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Krupa MM, Pienkowski T, Tankiewicz-Kwedlo A, Lyson T. Targeting the kynurenine pathway in gliomas: Insights into pathogenesis, therapeutic targets, and clinical advances. Biochim Biophys Acta Rev Cancer 2025; 1880:189343. [PMID: 40345262 DOI: 10.1016/j.bbcan.2025.189343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 04/29/2025] [Accepted: 05/05/2025] [Indexed: 05/11/2025]
Abstract
Gliomas, the most prevalent primary brain tumors, continue to present significant challenges in oncology due to poor patient prognosis despite advances in treatment such as immunotherapy and cancer vaccines. Recent research highlights the potential of targeting tryptophan metabolism, particularly the kynurenine pathway (KP) and combinatorial approaches with immunotherapies, as a promising strategy in cancer research. The key enzymes of the kynurenine pathway, such as IDO1, IDO2, and TDO, and metabolites like kynurenine, kynurenic acid, and quinolinic acid, are implicated in fostering an immunosuppressive tumor microenvironment and promoting glioma cell survival. In glioblastoma, a highly aggressive glioma subtype, elevated IDO and TDO expression correlates with reduced survival rates. KP metabolites, such as kynurenine (KYN), 3-hydroxykynurenine (3-HK), kynurenic acid (KYNA), and quinolinic acid (QUIN), are involved in modulating immune responses, oxidative stress, neuroprotection, and neurotoxicity. This review synthesizes recent findings on the kynurenine pathway involvement in glioma pathogenesis, examining potential therapeutic targets within this pathway and discussing ongoing clinical trials that draw attention to treatments based on this pathway. Furthermore, it highlights novel findings on the post-translational modifications of kynurenine pathway enzymes and their regulatory roles, presenting their potential as therapeutic targets in gliomas.
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Affiliation(s)
- Mikolaj Marek Krupa
- Department of Neurosurgery, Medical University of Bialystok, 15-276 Bialystok, Poland
| | - Tomasz Pienkowski
- Laboratory of Metabolomics and Proteomics, Clinical Research Centre, Medical University of Bialystok, 15-276 Bialystok, Poland.
| | - Anna Tankiewicz-Kwedlo
- Department of Pharmacodynamics, Medical University of Bialystok, 15-222 Bialystok, Poland
| | - Tomasz Lyson
- Department of Neurosurgery, Medical University of Bialystok, 15-276 Bialystok, Poland; Department of Interventional Neurology, Medical University of Bialystok, 15-276 Bialystok, Poland
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Masmoudi D, Villalba M, Alix-Panabières C. Natural killer cells: the immune frontline against circulating tumor cells. J Exp Clin Cancer Res 2025; 44:118. [PMID: 40211394 PMCID: PMC11983744 DOI: 10.1186/s13046-025-03375-x] [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: 01/10/2025] [Accepted: 03/25/2025] [Indexed: 04/14/2025] Open
Abstract
Natural killer (NK) play a key role in controlling tumor dissemination by mediating cytotoxicity towards cancer cells without the need of education. These cells are pivotal in eliminating circulating tumor cells (CTCs) from the bloodstream, thus limiting cancer spread and metastasis. However, aggressive CTCs can evade NK cell surveillance, facilitating tumor growth at distant sites. In this review, we first discuss the biology of NK cells, focusing on their functions within the tumor microenvironment (TME), the lymphatic system, and circulation. We then examine the immune evasion mechanisms employed by cancer cells to inhibit NK cell activity, including the upregulation of inhibitory receptors. Finally, we explore the clinical implications of monitoring circulating biomarkers, such as NK cells and CTCs, for therapeutic decision-making and emphasize the need to enhance NK cell-based therapies by overcoming immune escape mechanisms.
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Affiliation(s)
- Doryan Masmoudi
- Laboratory of Rare Circulating Human Cells, University Medical Center of Montpellier, Montpellier, France
| | - Martin Villalba
- IRMB, Univ Montpellier, INSERM, CHU Montpellier, CNRS, Montpellier, France
| | - Catherine Alix-Panabières
- Laboratory of Rare Circulating Human Cells, University Medical Center of Montpellier, Montpellier, France.
- CREEC/CANECEV, MIVEGEC (CREES), University of Montpellier, CNRS, Montpellier, IRD, France.
- European Liquid Biopsy Society (ELBS), Hamburg, Germany.
- LCCRH, Site Unique de Biologie (SUB), 641, Avenue du Doyen Gaston Giraud, Montpellier, 34093, France.
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3
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Qin Y, Li M, Liu H. Regulatory T cells: a promising new therapeutic target in ventricular remodeling after myocardial infarction. Front Immunol 2025; 16:1514335. [PMID: 40260235 PMCID: PMC12009920 DOI: 10.3389/fimmu.2025.1514335] [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: 10/20/2024] [Accepted: 03/24/2025] [Indexed: 04/23/2025] Open
Abstract
Myocardial infarction (MI) is one of the leading causes of death worldwide. It is triggered by thrombosis or vascular occlusion. After MI, damaged cardiomyocytes are replaced by scar tissue, leading to systolic and diastolic dysfunction, followed by adverse remodeling. Regulatory T cells (Tregs), as major immune cells, play a crucial role in post-MI inflammation and immunomodulation. Tregs improve cardiac remodeling after MI through various mechanisms, including inhibiting inflammatory cell infiltration, inducing anti-inflammatory macrophages, suppressing cell apoptosis, regulating fibroblast function, and promoting angiogenesis. The modulation of Tregs number or function may provide novel methods for improving post-MI remodeling. This review describes the immunoregulatory roles of Tregs, their regulatory mechanisms in post-MI ventricular remodeling, and the prospects and challenges for clinical application. However, the exact molecular mechanisms of Tregs in ventricular remodeling remain to be investigated. Although most of the current studies are at the preclinical stage, they hold great potential for further application in the future.
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Affiliation(s)
- Yiran Qin
- Department of Cardiology, Qingpu Hospital Affiliated to Fudan University, Shanghai, China
| | - Mingxuan Li
- Department of Cardiology, Huadong Hospital, Fudan University, Shanghai, China
| | - Haibo Liu
- Department of Cardiology, Qingpu Hospital Affiliated to Fudan University, Shanghai, China
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Tsuboi N, Rivera-Caraballo KA, Sahu U, Pacholczyk R, Douglass E, Johnson TS, Wang Q, Kolhe R, Hedrick CC, Munn DH, Hong B. Blocking Feedback Immunosuppression of Antigen Presentation in Brain Tumor During Oncolytic Virotherapy with oHSV-mshPKR. Mol Cancer Ther 2025; 24:444-452. [PMID: 39711419 PMCID: PMC11879753 DOI: 10.1158/1535-7163.mct-24-0629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 12/06/2024] [Accepted: 12/17/2024] [Indexed: 12/24/2024]
Abstract
Glioblastoma (GBM) is the most frequent malignant brain tumor. We recently discovered that oncolytic herpes simplex virus engineered to disable tumor-intrinsic protein kinase R (PKR) signaling (oHSV-shPKR) could increase oHSV oncolysis and antitumor immune response. However, in this study, we show that disabling tumor-intrinsic PKR signaling can also induce the activation of the indoleamine 2,3-dioxygenase (IDO) signaling pathway. Both GBM tumor progression and oHSV intratumoral therapy increased infiltration of IDO+CD11c+ dendritic cells (DC) into the tumor. The coculture of oHSV-infected human GBM neurospheres with monocyte-derived DCs (MoDC) dramatically increased IDO signaling activation in MoDCs through type-I IFN signaling. Addition of IDO inhibitor (indoximod) in the coculture significantly increased MoDC activation and reduced the consumption of tryptophan. Combining indoximod and oHSV significantly inhibited tumor growth and induced antigen-specific CD8+ T-cell activation. These results suggest that inhibition of the IDO pathway could significantly block feedback immunosuppression during oncolytic virotherapy of GBM.
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Affiliation(s)
- Nobushige Tsuboi
- Department of Pathology, Georgia Cancer Center at Augusta University, Augusta, GA, USA
| | | | - Upasana Sahu
- Department of Pathology, Georgia Cancer Center at Augusta University, Augusta, GA, USA
| | - Rafal Pacholczyk
- Department of Biochemistry and Molecular Biology, Georgia Cancer Center at Augusta University, 1410 Laney Walker Blvd, Augusta, GA, USA
| | - Eugene Douglass
- Department of Pharmaceutical & Biomedical Sciences, University of Georgia, Athens, GA, USA
| | - Theodore S. Johnson
- Department of Pediatrics, Pediatric Immunotherapy Program, Georgia Cancer Center at Augusta University, Augusta, GA, USA
| | - Qin Wang
- Department of Neuroscience & Regenerative Medicine, Augusta University, Augusta, GA, USA
| | - Ravindra Kolhe
- Department of Pathology, Georgia Cancer Center at Augusta University, Augusta, GA, USA
| | - Catherine C. Hedrick
- Department of Medicine, Immunology Center of Georgia, Augusta University, Augusta, GA, USA
| | - David H. Munn
- Department of Pediatrics, Pediatric Immunotherapy Program, Georgia Cancer Center at Augusta University, Augusta, GA, USA
| | - Bangxing Hong
- Department of Pathology, Georgia Cancer Center at Augusta University, Augusta, GA, USA
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5
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Han JW, Park SH. Advancing immunosuppression in liver transplantation: the role of regulatory T cells in immune modulation and graft tolerance. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:257-272. [PMID: 39696994 PMCID: PMC11732766 DOI: 10.4285/ctr.24.0059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 11/23/2024] [Accepted: 11/28/2024] [Indexed: 12/20/2024]
Abstract
Prolonged immunosuppressive therapy in liver transplantation (LT) is associated with significant adverse effects, such as nephrotoxicity, metabolic complications, and heightened risk of infection or malignancy. Regulatory T cells (Tregs) represent a promising target for inducing immune tolerance in LT, with the potential to reduce or eliminate the need for life-long immunosuppression. This review summarizes current knowledge on the roles of Tregs in LT, highlighting their mechanisms and the impact of various immunosuppressive agents on Treg stability and function. The liver's distinct immunological microenvironment, characterized by tolerogenic antigen-presenting cells and high levels of interleukin (IL)-10 and transforming growth factor-β, positions this organ as an ideal setting for Treg-mediated tolerance. We discuss Treg dynamics in LT, their association with rejection risk, and their utility as biomarkers of transplant outcomes. Emerging strategies, including the use of low-dose calcineurin inhibitors with mammalian target of rapamycin inhibitors, adoptive Treg therapy, and low-dose IL-2, aim to enhance Treg function while providing sufficient immunosuppression. Thus, the future of LT involves precision medicine approaches that integrate Treg monitoring with tailored immunosuppressive protocols to optimize long-term outcomes for LT recipients.
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Affiliation(s)
- Ji Won Han
- The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Su-Hyung Park
- Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea
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6
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Brescia C, Audia S, Pugliano A, Scaglione F, Iuliano R, Trapasso F, Perrotti N, Chiarella E, Amato R. Metabolic drives affecting Th17/Treg gene expression changes and differentiation: impact on immune-microenvironment regulation. APMIS 2024; 132:1026-1045. [PMID: 38239016 DOI: 10.1111/apm.13378] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Accepted: 01/02/2024] [Indexed: 11/26/2024]
Abstract
The CD4+ T-cell population plays a vital role in the adaptive immune system by coordinating the immune response against different pathogens. A significant transformation occurs in CD4+ cells during an immune response, as they shift from a dormant state to an active state. This transformation leads to extensive proliferation, differentiation, and cytokine production, which contribute to regulating and coordinating the immune response. Th17 and Treg cells are among the most intriguing CD4+ T-cell subpopulations in terms of genetics and metabolism. Gene expression modulation processes rely on and are linked to metabolic changes in cells. Lactylation is a new model that combines metabolism and gene modulation to drive Th17/Treg differentiation and functional processes. The focus of this review is on the metabolic pathways that impact lymphocyte gene modulation in a functionally relevant manner.
