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Ryba-Stanisławowska M. Unraveling Th subsets: insights into their role in immune checkpoint inhibitor therapy. Cell Oncol (Dordr) 2025; 48:295-312. [PMID: 39325360 PMCID: PMC11996958 DOI: 10.1007/s13402-024-00992-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2024] [Indexed: 09/27/2024] Open
Abstract
T helper (Th) cell subsets play pivotal roles in regulating immune responses within the tumor microenvironment, influencing both tumor progression and anti-tumor immunity. Among these subsets, Th1 cells promote cytotoxic responses through the production of IFN-γ, while Th2 cells and regulatory T cells (Tregs) exert immunosuppressive effects that support tumor growth. Th9 and Th17 cells have context-dependent roles, contributing to both pro-inflammatory and regulatory processes in tumor immunity. Tumor antigen-specific T cells within the tumor microenvironment often exhibit a dysfunctional phenotype due to increased expression of inhibitory receptors such as CTLA-4 and PD-1, leading to reduced antitumor activity. Monoclonal antibodies that block these inhibitory signals-collectively known as immune checkpoint inhibitors (ICIs)-can reactivate these T cells, enhancing their ability to target and destroy cancer cells. Recent advancements have highlighted the critical role of T helper subsets in modulating responses to ICIs, with their interactions remaining a focus of ongoing research. Both positive and negative effects of ICIs have been reported in relation to Th cell subsets, with some effects depending on the type of tumor microenvironment. This review summarizes the crucial roles of different T helper cell subsets in tumor immunity and their complex relationship with immune checkpoint inhibitor therapy.
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Affiliation(s)
- Monika Ryba-Stanisławowska
- Department of Medical Immunology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 1, Gdańsk, 80-211, Poland.
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Almawash S. Revolutionary Cancer Therapy for Personalization and Improved Efficacy: Strategies to Overcome Resistance to Immune Checkpoint Inhibitor Therapy. Cancers (Basel) 2025; 17:880. [PMID: 40075727 PMCID: PMC11899125 DOI: 10.3390/cancers17050880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 02/09/2025] [Accepted: 02/12/2025] [Indexed: 03/14/2025] Open
Abstract
Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].
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Affiliation(s)
- Saud Almawash
- Department of Pharmaceutics, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
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3
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Su H, Peng Y, Wu Y, Zeng X. Overcoming immune evasion with innovative multi-target approaches for glioblastoma. Front Immunol 2025; 16:1541467. [PMID: 39911397 PMCID: PMC11794508 DOI: 10.3389/fimmu.2025.1541467] [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: 12/07/2024] [Accepted: 01/02/2025] [Indexed: 02/07/2025] Open
Abstract
Glioblastoma (GBM) cells leverage complex endogenous and environmental regulatory mechanisms to drive proliferation, invasion, and metastasis. Tumor immune evasion, facilitated by a multifactorial network, poses a significant challenge to effective therapy, as evidenced by the limited clinical benefits of monotherapies, highlighting the adaptive nature of immune evasion. This review explores glioblastoma's immune evasion mechanisms, the role of ICIs in the tumor microenvironment, and recent clinical advancements, offering theoretical insights and directions for monotherapy and combination therapy in glioblastoma management.
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Affiliation(s)
- Hai Su
- Department of Neurosurgery, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Yin Peng
- Department of Neurosurgery, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Yilong Wu
- Department of Neurosurgery, Yongchuan Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoli Zeng
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Jiangxi “Flagship” Oncology Department of Synergy for Chinese and Western Medicine, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
- Department of Oncology, Jiangxi Clinical Research Center for Cancer, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
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4
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Xu R, He X, Xu J, Yu G, Wu Y. Immunometabolism: signaling pathways, homeostasis, and therapeutic targets. MedComm (Beijing) 2024; 5:e789. [PMID: 39492834 PMCID: PMC11531657 DOI: 10.1002/mco2.789] [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: 10/19/2023] [Revised: 09/20/2024] [Accepted: 09/25/2024] [Indexed: 11/05/2024] Open
Abstract
Immunometabolism plays a central role in sustaining immune system functionality and preserving physiological homeostasis within the organism. During the differentiation and activation, immune cells undergo metabolic reprogramming mediated by complex signaling pathways. Immune cells maintain homeostasis and are influenced by metabolic microenvironmental cues. A series of immunometabolic enzymes modulate immune cell function by metabolizing nutrients and accumulating metabolic products. These enzymes reverse immune cells' differentiation, disrupt intracellular signaling pathways, and regulate immune responses, thereby influencing disease progression. The huge population of immune metabolic enzymes, the ubiquity, and the complexity of metabolic regulation have kept the immune metabolic mechanisms related to many diseases from being discovered, and what has been revealed so far is only the tip of the iceberg. This review comprehensively summarized the immune metabolic enzymes' role in multiple immune cells such as T cells, macrophages, natural killer cells, and dendritic cells. By classifying and dissecting the immunometabolism mechanisms and the implications in diseases, summarizing and analyzing advancements in research and clinical applications of the inhibitors targeting these enzymes, this review is intended to provide a new perspective concerning immune metabolic enzymes for understanding the immune system, and offer novel insight into future therapeutic interventions.
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Affiliation(s)
- Rongrong Xu
- National Key Laboratory of Immunity and Inflammation & Institute of ImmunologyCollege of Basic Medical SciencesNaval Medical UniversityShanghaiChina
- School of Life SciencesFudan UniversityShanghaiChina
| | - Xiaobo He
- National Key Laboratory of Immunity and Inflammation & Institute of ImmunologyCollege of Basic Medical SciencesNaval Medical UniversityShanghaiChina
| | - Jia Xu
- National Key Laboratory of Immunity and Inflammation & Institute of ImmunologyCollege of Basic Medical SciencesNaval Medical UniversityShanghaiChina
| | - Ganjun Yu
- National Key Laboratory of Immunity and Inflammation & Institute of ImmunologyCollege of Basic Medical SciencesNaval Medical UniversityShanghaiChina
| | - Yanfeng Wu
- National Key Laboratory of Immunity and Inflammation & Institute of ImmunologyCollege of Basic Medical SciencesNaval Medical UniversityShanghaiChina
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5
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Zakrocka I, Urbańska EM, Załuska W, Kronbichler A. Kynurenine Pathway after Kidney Transplantation: Friend or Foe? Int J Mol Sci 2024; 25:9940. [PMID: 39337426 PMCID: PMC11432217 DOI: 10.3390/ijms25189940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 09/09/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Kidney transplantation significantly improves the survival of patients with end-stage kidney disease (ESKD) compared to other forms of kidney replacement therapy. However, kidney transplant recipients' outcomes are not fully satisfactory due to increased risk of cardiovascular diseases, infections, and malignancies. Immune-related complications remain the biggest challenge in the management of kidney graft recipients. Despite the broad spectrum of immunosuppressive agents available and more detailed methods used to monitor their effectiveness, chronic allograft nephropathy remains the most common cause of kidney graft rejection. The kynurenine (KYN) pathway is the main route of tryptophan (Trp) degradation, resulting in the production of a plethora of substances with ambiguous properties. Conversion of Trp to KYN by the enzyme indoleamine 2,3-dioxygenase (IDO) is the rate-limiting step determining the formation of the next agents from the KYN pathway. IDO activity, as well as the production of subsequent metabolites of the pathway, is highly dependent on the balance between pro- and anti-inflammatory conditions. Moreover, KYN pathway products themselves possess immunomodulating properties, e.g., modify the activity of IDO and control other immune-related processes. KYN metabolites were widely studied in neurological disorders but recently gained the attention of researchers in the context of immune-mediated diseases. Evidence that this route of Trp degradation may represent a peripheral tolerogenic pathway with significant implications for transplantation further fueled this interest. Our review aimed to present recent knowledge about the role of the KYN pathway in the pathogenesis, diagnosis, monitoring, and treatment of kidney transplant recipients' complications.
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Affiliation(s)
- Izabela Zakrocka
- Department of Nephrology, Medical University of Lublin, 20-093 Lublin, Poland; (I.Z.); (W.Z.)
| | - Ewa M. Urbańska
- Department of Experimental and Clinical Pharmacology, Medical University of Lublin, 20-093 Lublin, Poland;
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, 20-093 Lublin, Poland; (I.Z.); (W.Z.)
| | - Andreas Kronbichler
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, 6020 Innsbruck, Austria
- Department of Health, Medicine and Caring Sciences, Linköping University, 581 83 Linköping, Sweden
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Yazdanpanah E, Dadfar S, Shadab A, Orooji N, Nemati M, Pazoki A, Esmaeili S, Baharlou R, Haghmorad D. Berberine: A natural modulator of immune cells in multiple sclerosis. Immun Inflamm Dis 2024; 12:e1213. [PMID: 38477663 PMCID: PMC10936236 DOI: 10.1002/iid3.1213] [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: 08/25/2023] [Revised: 02/26/2024] [Accepted: 03/01/2024] [Indexed: 03/14/2024] Open
Abstract
Berberine is a benzylisoquinoline alkaloid found in such plants as Berberis vulgaris, Berberis aristata, and others, revealing a variety of pharmacological properties as a result of interacting with different cellular and molecular targets. Recent studies have shown the immunomodulatory effects of Berberine which result from its impacts on immune cells and immune response mediators such as diverse T lymphocyte subsets, dendritic cells (DCs), and different inflammatory cytokines. Multiple sclerosis (MS) is a chronic disabling and neurodegenerative disease of the central nervous system (CNS) characterized by the recruitment of autoreactive T cells into the CNS causing demyelination, axonal damage, and oligodendrocyte loss. There have been considerable changes discovered in MS regards to the function and frequency of T cell subsets such as Th1 cells, Th17 cells, Th2 cells, Treg cells, and DCs. In the current research, we reviewed the outcomes of in vitro, experimental, and clinical investigations concerning the modulatory effects that Berberine provides on the function and numbers of T cell subsets and DCs, as well as important cytokines that are involved in MS.
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Affiliation(s)
| | - Sepehr Dadfar
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | - Alireza Shadab
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | - Niloufar Orooji
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | - MohammadHossein Nemati
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | - Alireza Pazoki
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
| | | | - Rasoul Baharlou
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
- Cancer Research CenterSemnan University of Medical SciencesSemnanIran
| | - Dariush Haghmorad
- Department of Immunology, School of MedicineSemnan University of Medical SciencesSemnanIran
- Cancer Research CenterSemnan University of Medical SciencesSemnanIran
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Johnson TS, MacDonald TJ, Pacholczyk R, Aguilera D, Al-Basheer A, Bajaj M, Bandopadhayay P, Berrong Z, Bouffet E, Castellino RC, Dorris K, Eaton BR, Esiashvili N, Fangusaro JR, Foreman N, Fridlyand D, Giller C, Heger IM, Huang C, Kadom N, Kennedy EP, Manoharan N, Martin W, McDonough C, Parker RS, Ramaswamy V, Ring E, Rojiani A, Sadek RF, Satpathy S, Schniederjan M, Smith A, Smith C, Thomas BE, Vaizer R, Yeo KK, Bhasin MK, Munn DH. Indoximod-based chemo-immunotherapy for pediatric brain tumors: A first-in-children phase I trial. Neuro Oncol 2024; 26:348-361. [PMID: 37715730 PMCID: PMC10836763 DOI: 10.1093/neuonc/noad174] [Citation(s) in RCA: 24] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Indexed: 09/18/2023] Open
Abstract
BACKGROUND Recurrent brain tumors are the leading cause of cancer death in children. Indoleamine 2,3-dioxygenase (IDO) is a targetable metabolic checkpoint that, in preclinical models, inhibits anti-tumor immunity following chemotherapy. METHODS We conducted a phase I trial (NCT02502708) of the oral IDO-pathway inhibitor indoximod in children with recurrent brain tumors or newly diagnosed diffuse intrinsic pontine glioma (DIPG). Separate dose-finding arms were performed for indoximod in combination with oral temozolomide (200 mg/m2/day x 5 days in 28-day cycles), or with palliative conformal radiation. Blood samples were collected at baseline and monthly for single-cell RNA-sequencing with paired single-cell T cell receptor sequencing. RESULTS Eighty-one patients were treated with indoximod-based combination therapy. Median follow-up was 52 months (range 39-77 months). Maximum tolerated dose was not reached, and the pediatric dose of indoximod was determined as 19.2 mg/kg/dose, twice daily. Median overall survival was 13.3 months (n = 68, range 0.2-62.7) for all patients with recurrent disease and 14.4 months (n = 13, range 4.7-29.7) for DIPG. The subset of n = 26 patients who showed evidence of objective response (even a partial or mixed response) had over 3-fold longer median OS (25.2 months, range 5.4-61.9, p = 0.006) compared to n = 37 nonresponders (7.3 months, range 0.2-62.7). Four patients remain free of active disease longer than 36 months. Single-cell sequencing confirmed emergence of new circulating CD8 T cell clonotypes with late effector phenotype. CONCLUSIONS Indoximod was well tolerated and could be safely combined with chemotherapy and radiation. Encouraging preliminary evidence of efficacy supports advancing to Phase II/III trials for pediatric brain tumors.
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Affiliation(s)
- Theodore S Johnson
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Pediatrics, Augusta University, Augusta, Georgia, USA
| | - Tobey J MacDonald
- Aflac Cancer & Blood Disorders Center at Children’s Healthcare of Atlanta and Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Rafal Pacholczyk
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts, USA
| | - Dolly Aguilera
- Aflac Cancer & Blood Disorders Center at Children’s Healthcare of Atlanta and Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Ahmad Al-Basheer
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Radiation Oncology, Augusta University, Augusta, Georgia, USA
| | - Manish Bajaj
- Department of Radiology, Augusta University, Augusta, Georgia, USA
| | | | - Zuzana Berrong
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
| | - Eric Bouffet
- Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada
| | - Robert C Castellino
- Aflac Cancer & Blood Disorders Center at Children’s Healthcare of Atlanta and Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Kathleen Dorris
- Department of Pediatrics, Children’s Hospital Colorado, Aurora, Colorado, USA
| | - Bree R Eaton
- Department of Radiation Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
| | - Natia Esiashvili
- Department of Radiation Oncology and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
| | - Jason R Fangusaro
- Aflac Cancer & Blood Disorders Center at Children’s Healthcare of Atlanta and Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Nicholas Foreman
- Department of Pediatrics, Children’s Hospital Colorado, Aurora, Colorado, USA
| | - Diana Fridlyand
- Department of Pediatrics, Augusta University, Augusta, Georgia, USA
| | - Cole Giller
- Department of Neurosurgery, Augusta University, Augusta, Georgia, USA
| | - Ian M Heger
- Department of Neurosurgery, Augusta University, Augusta, Georgia, USA
| | - Chenbin Huang
- Department of Pediatrics, Emory University, Atlanta, Georgia, USA
- Department of Biomedical Informatics, Emory University, Atlanta, Georgia, USA
| | - Nadja Kadom
- Department of Radiology and Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
| | - Eugene P Kennedy
- Lumos Pharma, Inc. (formerly NewLink Genetics Corporation), Austin, Texas, USA
| | - Neevika Manoharan
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts, USA
| | - William Martin
- Department of Radiation Oncology, Augusta University, Augusta, Georgia, USA
| | - Colleen McDonough
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Pediatrics, Augusta University, Augusta, Georgia, USA
| | - Rebecca S Parker
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Pediatrics, Augusta University, Augusta, Georgia, USA
| | - Vijay Ramaswamy
- Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada
| | - Eric Ring
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Pediatrics, Augusta University, Augusta, Georgia, USA
| | - Amyn Rojiani
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Pathology, Augusta University, Augusta, Georgia, USA
| | - Ramses F Sadek
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Population Health Sciences, Augusta University, Augusta, Georgia, USA
| | - Sarthak Satpathy
- Department of Pediatrics, Emory University, Atlanta, Georgia, USA
- Department of Biomedical Informatics, Emory University, Atlanta, Georgia, USA
| | - Matthew Schniederjan
- Children’s Healthcare of Atlanta and Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA
| | - Amy Smith
- Department of Pediatrics, Arnold Palmer Hospital for Children, Orlando, Florida, USA
| | - Christopher Smith
- Lumos Pharma, Inc. (formerly NewLink Genetics Corporation), Austin, Texas, USA
| | - Beena E Thomas
- Department of Pediatrics, Emory University, Atlanta, Georgia, USA
| | - Rachel Vaizer
- Department of Pediatrics, Augusta University, Augusta, Georgia, USA
| | - Kee Kiat Yeo
- Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, Massachusetts, USA
| | - Manoj K Bhasin
- Aflac Cancer & Blood Disorders Center at Children’s Healthcare of Atlanta and Department of Pediatrics, Emory University, Atlanta, Georgia, USA
- Department of Pediatrics, Emory University, Atlanta, Georgia, USA
- Department of Biomedical Informatics, Emory University, Atlanta, Georgia, USA
| | - David H Munn
- Georgia Cancer Center, Augusta University, Augusta, Georgia, USA
- Department of Pediatrics, Augusta University, Augusta, Georgia, USA
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Song D, Ding Y. A new target of radiotherapy combined with immunotherapy: regulatory T cells. Front Immunol 2024; 14:1330099. [PMID: 38259489 PMCID: PMC10800811 DOI: 10.3389/fimmu.2023.1330099] [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: 10/30/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Radiotherapy is one important treatment for malignant tumours. It is widely believed today that radiotherapy has not only been used as a local tumour treatment method, but also can induce systemic anti-tumour responses by influencing the tumour microenvironment, but its efficacy is limited by the tumour immunosuppression microenvironment. With the advancement of technology, immunotherapy has entered a golden age of rapid development, gradually occupying a place in clinical tumour treatment. Regulatory T cells (Tregs) widely distributing in the tumour microenvironment play an important role in mediating tumour development. This article analyzes immunotherapy, the interaction between Tregs, tumours and radiotherapy. It briefly introduces immunotherapies targeting Tregs, aiming to provide new strategies for radiotherapy combined with Immunotherapy.
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Affiliation(s)
| | - Yun Ding
- Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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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: 11] [Impact Index Per Article: 5.5] [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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10
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Lei X, Wang Y, Broens C, Borst J, Xiao Y. Immune checkpoints targeting dendritic cells for antibody-based modulation in cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2023; 382:145-179. [PMID: 38225102 DOI: 10.1016/bs.ircmb.2023.07.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Dendritic cells (DC) are professional antigen-presenting cells which link innate to adaptive immunity. DC play a central role in regulating antitumor T-cell responses in both tumor-draining lymph nodes (TDLN) and the tumor microenvironment (TME). They modulate effector T-cell responses via immune checkpoint proteins (ICPs) that can be either stimulatory or inhibitory. Functions of DC are often impaired by the suppressive TME leading to tumor immune escape. Therefore, better understanding of the mechanisms of action of ICPs expressed by (tumor-infiltrating) DC will lead to potential new treatment strategies. Genetic manipulation and high-dimensional analyses have provided insight in the interactions between DC and T-cells in TDLN and the TME upon ICP targeting. In this review, we discuss (tumor-infiltrating) DC lineage cells and tumor tissue specific "mature" DC states and their gene signatures in relation to anti-tumor immunity. We also review a number of ICPs expressed by DC regarding their functions in phagocytosis, DC activation, or inhibition and outline position in, or promise for clinical trials in cancer immunotherapy. Collectively, we highlight the critical role of DC and their exact status in the TME for the induction and propagation of T-cell immunity to cancer.
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Affiliation(s)
- Xin Lei
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Yizhi Wang
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Chayenne Broens
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Jannie Borst
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands
| | - Yanling Xiao
- Department of Immunology and Oncode Institute, Leiden University Medical Center, Leiden, The Netherlands.
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11
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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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12
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Charehjoo A, Majidpoor J, Mortezaee K. Indoleamine 2,3-dioxygenase 1 in circumventing checkpoint inhibitor responses: Updated. Int Immunopharmacol 2023; 118:110032. [PMID: 36933494 DOI: 10.1016/j.intimp.2023.110032] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 01/30/2023] [Accepted: 02/07/2023] [Indexed: 03/18/2023]
Abstract
Metabolic alterations occur commonly in tumor cells as a way to adapt available energetic sources for their proliferation, survival and resistance. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular enzyme catalyzing tryptophan degradation into kynurenine. IDO1 expression shows a rise in the stroma of many types of human cancers, and it provides a negative feedback mechanism for cancer evasion from immunosurveillance. Upregulation of IDO1 correlates with cancer aggression, poor prognosis and shortened patient survival. The increased activity of this endogenous checkpoint impairs effector T cell function, increases regulatory T cell (Treg) population and induces immune tolerance, so its inhibition potentiates anti-tumor immune responses and reshapes immunogenic state of tumor microenvironment (TME) presumably through normalizing effector T cell activity. A point is that the expression of this immunoregulatory marker is upregulated after immune checkpoint inhibitor (ICI) therapy, and that it has inducible effect on expression of other checkpoints. These are indicative of the importance of IDO1 as an attractive immunotherapeutic target and rationalizing combination of IDO1 inhibitors with ICI drugs in patients with advanced solid cancers. In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper.
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Affiliation(s)
- Arian Charehjoo
- Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Keywan Mortezaee
- Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran; