affect the survival of these patients.
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Affiliation(s)
- Renata B Staub
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil
| | | | - Liane N Rotta
- Programa de Pós-Graduação em Ciências da Saúde, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil; Departamento de Métodos Diagnósticos, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, Brazil.
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