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Affiliation(s)
- Carolina Brescia
- Department of Health Science, Medical School, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
- Immuno-Genetics Lab, Department of Health Science, Medical School, University "Magna Graecia"of Catanzaro, Catanzaro, Italy
| | - Salvatore Audia
- Department of Health Science, Medical School, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
- Immuno-Genetics Lab, Department of Health Science, Medical School, University "Magna Graecia"of Catanzaro, Catanzaro, Italy
| | - Alessia Pugliano
- Department of Health Science, Medical School, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
- Immuno-Genetics Lab, Department of Health Science, Medical School, University "Magna Graecia"of Catanzaro, Catanzaro, Italy
| | - Federica Scaglione
- Department of Health Science, Medical School, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
- Immuno-Genetics Lab, Department of Health Science, Medical School, University "Magna Graecia"of Catanzaro, Catanzaro, Italy
| | - Rodolfo Iuliano
- Department of Health Science, Medical School, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Francesco Trapasso
- Department of Experimental and Clinical Medicine, Medical School, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Nicola Perrotti
- Department of Health Science, Medical School, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
| | - Emanuela Chiarella
- Immuno-Genetics Lab, Department of Health Science, Medical School, University "Magna Graecia"of Catanzaro, Catanzaro, Italy
- Department of Experimental and Clinical Medicine, Medical School, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
- Laboratory of Molecular Haematopoiesis and Stem Cell Biology, Department of Experimental and Clinical Medicine, University "Magna Græcia", Catanzaro, Italy
| | - Rosario Amato
- Department of Health Science, Medical School, University "Magna Graecia" of Catanzaro, Catanzaro, Italy
- Immuno-Genetics Lab, Department of Health Science, Medical School, University "Magna Graecia"of Catanzaro, Catanzaro, Italy
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7
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Wu J, Zeng W, Xie H, Cao M, Yang J, Xie Y, Luo Z, Zhang Z, Xu H, Huang W, Zhou T, Tan J, Wu X, Yang Z, Zhu S, Mao R, He Z, Lan P. Microbiota-induced alteration of kynurenine metabolism in macrophages drives formation of creeping fat in Crohn's disease. Cell Host Microbe 2024; 32:1927-1943.e9. [PMID: 39541945 DOI: 10.1016/j.chom.2024.10.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 08/28/2024] [Accepted: 10/15/2024] [Indexed: 11/17/2024]
Abstract
Hyperplasia of mesenteric tissues in Crohn's disease, called creeping fat (CrF), is associated with surgical recurrence. Although microbiota translocation and colonization have been found in CrF, convincing mouse phenotypes and the underlying mechanisms of CrF formation remain unclear. Utilizing single-nucleus RNA (snRNA) sequencing of CrF and different mouse models, we demonstrate that the commensal Achromobacter pulmonis induces mesenteric adipogenesis through macrophage alteration. Targeted metabolome analysis reveals that L-kynurenine is the most enriched metabolite in CrF. Upregulation of indoleamine 2,3-dioxygenase 1 (IDO1) enhances kynurenine metabolism and drives mesenteric adipogenesis. Leveraging single-cell RNA (scRNA) sequencing of mouse mesenteric tissues and macrophage-specific IDO1 knockout mice, we verify the role of macrophage-sourced L-kynurenine in mesenteric adipogenesis. Mechanistically, L-kynurenine-induced adipogenesis is mediated by the aryl hydrocarbon receptors in adipocytes. Administration of an IDO1 inhibitor or bacteria engineered to degrade L-kynurenine alleviates mesenteric adipogenesis in mice. Collectively, our study demonstrates that microbiota-induced modulation of macrophage metabolism potentiates CrF formation.
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Affiliation(s)
- Jinjie Wu
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Wanyi Zeng
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China
| | - Hongyu Xie
- Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Anesthesia, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Mujia Cao
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China
| | - Jingyi Yang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China
| | - Yanchun Xie
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China
| | - Zhanhao Luo
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China
| | - Zongjin Zhang
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China
| | - Haoyang Xu
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China
| | - Weidong Huang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Tingyue Zhou
- Key Laboratory of immune response and immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jinyu Tan
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaomin Wu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Zihuan Yang
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China
| | - Shu Zhu
- Key Laboratory of immune response and immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
| | - Ren Mao
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
| | - Zhen He
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Key Laboratory of Human Microbiome and Chronic Diseases, Sun Yat-sen University, Ministry of Education, Guangzhou, Guangdong, China.
| | - Ping Lan
- Department of General Surgery (Colorectal Surgery), The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; State Key Laboratory of Oncology in South China, Guangzhou, China.
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8
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Wen X, Fu J, Zhang X, Meng X, Tian Y, Li J, Yu G, Hao Y, Zhu Y. Achieving Immune Activation by Suppressing the IDO1 Checkpoint with Sono-Targeted Biobromination for Antitumor Combination Immunotherapy. J Am Chem Soc 2024; 146:24580-24590. [PMID: 39165059 DOI: 10.1021/jacs.4c07993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/22/2024]
Abstract
Indoleamine-2,3-dioxygenase-1 (IDO1) pathogenically suppresses immune cell infiltration and promotes tumor cell immune escape by overmetabolizing tryptophan to N-formyl kynurenine in the tumor microenvironment (TME). However, it remains challenging for IDO1 immune checkpoint inhibitors to achieve a significant potency of progression-free survival. Here, we developed a breakthrough in IDO1 inhibition by sono-targeted biobromination reaction using immunostimulating hypobromic-P-phenylperoxydibenzoic acid-linked metallic organic framework nanomedicine (H-MOF NM) to remodel the TME from debrominated hypoxia into hypobromated normoxia and activate the IDO1 immune pathway with in vitro and in vivo remarkable antitumor efficacy. H-MOF NM contains Br+ and O- active ingredients with an enlarged band gap to deactivate IDO1 through an innovative biochemical mechanism, taking control over brominating IDO1 amino acid residues at the active sites in the remodeled TME and subsequently activating the immune response, including DC maturation, T-cell activation, and macrophage polarization. Importantly, the H-MOF NM achieves multiple immune responses with high tumor regression potency by combination sono-immunotherapy. This study describes an excellent IDO1 inhibition strategy through the development of immune biobrominative H-MOF nanomedicine and highlights efficient combination immunotherapy for tumor treatment.
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Affiliation(s)
- Xiaoming Wen
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Science, Beijing 100049, P. R. China
| | - Jingke Fu
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Engineering Research Center of Innovative Orthopaedic Instruments and Personalized Medicine, Shanghai 200011, P. R. China
| | - Xiangkai Zhang
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China
| | - Xiaoyan Meng
- Department of Oral Maxillofacial & Head and Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China
| | - Yue Tian
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Science, Beijing 100049, P. R. China
| | - Jing Li
- Department of Immunology, College of Basic Medicine & National Key Laboratory of Inflammation and Immunology, Naval Medical University, 800 Xiangyin Road, Shanghai 200433, P. R. China
| | - Ganjun Yu
- Department of Immunology, College of Basic Medicine & National Key Laboratory of Inflammation and Immunology, Naval Medical University, 800 Xiangyin Road, Shanghai 200433, P. R. China
| | - Yongqiang Hao
- Shanghai Key Laboratory of Orthopaedic Implant, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Engineering Research Center of Innovative Orthopaedic Instruments and Personalized Medicine, Shanghai 200011, P. R. China
| | - Yingchun Zhu
- Key Laboratory of Inorganic Coating Materials CAS, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai 200050, P. R. China
- Center of Materials Science and Optoelectronics Engineering, University of Chinese Academy of Science, Beijing 100049, P. R. China
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9
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Yu J, Yan Y, Li S, Xu Y, Parolia A, Rizvi S, Wang W, Zhai Y, Xiao R, Li X, Liao P, Zhou J, Okla K, Lin H, Lin X, Grove S, Wei S, Vatan L, Hu J, Szumilo J, Kotarski J, Freeman ZT, Skala S, Wicha M, Cho KR, Chinnaiyan AM, Schon S, Wen F, Kryczek I, Wang S, Chen L, Zou W. Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance. Cell 2024; 187:4713-4732.e19. [PMID: 38968937 PMCID: PMC11344674 DOI: 10.1016/j.cell.2024.06.012] [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: 07/19/2023] [Revised: 02/09/2024] [Accepted: 06/09/2024] [Indexed: 07/07/2024]
Abstract
Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.
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Affiliation(s)
- Jiali Yu
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Yijian Yan
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Shasha Li
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Ying Xu
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Abhijit Parolia
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Syed Rizvi
- Department of Chemical Engineering, University of Michigan School of Engineering, Ann Arbor, MI, USA
| | - Weichao Wang
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Yiwen Zhai
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Rongxin Xiao
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Xiong Li
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Peng Liao
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Jiajia Zhou
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Karolina Okla
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland
| | - Heng Lin
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Xun Lin
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Sara Grove
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Shuang Wei
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Linda Vatan
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Jiantao Hu
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Justyna Szumilo
- Department of Clinical Pathomorphology, Medical University of Lublin, Lublin, Poland
| | - Jan Kotarski
- Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland
| | - Zachary T Freeman
- Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Stephanie Skala
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Max Wicha
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Kathleen R Cho
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Arul M Chinnaiyan
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Samantha Schon
- Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Fei Wen
- Department of Chemical Engineering, University of Michigan School of Engineering, Ann Arbor, MI, USA
| | - Ilona Kryczek
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA
| | - Shaomeng Wang
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Lieping Chen
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA
| | - Weiping Zou
- Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA.
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10
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Grobben Y. Targeting amino acid-metabolizing enzymes for cancer immunotherapy. Front Immunol 2024; 15:1440269. [PMID: 39211039 PMCID: PMC11359565 DOI: 10.3389/fimmu.2024.1440269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Despite the immune system's role in the detection and eradication of abnormal cells, cancer cells often evade elimination by exploitation of various immune escape mechanisms. Among these mechanisms is the ability of cancer cells to upregulate amino acid-metabolizing enzymes, or to induce these enzymes in tumor-infiltrating immunosuppressive cells. Amino acids are fundamental cellular nutrients required for a variety of physiological processes, and their inadequacy can severely impact immune cell function. Amino acid-derived metabolites can additionally dampen the anti-tumor immune response by means of their immunosuppressive activities, whilst some can also promote tumor growth directly. Based on their evident role in tumor immune escape, the amino acid-metabolizing enzymes glutaminase 1 (GLS1), arginase 1 (ARG1), inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and interleukin 4 induced 1 (IL4I1) each serve as a promising target for immunotherapeutic intervention. This review summarizes and discusses the involvement of these enzymes in cancer, their effect on the anti-tumor immune response and the recent progress made in the preclinical and clinical evaluation of inhibitors targeting these enzymes.
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11
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Okano S. Immunotherapy for head and neck cancer: Fundamentals and therapeutic development. Auris Nasus Larynx 2024; 51:684-695. [PMID: 38729034 DOI: 10.1016/j.anl.2024.05.001] [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: 12/26/2023] [Revised: 04/03/2024] [Accepted: 05/01/2024] [Indexed: 05/12/2024]
Abstract
Squamous cell carcinoma of the head and neck (SCCHN) has been treated by multidisciplinary therapy consisting of surgery, radiotherapy, and cancer chemotherapy, but the recent advent of immunotherapy has produced significant changes in treatment systems and the results of these therapies. Immunotherapy has greatly improved the outcome of recurrent metastatic SCCHN, and the development of new treatment methods based on immunotherapy is now being applied not only to recurrent metastatic cases but also to locally advanced cases. To understand and practice cancer immunotherapy, it is important to understand the immune environment surrounding cancer, and the changes to which it is subject. Currently, the anti-PD-1 antibody drugs nivolumab and pembrolizumab are the only immunotherapies with proven efficacy in head and neck cancer. However, anti-PD-L1 and anti-CTLA-4 antibody drugs have also been shown to be useful in other types of cancer and are being incorporated into clinical practice. In head and neck cancer, numerous clinical trials have aimed to improve efficacy and safety by combining immunotherapy with other drug therapies and treatment modalities. Combinations of immunotherapy with cancer drugs with different mechanisms of action (cytotoxic agents, molecular-targeted agents, immune checkpoint inhibitors), as well as with radiation therapy and surgery are being investigated, and have the potential to significantly change medical care for these patients. The application of cancer immunotherapy not only to daily clinical practice but also to further therapeutic development requires a clear and complete understanding of the fundamentals of cancer immunotherapy, and knowledge of the numerous clinical studies conducted, both past and present. The results of these trials are numerous, both positive and negative, and a comprehensive understanding of this wide range of completed and ongoing clinical trials is critical to a systematic and comprehensive understanding of their scope and lessons learnt. In this article, after outlining the concepts of ``cancer immune cycle,'' ``cancer immune editing,'' and ``tumor microenvironment'' to provide an understanding of the basics of cancer immunity, we summarize the basics and clinical trial data on representative immune checkpoint inhibitors used in various cancer types, as well as recent therapeutic developments in cancer immunotherapy and the current status of these new treatments.
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Affiliation(s)
- Susumu Okano
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba 277-8577, Japan.
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12
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Liu W, Zhou H, Lai W, Hu C, Wang Q, Yuan C, Luo C, Yang M, Hu M, Zhang R, Li G. Artesunate induces melanoma cell ferroptosis and augments antitumor immunity through targeting Ido1. Cell Commun Signal 2024; 22:378. [PMID: 39061097 PMCID: PMC11282746 DOI: 10.1186/s12964-024-01759-8] [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: 06/11/2024] [Accepted: 07/21/2024] [Indexed: 07/28/2024] Open
Abstract
Artesunate (ART), a natural product isolated from traditional Chinese plant Artemisia annua, has not been extensively explored for its anti-melanoma properties. In our study, we found that ART inhibited melanoma cell proliferation and induced melanoma cell ferroptosis. Mechanistic study revealed that ART directly targets Ido1, thereby suppressing Hic1-mediated transcription suppression of Hmox1, resulting in melanoma cell ferroptosis. In CD8+ T cells, ART does not cause cell ferroptosis due to the low expression of Hmox1. It also targets Ido1, elevating tryptophan levels, which inhibits NFATc1-mediated PD1 transcription, consequently activating CD8+ T cells. Our study uncovered a potent and synergistic anti-melanoma efficacy arising from ART-induced melanoma cell ferroptosis and concurrently enhancing CD8+ T cell-mediated immune response both in vivo and in vitro through directly targeting Ido1. Our study provides a novel mechanistic basis for the utilization of ART as an Ido1 inhibitor and application in clinical melanoma treatment.
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Affiliation(s)
- Wuyi Liu
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
| | - Huyue Zhou
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
| | - Wenjing Lai
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
| | - Changpeng Hu
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
| | - Qiaoling Wang
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
| | - Chengsha Yuan
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
| | - Chunmei Luo
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
| | - Mengmeng Yang
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
| | - Min Hu
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China
| | - Rong Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China.
| | - Guobing Li
- Department of Pharmacy, The Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China.
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13
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Wang D, Dou L, Sui L, Xue Y, Xu S. Natural killer cells in cancer immunotherapy. MedComm (Beijing) 2024; 5:e626. [PMID: 38882209 PMCID: PMC11179524 DOI: 10.1002/mco2.626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 05/30/2024] [Accepted: 05/30/2024] [Indexed: 06/18/2024] Open
Abstract
Natural killer (NK) cells, as innate lymphocytes, possess cytotoxic capabilities and engage target cells through a repertoire of activating and inhibitory receptors. Particularly, natural killer group 2, member D (NKG2D) receptor on NK cells recognizes stress-induced ligands-the MHC class I chain-related molecules A and B (MICA/B) presented on tumor cells and is key to trigger the cytolytic response of NK cells. However, tumors have developed sophisticated strategies to evade NK cell surveillance, which lead to failure of tumor immunotherapy. In this paper, we summarized these immune escaping strategies, including the downregulation of ligands for activating receptors, upregulation of ligands for inhibitory receptors, secretion of immunosuppressive compounds, and the development of apoptosis resistance. Then, we focus on recent advancements in NK cell immune therapies, which include engaging activating NK cell receptors, upregulating NKG2D ligand MICA/B expression, blocking inhibitory NK cell receptors, adoptive NK cell therapy, chimeric antigen receptor (CAR)-engineered NK cells (CAR-NK), and NKG2D CAR-T cells, especially several vaccines targeting MICA/B. This review will inspire the research in NK cell biology in tumor and provide significant hope for improving cancer treatment outcomes by harnessing the potent cytotoxic activity of NK cells.
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Affiliation(s)
- DanRu Wang
- National Key Lab of Immunity and Inflammation and Institute of Immunology Naval Medical University Shanghai China
| | - LingYun Dou
- National Key Lab of Immunity and Inflammation and Institute of Immunology Naval Medical University Shanghai China
| | - LiHao Sui
- National Key Lab of Immunity and Inflammation and Institute of Immunology Naval Medical University Shanghai China
| | - Yiquan Xue
- National Key Lab of Immunity and Inflammation and Institute of Immunology Naval Medical University Shanghai China
| | - Sheng Xu
- National Key Lab of Immunity and Inflammation and Institute of Immunology Naval Medical University Shanghai China
- Shanghai Institute of Stem Cell Research and Clinical Translation Dongfang Hospital Shanghai China
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14
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Wakasugi K, Yokosawa T. The high-affinity tryptophan uptake transport system in human cells. Biochem Soc Trans 2024; 52:1149-1158. [PMID: 38813870 PMCID: PMC11346423 DOI: 10.1042/bst20230742] [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: 02/28/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 05/31/2024]
Abstract
The L-tryptophan (Trp) transport system is highly selective for Trp with affinity in the nanomolar range. This transport system is augmented in human interferon (IFN)-γ-treated and indoleamine 2,3-dioxygenase 1 (IDO1)-expressing cells. Up-regulated cellular uptake of Trp causes a reduction in extracellular Trp and initiates immune suppression. Recent studies demonstrate that both IDO1 and tryptophanyl-tRNA synthetase (TrpRS), whose expression levels are up-regulated by IFN-γ, play a pivotal role in high-affinity Trp uptake into human cells. Furthermore, overexpression of tryptophan 2,3-dioxygenase (TDO2) elicits a similar effect as IDO1 on TrpRS-mediated high-affinity Trp uptake. In this review, we summarize recent findings regarding this Trp uptake system and put forward a possible molecular mechanism based on Trp deficiency induced by IDO1 or TDO2 and tryptophanyl-AMP production by TrpRS.
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Affiliation(s)
- Keisuke Wakasugi
- Komaba Organization for Educational Excellence, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Takumi Yokosawa
- Komaba Organization for Educational Excellence, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan
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15
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Kondo T, Okada Y, Shizuya S, Yamaguchi N, Hatakeyama S, Maruyama K. Neuroimmune modulation by tryptophan derivatives in neurological and inflammatory disorders. Eur J Cell Biol 2024; 103:151418. [PMID: 38729083 DOI: 10.1016/j.ejcb.2024.151418] [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: 12/25/2023] [Revised: 05/02/2024] [Accepted: 05/03/2024] [Indexed: 05/12/2024] Open
Abstract
The nervous and immune systems are highly developed, and each performs specialized physiological functions. However, they work together, and their dysfunction is associated with various diseases. Specialized molecules, such as neurotransmitters, cytokines, and more general metabolites, are essential for the appropriate regulation of both systems. Tryptophan, an essential amino acid, is converted into functional molecules such as serotonin and kynurenine, both of which play important roles in the nervous and immune systems. The role of kynurenine metabolites in neurodegenerative and psychiatric diseases has recently received particular attention. Recently, we found that hyperactivity of the kynurenine pathway is a critical risk factor for septic shock. In this review, we first outline neuroimmune interactions and tryptophan derivatives and then summarized the changes in tryptophan metabolism in neurological disorders. Finally, we discuss the potential of tryptophan derivatives as therapeutic targets for neuroimmune disorders.
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Affiliation(s)
- Takeshi Kondo
- Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido 060-8636, Japan
| | - Yuka Okada
- Department of Ophthalmology, Wakayama Medical University School of Medicine, Wakayama 641-0012, Japan
| | - Saika Shizuya
- Department of Ophthalmology, Wakayama Medical University School of Medicine, Wakayama 641-0012, Japan
| | - Naoko Yamaguchi
- Department of Pharmacology, School of Medicine, Aichi Medical University, Aichi 480-1195, Japan
| | - Shigetsugu Hatakeyama
- Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Hokkaido 060-8636, Japan
| | - Kenta Maruyama
- Department of Pharmacology, School of Medicine, Aichi Medical University, Aichi 480-1195, Japan.
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16
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Gerlini G, Susini P, Sestini S, Brandani P, Giannotti V, Borgognoni L. Langerhans Cells in Sentinel Lymph Nodes from Melanoma Patients. Cancers (Basel) 2024; 16:1890. [PMID: 38791968 PMCID: PMC11119378 DOI: 10.3390/cancers16101890] [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: 03/26/2024] [Revised: 05/05/2024] [Accepted: 05/11/2024] [Indexed: 05/26/2024] Open
Abstract
BACKGROUND Langerhans cells (LCs) are professional Dendritic Cells (DCs) involved in immunoregulatory functions. At the skin level, LCs are immature. In response to tissue injuries, they migrate to regional Lymph Nodes (LNs), reaching a full maturation state. Then, they become effective antigen-presenting cells (APCs) that induce anti-cancer responses. Notably, melanoma patients present several DC alterations in the Sentinel Lymph Node (SLN), where primary antitumoral immunity is generated. LCs are the most represented DCs subset in melanoma SLNs and are expected to play a key role in the anti-melanoma response. With this paper, we aim to review the current knowledge and future perspectives regarding LCs and melanoma. METHODS A systematic review was carried out according to the PRISMA statement using the PubMed (MEDLINE) library from January 2004 to January 2024, searching for original studies discussing LC in melanoma. RESULTS The final synthesis included 15 articles. Several papers revealed significant LCs-melanoma interactions. CONCLUSIONS Melanoma immune escape mechanisms include SLN LC alterations, favoring LN metastasis arrival/homing and melanoma proliferation. The SLN LCs of melanoma patients are defective but not irreversibly, and their function may be restored by appropriate stimuli. Thus, LCs represent a promising target for future immunotherapeutic strategies and cancer vaccines.
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Affiliation(s)
- Gianni Gerlini
- Plastic and Reconstructive Surgery Unit, Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Santa Maria Annunziata Hospital, 50012 Florence, Italy; (S.S.); (P.B.); (V.G.); (L.B.)
| | - Pietro Susini
- Plastic Surgery Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy;
| | - Serena Sestini
- Plastic and Reconstructive Surgery Unit, Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Santa Maria Annunziata Hospital, 50012 Florence, Italy; (S.S.); (P.B.); (V.G.); (L.B.)
| | - Paola Brandani
- Plastic and Reconstructive Surgery Unit, Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Santa Maria Annunziata Hospital, 50012 Florence, Italy; (S.S.); (P.B.); (V.G.); (L.B.)
| | - Vanni Giannotti
- Plastic and Reconstructive Surgery Unit, Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Santa Maria Annunziata Hospital, 50012 Florence, Italy; (S.S.); (P.B.); (V.G.); (L.B.)
| | - Lorenzo Borgognoni
- Plastic and Reconstructive Surgery Unit, Regional Melanoma Referral Center and Melanoma & Skin Cancer Unit, Santa Maria Annunziata Hospital, 50012 Florence, Italy; (S.S.); (P.B.); (V.G.); (L.B.)
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17
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Plebanek MP, Xue Y, Nguyen YV, DeVito NC, Wang X, Holtzhausen A, Beasley GM, Theivanthiran B, Hanks BA. A lactate-SREBP2 signaling axis drives tolerogenic dendritic cell maturation and promotes cancer progression. Sci Immunol 2024; 9:eadi4191. [PMID: 38728412 PMCID: PMC11926670 DOI: 10.1126/sciimmunol.adi4191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 04/12/2024] [Indexed: 05/12/2024]
Abstract
Conventional dendritic cells (DCs) are essential mediators of antitumor immunity. As a result, cancers have developed poorly understood mechanisms to render DCs dysfunctional within the tumor microenvironment (TME). After identification of CD63 as a specific surface marker, we demonstrate that mature regulatory DCs (mregDCs) migrate to tumor-draining lymph node tissues and suppress DC antigen cross-presentation in trans while promoting T helper 2 and regulatory T cell differentiation. Transcriptional and metabolic studies showed that mregDC functionality is dependent on the mevalonate biosynthetic pathway and its master transcription factor, SREBP2. We found that melanoma-derived lactate activates SREBP2 in tumor DCs and drives conventional DC transformation into mregDCs via homeostatic or tolerogenic maturation. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promoted antitumor CD8+ T cell activation and suppressed melanoma progression. CD63+ mregDCs were found to reside within the lymph nodes of several preclinical tumor models and in the sentinel lymph nodes of patients with melanoma. Collectively, this work suggests that a tumor lactate-stimulated SREBP2-dependent program promotes CD63+ mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME.
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Affiliation(s)
- Michael P. Plebanek
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Yue Xue
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Y-Van Nguyen
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Nicholas C. DeVito
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Xueying Wang
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA
| | - Alisha Holtzhausen
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Georgia M. Beasley
- Department of Surgery, Division of Surgical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Balamayooran Theivanthiran
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
| | - Brent A. Hanks
- Department of Medicine, Division of Medical Oncology, Duke Cancer Institute, Duke University, Durham, NC 27708, USA
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27708, USA
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18
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Burk AC, Apostolova P. Metabolic instruction of the graft-versus-leukemia immunity. Front Immunol 2024; 15:1347492. [PMID: 38500877 PMCID: PMC10944922 DOI: 10.3389/fimmu.2024.1347492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 02/05/2024] [Indexed: 03/20/2024] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is frequently performed to cure hematological malignancies, such as acute myeloid leukemia (AML), through the graft-versus-leukemia (GVL) effect. In this immunological process, donor immune cells eliminate residual cancer cells in the patient and exert tumor control through immunosurveillance. However, GVL failure and subsequent leukemia relapse are frequent and associated with a dismal prognosis. A better understanding of the mechanisms underlying AML immune evasion is essential for developing novel therapeutic strategies to boost the GVL effect. Cellular metabolism has emerged as an essential regulator of survival and cell fate for both cancer and immune cells. Leukemia and T cells utilize specific metabolic programs, including the orchestrated use of glucose, amino acids, and fatty acids, to support their growth and function. Besides regulating cell-intrinsic processes, metabolism shapes the extracellular environment and plays an important role in cell-cell communication. This review focuses on recent advances in the understanding of how metabolism might affect the anti-leukemia immune response. First, we provide a general overview of the mechanisms of immune escape after allo-HCT and an introduction to leukemia and T cell metabolism. Further, we discuss how leukemia and myeloid cell metabolism contribute to an altered microenvironment that impairs T cell function. Next, we review the literature linking metabolic processes in AML cells with their inhibitory checkpoint ligand expression. Finally, we focus on recent findings concerning the role of systemic metabolism in sustained GVL efficacy. While the majority of evidence in the field still stems from basic and preclinical studies, we discuss translational findings and propose further avenues for bridging the gap between bench and bedside.
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Affiliation(s)
- Ann-Cathrin Burk
- German Cancer Consortium (DKTK), partner site Freiburg, a partnership between DKFZ and Medical Center - University of Freiburg, Freiburg, Germany
- Department of Medicine I, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Petya Apostolova
- Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
- Division of Hematology, University Hospital Basel, Basel, Switzerland
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19
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Ebokaiwe AP, Olasehinde O, Chimezie IP, Odobi UR, Nvene C, Faith E. Zinc Ameliorates Cadmium-Induced Immunotoxicity by Modulating Splenic Immunosuppressive Indoleamine 2,3-Dioxygenase Activity, Hematological Indices, and CD4 + T Cells via Inhibition of Cadmium Uptake in Male Wistar Rats. Biol Trace Elem Res 2024; 202:1140-1149. [PMID: 37392360 DOI: 10.1007/s12011-023-03752-7] [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: 03/10/2023] [Accepted: 06/24/2023] [Indexed: 07/03/2023]
Abstract
Cadmium (Cd)-induced immunotoxicity has become a matter of public health concern owing to its prevalence in the environment consequently, great potential for human exposure. Zinc (Zn) has been known to possess antioxidant, anti-inflammatory, and immune-boosting properties. However, the ameliorating influence of Zn against Cd-induced immunotoxicity connecting the IDO pathway is lacking. Adult male Wistar rats were exposed to normal drinking water with no metal contaminants (group 1), group 2 received drinking water containing 200 μg/L of Cd, group 3 received drinking water containing 200 μg/L of Zn, and group 4 received Cd and Zn as above in drinking water for 42 days. Cd exposure alone significantly triggered the splenic oxidative-inflammatory stress, increased activities of immunosuppressive tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenases (IDO) activities/protein expression, and decreased CD4+ T cell count, and a corresponding increase in the serum kynurenine concentration, as well as alterations in the hematological parameters and histologic structure when compared with the control (p < 0.05). Zn alone did not have any effect relative to the control group while co-exposure significantly (p < 0.05) assuaged the Cd-induced alterations in the studied parameters relative to the control. Cd-induced modifications in IDO 1 protein expression, IDO/TDO activities, oxidative-inflammatory stress, hematological parameters/CD4+ T cell, and histological structure in the spleen of rats within the time course of the investigation were prevented by Zn co-exposure via inhibition of Cd uptake.
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Affiliation(s)
- Azubuike Peter Ebokaiwe
- Toxicology and Immunotherapy Research Unit, Department of Biochemistry, Alex Ekwueme Federal University Ndufu Alike, PMB 1010, Abakaliki, Ebonyi State, Nigeria.
| | | | - Iyiagwor P Chimezie
- Toxicology and Immunotherapy Research Unit, Department of Biochemistry, Alex Ekwueme Federal University Ndufu Alike, PMB 1010, Abakaliki, Ebonyi State, Nigeria
| | - Ushang R Odobi
- Toxicology and Immunotherapy Research Unit, Department of Biochemistry, Alex Ekwueme Federal University Ndufu Alike, PMB 1010, Abakaliki, Ebonyi State, Nigeria
| | - Chiamaka Nvene
- Toxicology and Immunotherapy Research Unit, Department of Biochemistry, Alex Ekwueme Federal University Ndufu Alike, PMB 1010, Abakaliki, Ebonyi State, Nigeria
| | - Ekoh Faith
- Toxicology and Immunotherapy Research Unit, Department of Biochemistry, Alex Ekwueme Federal University Ndufu Alike, PMB 1010, Abakaliki, Ebonyi State, Nigeria
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20
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Nicolini A, Rossi G, Ferrari P. Experimental and clinical evidence in favour of an effective immune stimulation in ER-positive, endocrine-dependent metastatic breast cancer. Front Immunol 2024; 14:1225175. [PMID: 38332913 PMCID: PMC10850262 DOI: 10.3389/fimmu.2023.1225175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 09/04/2023] [Indexed: 02/10/2024] Open
Abstract
In ER+ breast cancer, usually seen as the low immunogenic type, the main mechanisms favouring the immune response or tumour growth and immune evasion in the tumour microenvironment (TME) have been examined. The principal implications of targeting the oestrogen-mediated pathways were also considered. Recent experimental findings point out that anti-oestrogens contribute to the reversion of the immunosuppressive TME. Moreover, some preliminary clinical data with the hormone-immunotherapy association in a metastatic setting support the notion that the reversion of immune suppression in TME is likely favoured by the G0-G1 state induced by anti-oestrogens. Following immune stimulation, the reverted immune suppression allows the boosting of the effector cells of the innate and adaptive immune response. This suggests that ER+ breast cancer is a molecular subtype where a successful active immune manipulation can be attained. If this is confirmed by a prospective multicentre trial, which is expected in light of the provided evidence, the proposed hormone immunotherapy can also be tested in the adjuvant setting. Furthermore, the different rationale suggests a synergistic activity of our proposed immunotherapy with the currently recommended regimen consisting of antioestrogens combined with cyclin kinase inhibitors. Overall, this lays the foundation for a shift in clinical practice within this most prevalent molecular subtype of breast cancer.
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Affiliation(s)
- Andrea Nicolini
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy
| | - Giuseppe Rossi
- Epidemiology and Biostatistics Unit, Institute of Clinical Physiology, National Research Council and Gabriele Monasterio Foundation, Pisa, Italy
| | - Paola Ferrari
- Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy
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21
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Ma X, Liu D, Yu W, Han C. Alleviation of Rheumatoid Arthritis by Inducing IDO Expression with Trichinella spiralis Recombinant Protein 43. J Immunol Res 2024; 2024:8816919. [PMID: 38268530 PMCID: PMC10807947 DOI: 10.1155/2024/8816919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 11/14/2023] [Accepted: 12/30/2023] [Indexed: 01/26/2024] Open
Abstract
Rheumatoid arthritis (RA) represents the autoimmune disorder that shows aggressive arthritis as the main symptom. It is difficult to treat and can lead to joint deformation and function loss. At present, Trichinella spiralis (T. spiralis) antigen has attracted much attention because it plays a role in host immune regulatory mechanisms. Therefore, we selected T. spiralis recombinant protein 43 (Tsp43) to treat the bovine collagen type II (BCII)-induced mice RA model and explored its therapeutic mechanisms. This work first verified that Tsp43 could promote the expression of indoleamine 2, 3-dioxygenase (IDO) in dendritic cells (DCs) in vitro. Then, we randomized BALB/c mice (8 weeks old) into six groups, including control, phosphate buffer saline (PBS), BCII, BCII + heat inactivated Tsp43 (HiTsp43), BCII + Tsp43, and BCII + Tsp43 + 1-methyl-troptophan (1-MT) groups. To determine the therapeutic effect of Tsp43 on the BCII-induced mice RA model, relevant cytokines in each group and pathological changes in ankle joints were detected. To explore the mechanisms of Tsp43 on the BCII-induced mice RA model, we checked the expression of IDO in each group, CD4+T cell proliferation, and apoptosis. Collectively, Tsp43 decreased tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) expression in BCII-induced mice RA model and recovered the ankle injury to a certain extent. Tsp43 promoted high expression of IDO, caused expression of related apoptotic proteins in CD4+T cells, and caused apoptosis in CD4+T cells. In addition, Tsp43 reduced the proliferation of CD4+T cells. However, these effects can be inhibited by 1-MT (IDO inhibitor). These results suggested that Tsp43 played an important role in the treatment of arthritis by inhibiting the proliferation of CD4+T cells and inducing CD4+T cells apoptosis through the high expression of IDO. The purpose of this experiment was to provide a new idea for the treatment of RA and lay a foundation for the development of parasite-derived drugs for the treatment of RA.
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Affiliation(s)
- Xiao Ma
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
- Heilongjiang Key Laboratory of Zoonosis, Harbin, China
| | - Dongming Liu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
- Heilongjiang Key Laboratory of Zoonosis, Harbin, China
| | - Wenhao Yu
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
- Heilongjiang Key Laboratory of Zoonosis, Harbin, China
| | - Caixia Han
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, China
- Heilongjiang Key Laboratory of Zoonosis, Harbin, China
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22
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Mao XF, Zhang XQ, Yao ZY, Mao HJ. Advances in mesenchymal stem cells therapy for tendinopathies. Chin J Traumatol 2024; 27:11-17. [PMID: 38052701 PMCID: PMC10859297 DOI: 10.1016/j.cjtee.2023.11.002] [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: 02/23/2023] [Revised: 10/13/2023] [Accepted: 11/07/2023] [Indexed: 12/07/2023] Open
Abstract
Tendinopathies are chronic diseases of an unknown etiology and associated with inflammation. Mesenchymal stem cells (MSCs) have emerged as a viable therapeutic option to combat the pathological progression of tendinopathies, not only because of their potential for multidirectional differentiation and self-renewal, but also their excellent immunomodulatory properties. The immunomodulatory effects of MSCs are increasingly being recognized as playing a crucial role in the treatment of tendinopathies, with MSCs being pivotal in regulating the inflammatory microenvironment by modulating the immune response, ultimately contributing to improved tissue repair. This review will discuss the current knowledge regarding the application of MSCs in tendinopathy treatments through the modulation of the immune response.
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Affiliation(s)
- Xu-Feng Mao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang province, China
| | - Xi-Qian Zhang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang province, China
| | - Zhe-Yu Yao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang province, China
| | - Hai-Jiao Mao
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, Zhejiang province, China.
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23
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Liu J, Tian R, Sun C, Guo Y, Dong L, Li Y, Song X. Microbial metabolites are involved in tumorigenesis and development by regulating immune responses. Front Immunol 2023; 14:1290414. [PMID: 38169949 PMCID: PMC10758836 DOI: 10.3389/fimmu.2023.1290414] [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: 09/07/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024] Open
Abstract
The human microbiota is symbiotic with the host and can create a variety of metabolites. Under normal conditions, microbial metabolites can regulate host immune function and eliminate abnormal cells in a timely manner. However, when metabolite production is abnormal, the host immune system might be unable to identify and get rid of tumor cells at the early stage of carcinogenesis, which results in tumor development. The mechanisms by which intestinal microbial metabolites, including short-chain fatty acids (SCFAs), microbial tryptophan catabolites (MTCs), polyamines (PAs), hydrogen sulfide, and secondary bile acids, are involved in tumorigenesis and development by regulating immune responses are summarized in this review. SCFAs and MTCs can prevent cancer by altering the expression of enzymes and epigenetic modifications in both immune cells and intestinal epithelial cells. MTCs can also stimulate immune cell receptors to inhibit the growth and metastasis of the host cancer. SCFAs, MTCs, bacterial hydrogen sulfide and secondary bile acids can control mucosal immunity to influence the occurrence and growth of tumors. Additionally, SCFAs, MTCs, PAs and bacterial hydrogen sulfide can also affect the anti-tumor immune response in tumor therapy by regulating the function of immune cells. Microbial metabolites have a good application prospect in the clinical diagnosis and treatment of tumors, and our review provides a good basis for related research.
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Affiliation(s)
- Jiahui Liu
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Ruxian Tian
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Caiyu Sun
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Ying Guo
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Lei Dong
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Yumei Li
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
| | - Xicheng Song
- Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
- Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, China
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24
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Ren X, Wei Y, Zhao H, Shao J, Zeng F, Wang Z, Li L. A comprehensive review and comparison of L-tryptophan biosynthesis in Saccharomyces cerevisiae and Escherichia coli. Front Bioeng Biotechnol 2023; 11:1261832. [PMID: 38116200 PMCID: PMC10729320 DOI: 10.3389/fbioe.2023.1261832] [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: 07/20/2023] [Accepted: 11/22/2023] [Indexed: 12/21/2023] Open
Abstract
L-tryptophan and its derivatives are widely used in the chemical, pharmaceutical, food, and feed industries. Microbial fermentation is the most commonly used method to produce L-tryptophan, which calls for an effective cell factory. The mechanism of L-tryptophan biosynthesis in Escherichia coli, the widely used producer of L-tryptophan, is well understood. Saccharomyces cerevisiae also plays a significant role in the industrial production of biochemicals. Because of its robustness and safety, S. cerevisiae is favored for producing pharmaceuticals and food-grade biochemicals. However, the biosynthesis of L-tryptophan in S. cerevisiae has been rarely summarized. The synthetic pathways and engineering strategies of L-tryptophan in E. coli and S. cerevisiae have been reviewed and compared in this review. Furthermore, the information presented in this review pertains to the existing understanding of how L-tryptophan affects S. cerevisiae's stress fitness, which could aid in developing a novel plan to produce more resilient industrial yeast and E. coli cell factories.
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Affiliation(s)
- Xinru Ren
- College of Science and Technology, Hebei Agricultural University, Cangzhou, China
| | - Yue Wei
- College of Science and Technology, Hebei Agricultural University, Cangzhou, China
| | - Honglu Zhao
- College of Science and Technology, Hebei Agricultural University, Cangzhou, China
| | - Juanjuan Shao
- College of Science and Technology, Hebei Agricultural University, Cangzhou, China
| | - Fanli Zeng
- College of Life Sciences, Hebei Agricultural University, Baoding, China
- Hebei Key Laboratory of Analysis and Control of Zoonotic Pathogenic Microorganism, Baoding, China
| | - Zhen Wang
- College of Science and Technology, Hebei Agricultural University, Cangzhou, China
- Hebei Key Laboratory of Analysis and Control of Zoonotic Pathogenic Microorganism, Baoding, China
| | - Li Li
- College of Science and Technology, Hebei Agricultural University, Cangzhou, China
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25
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Peixoto PM, Bromfield JJ, Ribeiro ES, Santos JEP, Thatcher WW, Bisinotto RS. Transcriptome changes associated with elongation of bovine conceptuses II: Differentially expressed transcripts in the endometrium on day 17 after insemination. J Dairy Sci 2023; 106:9763-9777. [PMID: 37641338 DOI: 10.3168/jds.2023-23399] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 06/15/2023] [Indexed: 08/31/2023]
Abstract
The objective was to characterize endometrial transcriptome on d 17 of gestation in dairy cows according to conceptus length. Nonlactating Holstein cows (n = 48) were slaughtered 17 d after AI and the uterine horn ipsilateral to the corpus luteum (CL) was flushed with saline solution. Recovered conceptuses were classified as small (1.2-6.9 cm; n = 9), medium (10.5-16.0 cm; n = 9), or large (18.0-26.4 cm; n = 10). Samples of intercaruncular endometrium dissected from the caudal, intermediate, and cranial portions of the uterine horn ipsilateral to the pregnancy were pooled for analyses. Total mRNA was extracted from endometrial tissue and subjected to transcriptome analyses using the Affymetrix Gene Chip Bovine array. Data were normalized using the GCRMA method and analyzed by robust regression using the Linear Models for Microarray library within Bioconductor in R. Transcripts with P ≤ 0.05 after adjustment for false discovery rate and fold change ≥1.5 were considered differentially expressed. Functional analyses were conducted using the Ingenuity Pathway Analysis platform. Comparisons between endometria of cows carrying large versus small (LvsS), large versus medium (LvsM), and medium versus small (MvsS) conceptuses yielded a total of 235, 21, and 94 differentially expressed transcripts, respectively. Top canonical pathways included the antigen presentation pathway and Th1/Th2 activation pathways, both for LvsS and MvsS. Interferon-α and -γ were identified as activated upstream regulators, primarily based on differently expressed transcripts such as IDO1, ISG20, WARS, LGALS9, IFI44, and PSMB9 (LvsS and MvsS). For LvsS, regulator analyses revealed predicted activation of FOXO1, IFN, NFACTC2, IL-12, IL-6, and IL-18, whereas it depicted inhibition of IL10RA and ZBTB1. Changes in these regulators were associated with a downstream activation of leukocytes, as well as quantity and expansion of T lymphocytes. Canonical pathways associated with the comparison LvsM included cell cycle G2/M DNA damage checkpoint regulation, cell cycle control of chromosomal replication. Moreover, tretinoin was predicted, as activated in upstream analysis for the same comparison. In conclusion, most of the differently expressed transcripts in the endometrium on d 17 of gestation were identified between cows carrying small conceptuses compared with counterparts carrying medium and large conceptuses and were involved with pathways associated with modulation of the immune response.
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Affiliation(s)
- P M Peixoto
- Department of Large Animal Clinical Sciences, D. H. Barron Reproductive, and Perinatal Biology Research Program, University of Florida, Gainesville, FL 32610
| | - J J Bromfield
- Department of Animal Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, FL 32608
| | - E S Ribeiro
- Department of Animal Biosciences, University of Guelph, Guelph, ON N1G 2W1, Canada
| | - J E P Santos
- Department of Animal Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, FL 32608
| | - W W Thatcher
- Department of Animal Sciences, D. H. Barron Reproductive and Perinatal Biology Research Program, University of Florida, Gainesville, FL 32608
| | - R S Bisinotto
- Department of Large Animal Clinical Sciences, D. H. Barron Reproductive, and Perinatal Biology Research Program, University of Florida, Gainesville, FL 32610.
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26
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Yokosawa T, Wakasugi K. Tryptophan-Starved Human Cells Overexpressing Tryptophanyl-tRNA Synthetase Enhance High-Affinity Tryptophan Uptake via Enzymatic Production of Tryptophanyl-AMP. Int J Mol Sci 2023; 24:15453. [PMID: 37895133 PMCID: PMC10607379 DOI: 10.3390/ijms242015453] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/18/2023] [Accepted: 10/21/2023] [Indexed: 10/29/2023] Open
Abstract
Our previous study demonstrated that L-tryptophan (Trp)-depleted cells display a marked enhancement in Trp uptake facilitated by extracellular tryptophanyl-tRNA synthetase (TrpRS). Here, we show that Trp uptake into TrpRS-overexpressing cells is also markedly elevated upon Trp starvation. These findings indicate that a Trp-deficient condition is critical for Trp uptake, not only into cells to which TrpRS protein has been added but also into TrpRS-overexpressing cells. We also show that overexpression of TrpRS mutants, which cannot synthesize tryptophanyl-AMP, does not promote Trp uptake, and that inhibition of tryptophanyl-AMP synthesis suppresses this uptake. Overall, these data suggest that tryptophanyl-AMP production by TrpRS is critical for high-affinity Trp uptake.
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Affiliation(s)
- Takumi Yokosawa
- Komaba Organization for Educational Excellence, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan
| | - Keisuke Wakasugi
- Komaba Organization for Educational Excellence, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan
- Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, 3-8-1 Komaba, Meguro-ku, Tokyo 153-8902, Japan
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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27
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Yousuf S, Qiu M, Voith von Voithenberg L, Hulkkonen J, Macinkovic I, Schulz AR, Hartmann D, Mueller F, Mijatovic M, Ibberson D, AlHalabi KT, Hetzer J, Anders S, Brüne B, Mei HE, Imbusch CD, Brors B, Heikenwälder M, Gaida MM, Büchler MW, Weigert A, Hackert T, Roth S. Spatially Resolved Multi-Omics Single-Cell Analyses Inform Mechanisms of Immune Dysfunction in Pancreatic Cancer. Gastroenterology 2023; 165:891-908.e14. [PMID: 37263303 DOI: 10.1053/j.gastro.2023.05.036] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2022] [Revised: 05/22/2023] [Accepted: 05/23/2023] [Indexed: 06/03/2023]
Abstract
BACKGROUND & AIMS As pancreatic ductal adenocarcinoma (PDAC) continues to be recalcitrant to therapeutic interventions, including poor response to immunotherapy, albeit effective in other solid malignancies, a more nuanced understanding of the immune microenvironment in PDAC is urgently needed. We aimed to unveil a detailed view of the immune micromilieu in PDAC using a spatially resolved multimodal single-cell approach. METHODS We applied single-cell RNA sequencing, spatial transcriptomics, multiplex immunohistochemistry, and mass cytometry to profile the immune compartment in treatment-naïve PDAC tumors and matched adjacent normal pancreatic tissue, as well as in the systemic circulation. We determined prognostic associations of immune signatures and performed a meta-analysis of the immune microenvironment in PDAC and lung adenocarcinoma on single-cell level. RESULTS We provided a spatially resolved fine map of the immune landscape in PDAC. We substantiated the exhausted phenotype of CD8 T cells and immunosuppressive features of myeloid cells, and highlighted immune subsets with potentially underappreciated roles in PDAC that diverged from immune populations within adjacent normal areas, particularly CD4 T cell subsets and natural killer T cells that are terminally exhausted and acquire a regulatory phenotype. Differential analysis of immune phenotypes in PDAC and lung adenocarcinoma revealed the presence of extraordinarily immunosuppressive subtypes in PDAC, along with a distinctive immune checkpoint composition. CONCLUSIONS Our study sheds light on the multilayered immune dysfunction in PDAC and presents a holistic view of the immune landscape in PDAC and lung adenocarcinoma, providing a comprehensive resource for functional studies and the exploration of therapeutically actionable targets in PDAC.
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Affiliation(s)
- Suhail Yousuf
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Mengjie Qiu
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | | | - Johannes Hulkkonen
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Igor Macinkovic
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | | | - Domenic Hartmann
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Florian Mueller
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Margarete Mijatovic
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany
| | - David Ibberson
- Deep Sequencing Core Facility, BioQuant, Heidelberg University, Heidelberg, Germany
| | - Karam T AlHalabi
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Jenny Hetzer
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Simon Anders
- BioQuant Center, Heidelberg University, Heidelberg, Germany
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany; Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany; German Cancer Consortium, Partner Site Frankfurt, Germany
| | - Henrik E Mei
- German Rheumatism Research Center, Berlin, Germany
| | - Charles D Imbusch
- Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany
| | - Benedikt Brors
- Division of Applied Bioinformatics, German Cancer Research Center, Heidelberg, Germany
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, Heidelberg, Germany
| | - Matthias M Gaida
- Institute of Pathology, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany; Research Center for Immunotherapy, University Medical Center Mainz, Johannes Gutenberg University, Mainz, Germany; Joint Unit Immunopathology, Institute of Pathology, University Medical Center, Johannes Gutenberg University and Translational Oncology, University Medical Center Mainz, Mainz, Germany
| | - Markus W Büchler
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Andreas Weigert
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Frankfurt, Germany; Frankfurt Cancer Institute, Goethe-University Frankfurt, Frankfurt, Germany; German Cancer Consortium, Partner Site Frankfurt, Germany
| | - Thilo Hackert
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany
| | - Susanne Roth
- Department of Surgery, Heidelberg University Hospital, Heidelberg, Germany.
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28
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Mohapatra SK, Chaudhary D, Panda BSK, Kamboj A, Kapila R, Dang AK. Indoleamine 2, 3-dioxygenase 1 mediated alterations in the functionality of immune cells, deciphers the pregnancy outcomes in crossbred dairy cows. J Reprod Immunol 2023; 158:103972. [PMID: 37302363 DOI: 10.1016/j.jri.2023.103972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 05/25/2023] [Accepted: 05/28/2023] [Indexed: 06/13/2023]
Abstract
Pregnancy establishment in bovines requires maternal immune cell modulation. Present study investigated possible role of immunosuppressive indolamine-2, 3-dioxygenase 1 (IDO1) enzyme in the alteration of neutrophil (NEUT) and peripheral blood mononuclear cells (PBMCs) functionality of crossbred cows. Blood was collected from non-pregnant (NP) and pregnant (P) cows, followed by isolation of NEUT and PBMCs. Plasma pro-inflammatory (IFNγ and TNFα) and anti-inflammatory cytokines (IL-4 and IL-10) were estimated by ELISA and analysis of IDO1 gene in NEUT and PBMCs by RT-qPCR. Neutrophil functionality was assessed by chemotaxis, measuring activity of myeloperoxidase and β-D glucuronidase enzyme and evaluating nitric oxide production. Changes in PBMCs functionality was determined by transcriptional expression of pro-inflammatory (IFNγ, TNFα) and anti-inflammatory cytokine (IL-4, IL-10, TGFβ1) genes. Significantly elevated (P < 0.05) anti-inflammatory cytokines, increased IDO1 expression, reduced NEUT velocity, MPO activity and NO production observed only in P cows. Significantly higher (P < 0.05) expression of anti-inflammatory cytokines and TNFα genes were observed in PBMCs. Study highlights possible role of IDO1 in modulating the immune cell and cytokine activity during early pregnancy and may be targeted as early pregnancy biomarkers.
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Affiliation(s)
- Sunil Kumar Mohapatra
- Department of Animal Biochemistry, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Dheeraj Chaudhary
- Lactation and Immuno-Physiology Laboratory, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Bibhudatta S K Panda
- Lactation and Immuno-Physiology Laboratory, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Aarti Kamboj
- Lactation and Immuno-Physiology Laboratory, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Rajeev Kapila
- Department of Animal Biochemistry, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India
| | - Ajay Kumar Dang
- Lactation and Immuno-Physiology Laboratory, ICAR-National Dairy Research Institute, Karnal, Haryana 132001, India.
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29
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Chen SY, Cao JL, Li KP, Wan S, Yang L. BIN1 in cancer: biomarker and therapeutic target. J Cancer Res Clin Oncol 2023; 149:7933-7944. [PMID: 36890396 DOI: 10.1007/s00432-023-04673-7] [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: 12/27/2022] [Accepted: 02/28/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND The bridging integrator 1 (BIN1) protein was originally identified as a pro-apoptotic tumor suppressor that binds to and inhibits oncogenic MYC transcription factors. BIN1 has complex physiological functions participating in endocytosis, membrane cycling, cytoskeletal regulation, DNA repair deficiency, cell-cycle arrest, and apoptosis. The expression of BIN1 is closely related to the development of various diseases such as cancer, Alzheimer's disease, myopathy, heart failure, and inflammation. PURPOSE Because BIN1 is commonly expressed in terminally differentiated normal tissues and is usually undetectable in refractory or metastatic cancer tissues, this differential expression has led us to focus on human cancers associated with BIN1. In this review, we discuss the potential pathological mechanisms of BIN1 during cancer development and its feasibility as a prognostic marker and therapeutic target for related diseases based on recent findings on its molecular, cellular, and physiological roles. CONCLUSION BIN1 is a tumor suppressor that regulates cancer development through a series of signals in tumor progression and microenvironment. It also makes BIN1 a feasible early diagnostic or prognostic marker for cancer.
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Affiliation(s)
- Si-Yu Chen
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Jin-Long Cao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Kun-Peng Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Shun Wan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Li Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China.
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Struckmeier AK, Radermacher A, Fehrenz M, Bellin T, Alansary D, Wartenberg P, Boehm U, Wagner M, Scheller A, Hess J, Moratin J, Freudlsperger C, Hoffmann J, Thurner L, Roemer K, Freier K, Horn D. IDO1 is highly expressed in macrophages of patients in advanced tumour stages of oral squamous cell carcinoma. J Cancer Res Clin Oncol 2023; 149:3623-3635. [PMID: 35963900 PMCID: PMC10314853 DOI: 10.1007/s00432-022-04277-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 08/09/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE Strategies for Indolamine-2,3-dioxygenase 1 (IDO1) inhibition in cancer immunotherapy once produced encouraging results, but failed in clinical trials. Recent evidence indicates that immune cells in the tumour microenvironment, especially macrophages, contribute to immune dysregulation and therefore might play a critical role in drug resistance. METHODS In this study, we investigated the significance of IDO1 expressing immune cells in primary tumours and corresponding lymph node metastases (LNMs) in oral squamous cell carcinoma (OSCC) by immunohistochemistry. The link between IDO1 and macrophages was investigated by flow cytometry in tumour tissue, healthy adjacent tissue and peripheral blood mononuclear cells (PBMCs). IDO1 activity (measured as Kynurenine/Tryptophan ratio) was assessed by ELISAs. RESULTS High IDO1 expression in tumour-infiltrating immune cells was significantly correlated with advanced stages [Spearman's rank correlation (SRC), p = 0.027] and reduced progression-free survival (multivariate Cox regression, p = 0.034). IDO1 was significantly higher expressed in PBMCs of patients in advanced stages than in healthy controls (ANOVA, p < 0.05) and IDO1+ macrophages were more abundant in intratumoural areas than peritumoural (t test, p < 0.001). IDO1 expression in PBMCs was significantly correlated with IDO1 activity in serum (SRC, p < 0.05). IDO1 activity was significantly higher in patients with LNMs (t test, p < 0.01). CONCLUSION All in all, IDO1 expressing immune cells, especially macrophages, are more abundant in advanced stages of OSCC and are associated with reduced progression-free survival. Further investigations are needed to explore their role in local and systemic immune response. The IDO1 activity might be a suitable biomarker of metastasis in OSCC patients.
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Affiliation(s)
- Ann-Kristin Struckmeier
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany.
| | - Anne Radermacher
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
| | - Michael Fehrenz
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
| | - Tamara Bellin
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
| | - Dalia Alansary
- Institute of Biophysics, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Saar, Germany
| | - Philipp Wartenberg
- Department of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Saar, Germany
| | - Ulrich Boehm
- Department of Experimental and Clinical Pharmacology and Toxicology, Center for Molecular Signaling (PZMS), Saarland University, Homburg, Saar, Germany
| | - Mathias Wagner
- Department of Pathology, Saarland University Medical Center, Homburg, Saar, Germany
| | - Anja Scheller
- Department of Molecular Physiology, Center for Integrative Physiology and Molecular Medicine (CIPMM), Saarland University, Homburg, Saar, Germany
| | - Jochen Hess
- Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Heidelberg, and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Julius Moratin
- Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Christian Freudlsperger
- Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Jürgen Hoffmann
- Department of Oral and Maxillofacial Surgery, University Hospital Heidelberg, Heidelberg, Germany
| | - Lorenz Thurner
- Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology, and Rheumatology), Saarland University Medical Center, Homburg, Saar, Germany
| | - Klaus Roemer
- José Carreras Center for Immuno and Gene Therapy, Saarland University, Homburg, Saar, Germany
| | - Kolja Freier
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
| | - Dominik Horn
- Department of Oral and Maxillofacial Surgery, Saarland University Medical Center, Kirrberger Str. 100, 66421, Homburg, Saar, Germany
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31
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Giannoukakis N. Tolerogenic dendritic cells in type 1 diabetes: no longer a concept. Front Immunol 2023; 14:1212641. [PMID: 37388741 PMCID: PMC10303908 DOI: 10.3389/fimmu.2023.1212641] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 05/31/2023] [Indexed: 07/01/2023] Open
Abstract
Tolerogenic dendritic cells (tDC) arrest the progression of autoimmune-driven dysglycemia into clinical, insulin-requiring type 1 diabetes (T1D) and preserve a critical mass of β cells able to restore some degree of normoglycemia in new-onset clinical disease. The safety of tDC, generated ex vivo from peripheral blood leukocytes, has been demonstrated in phase I clinical studies. Accumulating evidence shows that tDC act via multiple layers of immune regulation arresting the action of pancreatic β cell-targeting effector lymphocytes. tDC share a number of phenotypes and mechanisms of action, independent of the method by which they are generated ex vivo. In the context of safety, this yields confidence that the time has come to test the best characterized tDC in phase II clinical trials in T1D, especially given that tDC are already being tested for other autoimmune conditions. The time is also now to refine purity markers and to "universalize" the methods by which tDC are generated. This review summarizes the current state of tDC therapy for T1D, presents points of intersection of the mechanisms of action that the different embodiments use to induce tolerance, and offers insights into outstanding matters to address as phase II studies are imminent. Finally, we present a proposal for co-administration and serially-alternating administration of tDC and T-regulatory cells (Tregs) as a synergistic and complementary approach to prevent and treat T1D.
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Affiliation(s)
- Nick Giannoukakis
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
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32
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Ruiz-Fernández de Córdoba B, Martínez-Monge R, Lecanda F. ENPP1 Immunobiology as a Therapeutic Target. Clin Cancer Res 2023; 29:2184-2193. [PMID: 36719675 PMCID: PMC10261920 DOI: 10.1158/1078-0432.ccr-22-1681] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 11/17/2022] [Accepted: 01/13/2023] [Indexed: 02/01/2023]
Abstract
ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase) participates in the hydrolysis of different purine nucleotides in an array of physiologic processes. However, ENPP1 is frequently overexpressed in local relapses and tumor metastases, which are associated with poor prognosis and survival in a range of solid tumors. ENPP1 promotes an immunosuppressive tumor microenvironment (TME) by tilting the balance of ATP/adenosine (Ado) in conjunction with other components (CD38, CD39/ENTPD1, and CD73/NT5E). Moreover, ENPP1 intersects with the stimulator of interferon genes (STING), impairing its robust immune response through the hydrolysis of the effector 2´,3´-cyclic GMP-AMP. Thus, ENPP1 blockade emerges as a unique target eliciting immune remodeling and leveraging the STING pathway. Several ENPP1 inhibitors have shown an immunostimulatory effect, and their combination with other therapeutic modalities, such as immune-checkpoint blockade, STING activation, DNA damage response (DDR) inhibitors, and radiotherapy (RT), represents a promising avenue to boost antitumor-immune responses and to improve current clinical outcomes in several tumors. This comprehensive review summarizes the current state of the art and opens new perspectives for novel treatment strategies.
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Affiliation(s)
- Borja Ruiz-Fernández de Córdoba
- Solid Tumors Program. Division of Oncology, Center for Applied Medical Research, University of Navarra (CIMA), Navarra, Spain
| | - Rafael Martínez-Monge
- Oncology, Clínica University of Navarra, Navarra, Spain
- Radiation Oncology, Clínica University of Navarra, Navarra, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Pamplona, Spain
| | - Fernando Lecanda
- Solid Tumors Program. Division of Oncology, Center for Applied Medical Research, University of Navarra (CIMA), Navarra, Spain
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Pamplona, Spain
- School of Medicine, Department of Pathology, Anatomy and Physiology, University of Navarra, Navarra, Spain
- IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
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Plebanek MP, Xue Y, Nguyen YV, DeVito NC, Wang X, Holtzhausen A, Beasley GM, Yarla N, Thievanthiran B, Hanks BA. A SREBF2-dependent gene program drives an immunotolerant dendritic cell population during cancer progression. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.26.538456. [PMID: 37162965 PMCID: PMC10168385 DOI: 10.1101/2023.04.26.538456] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Dendritic cells (cDCs) are essential mediators of anti-tumor immunity. Cancers have developed mechanisms to render DCs dysfunctional within the tumor microenvironment. Utilizing CD63 as a unique surface marker, we demonstrate that mature regulatory DCs (mregDCs) suppress DC antigen cross-presentation while driving T H 2 and regulatory T cell differentiation within tumor-draining lymph node tissues. Transcriptional and metabolic studies show that mregDC functionality is dependent upon the mevalonate biosynthetic pathway and the master transcription factor, SREBP2. Melanoma-derived lactate activates DC SREBP2 in the tumor microenvironment (TME) and drives mregDC development from conventional DCs. DC-specific genetic silencing and pharmacologic inhibition of SREBP2 promotes anti-tumor CD8 + T cell activation and suppresses melanoma progression. CD63 + mregDCs reside within the sentinel lymph nodes of melanoma patients. Collectively, this work describes a tumor-driven SREBP2-dependent program that promotes CD63 + mregDC development and function while serving as a promising therapeutic target for overcoming immune tolerance in the TME. One Sentence Summary The metabolic transcription factor, SREBF2, regulates the development and tolerogenic function of the mregDC population within the tumor microenvironment.
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34
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Duan Z, Shi L, He ZNT, Kuang C, Han T, Yang Q. The Protective Effect of IDO1 Inhibition in Aβ-Treated Neurons and APP/PS1 Mice. Am J Alzheimers Dis Other Demen 2023; 38:15333175231214861. [PMID: 37944012 PMCID: PMC10637170 DOI: 10.1177/15333175231214861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Alzheimer's disease (AD) is an inflammatory associated disease, in which dysregulated kynurenine pathway (KP) plays a key role. Through KP, L-tryptophan is catabolized into neurotoxic and neuroprotective metabolites. The overactivation of indolamine 2,3-dioxygenase1 (IDO1), the first rate-limiting enzyme of KP, and the abnormal accumulation of KP metabolites have been noted in AD, and blocking IDO1 has been suggested as a therapeutic strategy. However, the expression patterns of KP enzymes in AD, and whether these enzymes are related to AD pathogenesis, have not been fully studied. Herein, we examined the expression patterns of inflammatory cytokines, neurotrophic factors and KP enzymes, and the activity of IDO1 and IDO1 effector pathway AhR (aryl hydrocarbon receptor) in AD mice. We studied the effects of IDO1 inhibitors on Aβ-related neuroinflammation in rat primary neurons, mouse hippocampal neuronal cells, and APP/PS1 mice. The results further demonstrated the importance of IDO1-catalyzed KP in neuroinflammation in Alzheimer's disease.
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Affiliation(s)
- Zhenzhen Duan
- School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Lei Shi
- School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Zhen Ning Tony He
- School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
| | - Chunxiang Kuang
- Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Shanghai, China
| | - Tianxiong Han
- Department of Traditional Chinese Medicine, Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Qing Yang
- School of Life Sciences, Shanghai Engineering Research Center of Industrial Microorganisms, Fudan University, Shanghai, China
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35
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Chen Z, Lan H, Liao Z, Huang J, Jian X, Hu J, Liao H. Regulatory T cells-centered regulatory networks of skeletal muscle inflammation and regeneration. Cell Biosci 2022; 12:112. [PMID: 35869487 PMCID: PMC9308315 DOI: 10.1186/s13578-022-00847-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 07/08/2022] [Indexed: 11/10/2022] Open
Abstract
As the understanding of skeletal muscle inflammation is increasingly clarified, the role of Treg cells in the treatment of skeletal muscle diseases has attracted more attention in recent years. A consensus has been reached that the regulation of Treg cells is the key to completing the switch of inflammation and repair of skeletal muscle, whose presence directly determine the repairing quality of the injured skeletal muscle. However, the functioning process of Treg cells remains unreported, thereby making it necessary to summarize the current role of Treg cells in skeletal muscle. In this review, the characteristics, origins, and cellular kinetics of these Treg cells are firstly described; Then, the relationship between Treg cells and muscle satellite cells (MuSCs), conventional T cells (Tconv) is discussed (the former is involved in the entire repair and regeneration process, while the latter matters considerably in causing most skeletal muscle autoimmune diseases); Next, focus is placed on the control of Treg cells on the phenotypic switch of macrophages, which is the key to the switch of inflammation; Finally, factors regulating the functional process of Treg cells are analyzed, and a regulatory network centered on Treg cells is summarized. The present study summarizes the cell-mediated interactions in skeletal muscle repair over the past decade, and elucidates the central role of regulatory T cells in this process, so that other researchers can more quickly and comprehensively understand the development and direction of this very field. It is believed that the hereby proposed viewpoints and problems can provide fresh visions for the latecomers.
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36
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Stone TW, Clanchy FIL, Huang YS, Chiang NY, Darlington LG, Williams RO. An integrated cytokine and kynurenine network as the basis of neuroimmune communication. Front Neurosci 2022; 16:1002004. [PMID: 36507331 PMCID: PMC9729788 DOI: 10.3389/fnins.2022.1002004] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Accepted: 10/31/2022] [Indexed: 11/25/2022] Open
Abstract
Two of the molecular families closely associated with mediating communication between the brain and immune system are cytokines and the kynurenine metabolites of tryptophan. Both groups regulate neuron and glial activity in the central nervous system (CNS) and leukocyte function in the immune system, although neither group alone completely explains neuroimmune function, disease occurrence or severity. This essay suggests that the two families perform complementary functions generating an integrated network. The kynurenine pathway determines overall neuronal excitability and plasticity by modulating glutamate receptors and GPR35 activity across the CNS, and regulates general features of immune cell status, surveillance and tolerance which often involves the Aryl Hydrocarbon Receptor (AHR). Equally, cytokines and chemokines define and regulate specific populations of neurons, glia or immune system leukocytes, generating more specific responses within restricted CNS regions or leukocyte populations. In addition, as there is a much larger variety of these compounds, their homing properties enable the superimposition of dynamic variations of cell activity upon local, spatially limited, cell populations. This would in principle allow the targeting of potential treatments to restricted regions of the CNS. The proposed synergistic interface of 'tonic' kynurenine pathway affecting baseline activity and the superimposed 'phasic' cytokine system would constitute an integrated network explaining some features of neuroimmune communication. The concept would broaden the scope for the development of new treatments for disorders involving both the CNS and immune systems, with safer and more effective agents targeted to specific CNS regions.
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Affiliation(s)
- Trevor W. Stone
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom,*Correspondence: Trevor W. Stone,
| | - Felix I. L. Clanchy
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Yi-Shu Huang
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - Nien-Yi Chiang
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
| | - L. Gail Darlington
- Department of Internal Medicine, Ashtead Hospital, Ashtead, United Kingdom
| | - Richard O. Williams
- The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, United Kingdom
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Crump LS, Kines KT, Richer JK, Lyons TR. Breast cancers co-opt normal mechanisms of tolerance to promote immune evasion and metastasis. Am J Physiol Cell Physiol 2022; 323:C1475-C1495. [PMID: 36189970 PMCID: PMC9662806 DOI: 10.1152/ajpcell.00189.2022] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/22/2022] [Accepted: 09/27/2022] [Indexed: 11/22/2022]
Abstract
Normal developmental processes, such as those seen during embryonic development and postpartum mammary gland involution, can be reactivated by cancer cells to promote immune suppression, tumor growth, and metastatic spread. In mammalian embryos, paternal-derived antigens are at risk of being recognized as foreign by the maternal immune system. Suppression of the maternal immune response toward the fetus, which is mediated in part by the trophoblast, is critical to ensure embryonic survival and development. The postpartum mammary microenvironment also exhibits immunosuppressive mechanisms accompanying the massive cell death and tissue remodeling that occurs during mammary gland involution. These normal immunosuppressive mechanisms are paralleled during malignant transformation, where tumors can develop neoantigens that may be recognized as foreign by the immune system. To circumvent this, tumors can dedifferentiate and co-opt immune-suppressive mechanisms normally utilized during fetal tolerance and postpartum mammary involution. In this review, we discuss those similarities and how they can inform our understanding of cancer progression and metastasis.
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Affiliation(s)
- Lyndsey S Crump
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Kelsey T Kines
- Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jennifer K Richer
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- University of Colorado Cancer Center, Aurora, Colorado
| | - Traci R Lyons
- Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Young Women's Breast Cancer Translational Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- University of Colorado Cancer Center, Aurora, Colorado
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Wiśnicki K, Donizy P, Remiorz A, Janczak D, Krajewska M, Banasik M. Significance of Indoleamine 2,3-Dioxygenase Expression in the Immunological Response of Kidney Graft Recipients. Diagnostics (Basel) 2022; 12:2353. [PMID: 36292041 PMCID: PMC9600090 DOI: 10.3390/diagnostics12102353] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Revised: 09/24/2022] [Accepted: 09/25/2022] [Indexed: 11/17/2022] Open
Abstract
Kidney transplantation is unquestionably the most advantageous and preferred treatment when patients with end-stage renal disease are considered. It does have a substantially positive influence on both the quality and expectancy of their lives. Thus, it is quintessential to extend the survival rate of kidney grafts. On account of T-cell-focused treatment, this is being exponentially achieved. The kynurenine pathway, as an immunosuppressive apparatus, and indoleamine 2,3-dioxygenase (IDO1), as its main regulator, are yet to be exhaustively explored. This review presents the recognised role of IDO1 and its influence on the kynurenine pathway, with emphasis on immunosuppression in kidney transplant protection.
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Affiliation(s)
- Krzysztof Wiśnicki
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Piotr Donizy
- Department of Clinical and Experimental Pathology, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Agata Remiorz
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Dariusz Janczak
- Department of Vascular, General and Transplantation Surgery, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Magdalena Krajewska
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland
| | - Mirosław Banasik
- Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, 50-556 Wroclaw, Poland
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Dendritic Cells: The Long and Evolving Road towards Successful Targetability in Cancer. Cells 2022; 11:cells11193028. [PMID: 36230990 PMCID: PMC9563837 DOI: 10.3390/cells11193028] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/19/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Dendritic cells (DCs) are a unique myeloid cell lineage that play a central role in the priming of the adaptive immune response. As such, they are an attractive target for immune oncology based therapeutic approaches. However, targeting these cells has proven challenging with many studies proving inconclusive or of no benefit in a clinical trial setting. In this review, we highlight the known and unknown about this rare but powerful immune cell. As technologies have expanded our understanding of the complexity of DC development, subsets and response features, we are now left to apply this knowledge to the design of new therapeutic strategies in cancer. We propose that utilization of these technologies through a multiomics approach will allow for an improved directed targeting of DCs in a clinical trial setting. In addition, the DC research community should consider a consensus on subset nomenclature to distinguish new subsets from functional or phenotypic changes in response to their environment.
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40
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Liang F, Wang GZ, Wang Y, Yang YN, Wen ZS, Chen DN, Fang WF, Zhang B, Yang L, Zhang C, Han SC, Yang FY, Wang D, Liang LJ, Wang Z, Zhao Y, Wang CL, Zhang L, Zhou GB. Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1. Signal Transduct Target Ther 2022; 7:311. [PMID: 36068203 PMCID: PMC9448807 DOI: 10.1038/s41392-022-01127-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/27/2022] [Accepted: 07/07/2022] [Indexed: 12/24/2022] Open
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1), the enzyme that catabolizes tryptophan (Trp) metabolism to promote regulatory T cells (Tregs) and suppress CD8+ T cells, is regulated by several intrinsic signaling pathways. Here, we found that tobacco smoke, a major public health concern that kills 8 million people each year worldwide, induced IDO1 in normal and malignant lung epithelial cells in vitro and in vivo. The carcinogen nicotine-derived nitrosaminoketone (NNK) was the tobacco compound that upregulated IDO1 via activation of the transcription factor c-Jun, which has a binding site for the IDO1 promoter. The NNK receptor α7 nicotinic acetylcholine receptor (α7nAChR) was required for NNK-induced c-Jun activation and IDO1 upregulation. In A/J mice, NNK reduced CD8+ T cells and increased Tregs. Clinically, smoker patients with non-small-cell lung cancer (NSCLC) exhibited high IDO1 levels and low Trp/kynurenine (Kyn) ratios. In NSCLC patients, smokers with lower IDO1 responded better to anti-PD1 antibody treatment than those with higher IDO1. These data indicate that tobacco smoke induces IDO1 to catabolize Trp metabolism and immune suppression to promote carcinogenesis, and lower IDO1 might be a potential biomarker for anti-PD1 antibodies in smoker patients, whereas IDO1-high smoker patients might benefit from IDO1 inhibitors in combination with anti-PD1 antibodies.
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Affiliation(s)
- Fan Liang
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Gui-Zhen Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yan Wang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ya-Ning Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhe-Sheng Wen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Medical Oncology Department, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Dong-Ni Chen
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Medical Oncology Department, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Wen-Feng Fang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Medical Oncology Department, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Bin Zhang
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Lu Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Medical Oncology and Radiation Sickness, Peking University Third Hospital, Beijing, China
| | - Chen Zhang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Si-Chong Han
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Fu-Ying Yang
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Di Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Li-Jun Liang
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zheng Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Chang-Li Wang
- Department of Lung Cancer, Tianjin Lung Cancer Center, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Li Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Medical Oncology Department, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Guang-Biao Zhou
- State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Souissi S, Ghedira R, Macherki Y, Ben‐Haj‐Ayed A, Gabbouj S, Remadi Y, Sfar I, Chadli Z, Aouam K, Hassine M, Bouaouina N, Zakhama A, Hassen E. Indoleamine 2,3-dioxygenase gene expression and kynurenine to tryptophan ratio correlation with nasopharyngeal carcinoma progression and survival. Immun Inflamm Dis 2022; 10:e690. [PMID: 36039641 PMCID: PMC9425015 DOI: 10.1002/iid3.690] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 06/27/2022] [Accepted: 08/04/2022] [Indexed: 01/19/2023] Open
Abstract
INTRODUCTION Indoleamine 2,3-dioxygenase (IDO) is an immunosuppressive tryptophan-depleting enzyme expressed in nasopharyngeal carcinoma (NPC) tissue. However, IDO has not been reported in the peripheral blood of NPC patients. The aim of this study was to analyze, IDO1 and IDO2 messenger RNA (mRNA) expression, the kynurenine (Kyn) and tryptophan (Trp) plasma levels, their clinical values and their relationship with cytokine levels in NPC. METHODS We evaluated IDO1 and IDO2 mRNA expression in peripheral blood mononuclear cells (PBMC) by quantitative real-time PCR, plasma Trp and Kyn levels by HPLC, and cytokine levels by ELISA in 75 NPC patients and 51 healthy controls. RESULTS Compared to controls, IDO1 mRNA expression was significantly upregulated and IDO2 mRNA expression was significantly downregulated in PBMC of patients. Also compared to controls, plasma Kyn levels and Kyn/Trp ratio were significantly higher in patients. At the time of diagnosis, the plasma Kyn/Trp ratio was associated with advanced cancer status and was an independent prognostic factor for worse disease-specific survival. According to cancer stages, IDO1 mRNA expression was positively correlated with plasma Kyn/Trp ratio in patients with earlier stages (I-II-III) but negatively correlated in patients with the late-stage cancer (IV). Tumor necrosis factor-α, interleukin (IL)-6 and IL-10 levels were significantly higher in patients compared to controls. Moreover, and despite treatment, patients simultaneously carrying high plasma Kyn/Trp ratio and high plasma IL-6 and IL-10 levels at diagnosis died approximately 1 year after first diagnosis. CONCLUSION Measuring blood IDO mRNA expression and Kyn/Trp ratio at diagnosis could be a potential marker to evaluate NPC progression and predict survival outcome.
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Affiliation(s)
- Sameh Souissi
- Laboratory of Molecular Immuno‐Oncology, Faculty of Medicine of MonastirUniversity of MonastirMonastirTunisia
- Higher Institute of Biotechnology of MonastirUniversity of MonastirMonastirTunisia
| | - Randa Ghedira
- Laboratory of Molecular Immuno‐Oncology, Faculty of Medicine of MonastirUniversity of MonastirMonastirTunisia
| | - Yosra Macherki
- Laboratory of Molecular Immuno‐Oncology, Faculty of Medicine of MonastirUniversity of MonastirMonastirTunisia
| | - Ahlem Ben‐Haj‐Ayed
- Laboratory of Molecular Immuno‐Oncology, Faculty of Medicine of MonastirUniversity of MonastirMonastirTunisia
| | - Sallouha Gabbouj
- Laboratory of Molecular Immuno‐Oncology, Faculty of Medicine of MonastirUniversity of MonastirMonastirTunisia
| | - Yasmine Remadi
- Laboratory of Molecular Immuno‐Oncology, Faculty of Medicine of MonastirUniversity of MonastirMonastirTunisia
| | - Imen Sfar
- Research Laboratory in Immunology of Renal Transplantation and ImmunopathologyTunis El Manar UniversityTunisTunisia
| | - Zohra Chadli
- Department of PharmacologyUniversity of MonastirMonastirTunisia
| | - Karim Aouam
- Department of PharmacologyUniversity of MonastirMonastirTunisia
| | - Mohsen Hassine
- Department of HematologyFattouma Bourguiba University HospitalMonastirTunisia
| | - Noureddine Bouaouina
- Laboratory of Molecular Immuno‐Oncology, Faculty of Medicine of MonastirUniversity of MonastirMonastirTunisia
- Department of Cancerology and RadiotherapyFarhat Hached University HospitalSousseTunisia
| | - Abdelfattah Zakhama
- Laboratory of Molecular Immuno‐Oncology, Faculty of Medicine of MonastirUniversity of MonastirMonastirTunisia
| | - Elham Hassen
- Laboratory of Molecular Immuno‐Oncology, Faculty of Medicine of MonastirUniversity of MonastirMonastirTunisia
- Higher Institute of Biotechnology of MonastirUniversity of MonastirMonastirTunisia
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Hosseinalizadeh H, Mahmoodpour M, Samadani AA, Roudkenar MH. The immunosuppressive role of indoleamine 2, 3-dioxygenase in glioblastoma: mechanism of action and immunotherapeutic strategies. Med Oncol 2022; 39:130. [PMID: 35716323 PMCID: PMC9206138 DOI: 10.1007/s12032-022-01724-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 03/30/2022] [Indexed: 12/14/2022]
Abstract
Glioblastoma multiforme (GBM) is a fatal brain tumor in adults with a bleak diagnosis. Expansion of immunosuppressive and malignant CD4 + FoxP3 + GITR + regulatory T cells is one of the hallmarks of GBM. Importantly, most of the patients with GBM expresses the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO). While IDO1 is generally not expressed at appreciable levels in the adult central nervous system, it is rapidly stimulated and highly expressed in response to ongoing immune surveillance in cancer. Increased levels of immune surveillance in cancer are thus related to higher intratumoral IDO expression levels and, as a result, a worse OS in GBM patients. Conversion of the important amino acid tryptophan into downstream catabolite known as kynurenines is the major function of IDO. Decreasing tryptophan and increasing the concentration of immunomodulatory tryptophan metabolites has been shown to induce T-cell apoptosis, increase immunosuppressive programming, and death of tumor antigen-presenting dendritic cells. This observation supported the immunotherapeutic strategy, and the targeted molecular therapy that suppresses IDO1 activity. We review the current understanding of the role of IDO1 in tumor immunological escape in brain tumors, the immunomodulatory effects of its primary catabolites, preclinical research targeting this enzymatic pathway, and various issues that need to be overcome to increase the prospective immunotherapeutic relevance in the treatment of GBM malignancy.
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Affiliation(s)
- Hamed Hosseinalizadeh
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Mehrdad Mahmoodpour
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Ali Akbar Samadani
- Guilan Road Trauma Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Mehryar Habibi Roudkenar
- Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Parastar St., 41887-94755, Rasht, Iran.
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Ye X, Li H, Anjum K, Zhong X, Miao S, Zheng G, Liu W, Li L. Dual Role of Indoles Derived From Intestinal Microbiota on Human Health. Front Immunol 2022; 13:903526. [PMID: 35784338 PMCID: PMC9248744 DOI: 10.3389/fimmu.2022.903526] [Citation(s) in RCA: 87] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/23/2022] [Indexed: 12/12/2022] Open
Abstract
Endogenous indole and its derivatives (indoles), considered as promising N-substituted heterocyclic compounds, are tryptophan metabolites derived from intestinal microbiota and exhibit a range of biological activities. Recent studies indicate that indoles contribute to maintaining the biological barrier of the human intestine, which exert the anti-inflammatory activities mainly through activating AhR and PXR receptors to affect the immune system’s function, significantly improving intestinal health (inflammatory bowel disease, hemorrhagic colitis, colorectal cancer) and further promote human health (diabetes mellitus, central system inflammation, and vascular regulation). However, the revealed toxic influences cannot be ignored. Indoxyl sulfate, an indole derivative, performs nephrotoxicity and cardiovascular toxicity. We addressed the interaction between indoles and intestinal microbiota and the indoles’ effects on human health as double-edged swords. This review provides scientific bases for the correlation of indoles with diseases moreover highlights several directions for subsequent indoles-related studies.
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Affiliation(s)
- Xuewei Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
- Department of Basic Medical Sciences, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Haiyi Li
- Department of Basic Medical Sciences, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Komal Anjum
- Department of Medicine and pharmacy, Ocean University of China, Qingdao, China
| | - Xinye Zhong
- Department of Basic Medical Sciences, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Shuping Miao
- Department of Basic Medical Sciences, Shulan International Medical College, Zhejiang Shuren University, Hangzhou, China
| | - Guowan Zheng
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, China
- Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People’s Hospital (Affiliated People’s Hospital, Hangzhou Medical College), Hangzhou, China
| | - Wei Liu
- Institute of Plant Protection and Microbiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, China
- *Correspondence: Lanjuan Li, ; Wei Liu,
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China
- *Correspondence: Lanjuan Li, ; Wei Liu,
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44
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Nguyen HO, Salvi V, Tiberio L, Facchinetti F, Govoni M, Villetti G, Civelli M, Barbazza I, Gaudenzi C, Passari M, Schioppa T, Sozio F, Del Prete A, Sozzani S, Bosisio D. The PDE4 inhibitor tanimilast shows distinct immunomodulatory properties associated with a type 2 endotype and CD141 upregulation. J Transl Med 2022; 20:203. [PMID: 35538539 PMCID: PMC9092691 DOI: 10.1186/s12967-022-03402-x] [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: 03/26/2022] [Accepted: 04/20/2022] [Indexed: 12/01/2022] Open
Abstract
Background Tanimilast is a novel and selective inhaled inhibitor of phosphodiesterase-4 in advanced clinical development for chronic obstructive pulmonary disease (COPD). Tanimilast is known to exert prominent anti-inflammatory activity when tested in preclinical experimental models as well as in human clinical studies. Recently, we have demonstrated that it also finely tunes, rather than suppressing, the cytokine network secreted by activated dendritic cells (DCs). This study was designed to characterize the effects of tanimilast on T-cell polarizing properties of DCs and to investigate additional functional and phenotypical features induced by tanimilast. Methods DCs at day 6 of culture were stimulated with LPS in the presence or absence of tanimilast or the control drug budesonide. After 24 h, DCs were analyzed for the expression of surface markers of maturation and activation by flow cytometry and cocultured with T cells to investigate cell proliferation and activation/polarization. The regulation of type 2-skewing mediators was investigated by real-time PCR in DCs and compared to results obtained in vivo in a randomized placebo-controlled trial on COPD patients treated with tanimilast. Results Our results show that both tanimilast and budesonide reduced the production of the immunostimulatory cytokine IFN-γ by CD4+ T cells. However, the two drugs acted at different levels since budesonide mainly blocked T cell proliferation, while tanimilast skewed T cells towards a Th2 phenotype without affecting cell proliferation. In addition, only DCs matured in the presence of tanimilast displayed increased CD86/CD80 ratio and CD141 expression, which correlated with Th2 T cell induction and dead cell uptake respectively. These cells also upregulated cAMP-dependent immunosuppressive molecules such as IDO1, TSP1, VEGF-A and Amphiregulin. Notably, the translational value of these data was confirmed by the finding that these same genes were upregulated also in sputum cells of COPD patients treated with tanimilast as add-on to inhaled glucocorticoids and bronchodilators. Conclusion Taken together, these findings demonstrate distinct immunomodulatory properties of tanimilast associated with a type 2 endotype and CD141 upregulation in DCs and provide a mechanistic rationale for the administration of tanimilast on top of inhaled corticosteroids.
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Affiliation(s)
- Hoang Oanh Nguyen
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Valentina Salvi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Laura Tiberio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Fabrizio Facchinetti
- Department of Experimental Pharmacology and Translational Science, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy
| | - Mirco Govoni
- Global Clinical Development, Chiesi Farmaceutici S.p.A., Parma, Italy
| | - Gino Villetti
- Department of Experimental Pharmacology and Translational Science, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy
| | - Maurizio Civelli
- Department of Experimental Pharmacology and Translational Science, Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A., Parma, Italy
| | - Ilaria Barbazza
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Carolina Gaudenzi
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Mauro Passari
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Tiziana Schioppa
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Francesca Sozio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Annalisa Del Prete
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
| | - Silvano Sozzani
- Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy. .,IRCCS Neuromed, Pozzilli, IS, Italy.
| | - Daniela Bosisio
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
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45
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Pashaei S, Yarani R, Mohammadi P, Emami Aleagha MS. The potential roles of amino acids and their major derivatives in the management of multiple sclerosis. Amino Acids 2022; 54:841-858. [PMID: 35471671 DOI: 10.1007/s00726-022-03162-4] [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] [Received: 11/05/2021] [Accepted: 04/05/2022] [Indexed: 11/29/2022]
Abstract
Recently, we reviewed the important role of carbohydrates and lipids metabolism in different clinical aspects of multiple sclerosis (MS) disease. In the current paper, we aimed to review the contribution of amino acids and their major derivatives to different clinical outcomes of the disease, including etiology, pathogenesis, diagnosis, prognosis, and treatment. In this line, Thr (threonine), Phe (phenylalanine), Glu (glutamate), Trp (tryptophan), and Sero (serotonin) are the main examples of biomolecules that have been suggested for MS therapy. It has been concluded that different amino acids and their derivatives might be considered prominent tools for the clinical management of MS disease.
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Affiliation(s)
- Somayeh Pashaei
- Department of Clinical Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Sorkhe-Ligeh Street, Kermanshah, Iran
| | - Reza Yarani
- Translational Type 1 Diabetes Biology, Department of Clinical Research, Steno Diabetes Center Copenhagen, Copenhagen, Denmark.,Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA, 94304, USA
| | - Pantea Mohammadi
- Medical Biology Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mohammad Sajad Emami Aleagha
- Department of Clinical Biochemistry, School of Medicine, Kermanshah University of Medical Sciences, Sorkhe-Ligeh Street, Kermanshah, Iran.
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46
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Mangaonkar AA, Patnaik MM. Role of the bone marrow immune microenvironment in chronic myelomonocytic leukemia pathogenesis: novel mechanisms and insights into clonal propagation. Leuk Lymphoma 2022; 63:1792-1800. [PMID: 35377828 DOI: 10.1080/10428194.2022.2056175] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Recent studies in chronic myelomonocytic leukemia (CMML) involving clonal dendritic cell (DC) aggregates and association with systemic immune dysregulation have highlighted novel and potentially targetable pathways of disease progression. CMML DC aggregates are populated by heterogeneous cell types such as CD123+ plasmacytoid dendritic cells (pDCs), CD11c + myeloid-derived DCs (mDCs), myeloid-derived suppressor cells (MDSCs), monocytes, and associate with an immune checkpoint called indoleamine 2,3-dioxygenase (IDO). Systemically, these IDO + DC aggregates are associated with immune tolerance marked by regulatory T cell expansion, likely mediated by aberrant DC-T cell interactions occurring within the bone marrow (BM) microenvironment. Somatic mutational events in CMML such as ASXL1 and NRAS mutations cooperate to induce T cell exhaustion and contribute toward disease progression to acute myeloid leukemia (AML). In this review, we explore the role of aging-induced alterations in the BM immune microenvironment, aberrant innate immune and proinflammatory signaling, and the adaptive immune system in CMML.
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Affiliation(s)
| | - Mrinal M Patnaik
- Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA
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47
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Ghosh A, Das C, Ghose S, Maitra A, Roy B, Majumder PP, Biswas NK. Integrative analysis of genomic and transcriptomic data of normal, tumour and co-occurring leukoplakia tissue triads drawn from patients with gingivobuccal oral cancer identifies signatures of tumour initiation and progression. J Pathol 2022; 257:593-606. [PMID: 35358331 PMCID: PMC9545831 DOI: 10.1002/path.5900] [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: 12/16/2021] [Revised: 03/25/2022] [Accepted: 03/28/2022] [Indexed: 11/16/2022]
Abstract
A thickened, white patch — leukoplakia — in the oral cavity is usually benign, but sometimes (in ~9% of individuals) it progresses to malignant tumour. Because the genomic basis of this progression is poorly understood, we undertook this study and collected samples of four tissues — leukoplakia, tumour, adjacent normal, and blood — from each of 28 patients suffering from gingivobuccal oral cancer. We performed multiomics analysis of the 112 collected tissues (four tissues per patient from 28 patients) and integrated information on progressive changes in the mutational and transcriptional profiles of each patient to create this genomic narrative. Additionally, we generated and analysed whole‐exome sequence data from leukoplakia tissues collected from 11 individuals not suffering from oral cancer. Nonsynonymous somatic mutations in the CASP8 gene were identified as the likely events to initiate malignant transformation, since these were frequently shared between tumour and co‐occurring leukoplakia. CASP8 alterations were also shown to enhance expressions of genes that favour lateral spread of mutant cells. During malignant transformation, additional pathogenic mutations are acquired in key genes (TP53, NOTCH1, HRAS) (41% of patients); chromosomal‐instability (arm‐level deletions of 19p and q, focal‐deletion of DNA‐repair pathway genes and NOTCH1, amplification of EGFR) (77%), and increased APOBEC‐activity (23%) are also observed. These additional alterations were present singly (18% of patients) or in combination (68%). Some of these alterations likely impact immune‐dynamics of the evolving transformed tissue; progression to malignancy is associated with immune suppression through infiltration of regulatory T‐cells (56%), depletion of cytotoxic T‐cells (68%), and antigen‐presenting dendritic cells (72%), with a concomitant increase in inflammation (92%). Patients can be grouped into three clusters by the estimated time to development of cancer from precancer by acquiring additional mutations (range: 4–10 years). Our findings provide deep molecular insights into the evolutionary processes and trajectories of oral cancer initiation and progression. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Arnab Ghosh
- National Institute of Biomedical Genomics, Kalyani, India
| | | | - Sandip Ghose
- Dr. R. Ahmed Dental College and Hospital, Kolkata, India
| | - Arindam Maitra
- National Institute of Biomedical Genomics, Kalyani, India
| | - Bidyut Roy
- Indian Statistical Institute, Kolkata, India
| | - Partha P Majumder
- National Institute of Biomedical Genomics, Kalyani, India.,Indian Statistical Institute, Kolkata, India
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Tolerogenic IDO1 +CD83 - Langerhans Cells in Sentinel Lymph Nodes of Patients with Melanoma. Int J Mol Sci 2022; 23:ijms23073441. [PMID: 35408802 PMCID: PMC8998685 DOI: 10.3390/ijms23073441] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/13/2022] [Accepted: 03/16/2022] [Indexed: 02/05/2023] Open
Abstract
Langerhans cells (LCs) are crucial regulators of anti-cancer immune responses. Cancer, however, can alter DCs functions leading to tolerance. The enzyme indoleamine 2,3-dioxygenase (IDO1) plays a crucial role in this process. In sentinel lymph nodes (SLNs) of patients with melanoma, LCs show phenotypical and functional alterations favoring tolerance. Herein we aimed to investigate IDO1 expression in SLN LCs from patients with melanoma. We showed by immunofluorescence analysis that a portion of Langerin+ LCs, located in the SLN T cell-rich area, displayed the typical dendritic morphology and expressed IDO1. There was no significant difference in the expression of IDO between SLN with or without metastases. Double IDO1/CD83 staining identified four LCs subsets: real mature IDO1−CD83+ LCs; real immature IDO1−CD83− LCs; tolerogenic mature IDO1+CD83+ LCs; tolerogenic immature IDO1+CD83− LCs. The latter subset was significantly increased in metastatic SLNs as compared to negative ones (p < 0.05), and in SLN LCs of patients with mitotic rate (MR) > 1 in primary melanoma, as compared to MR ≤ 1 (p < 0.05). Finally, immature SLN LCs, after in vitro stimulation by inflammatory cytokines, acquired a maturation profile by CD83 up-regulation. These results provide new input for immunotherapeutic approaches targeting in vivo LC of patients with melanoma.
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Wilczyński JR, Nowak M. Cancer Immunoediting: Elimination, Equilibrium, and Immune Escape in Solid Tumors. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:1-57. [PMID: 35165859 DOI: 10.1007/978-3-030-91311-3_1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Emphasizing the dynamic processes between cancer and host immune system, the initially discovered concept of cancer immunosurveillance has been replaced by the current concept of cancer immunoediting consisting of three phases: elimination, equilibrium, and escape. Solid tumors composed of both cancer and host stromal cells are an example how the three phases of cancer immunoediting functionally evolve and how tumor shaped by the host immune system gets finally resistant phenotype. The elimination, equilibrium, and escape have been described in this chapter in details, including the role of immune surveillance, cancer dormancy, disruption of the antigen-presenting machinery, tumor-infiltrating immune cells, resistance to apoptosis, as well as the function of tumor stroma, microvesicles, exosomes, and inflammation.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecologic Surgery and Gynecologic Oncology, Medical University of Lodz, Lodz, Poland.
| | - Marek Nowak
- Department of Operative Gynecology and Gynecologic Oncology, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
- Department of Operative and Endoscopic Gynecology, Medical University of Lodz, Lodz, Poland
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50
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Bourque J, Hawiger D. Variegated Outcomes of T Cell Activation by Dendritic Cells in the Steady State. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 208:539-547. [PMID: 35042789 DOI: 10.4049/jimmunol.2100932] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022]
Abstract
Conventional dendritic cells (cDC) control adaptive immunity by sensing damage- and pathogen-associated molecular patterns and then inducing defined differentiation programs in T cells. Nevertheless, in the absence of specific proimmunogenic innate signals, generally referred to as the steady state, cDC also activate T cells to induce specific functional fates. Consistent with the maintenance of homeostasis, such specific outcomes of T cell activation in the steady state include T cell clonal anergy, deletion, and conversion of peripheral regulatory T cells (pTregs). However, the robust induction of protolerogenic mechanisms must be reconciled with the initiation of autoimmune responses and cancer immunosurveillance that are also observed under homeostatic conditions. Here we review the diversity of fates and functions of T cells involved in the opposing immunogenic and tolerogenic processes induced in the steady state by the relevant mechanisms of systemic cDC present in murine peripheral lymphoid organs.
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Affiliation(s)
- Jessica Bourque
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO
| | - Daniel Hawiger
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO
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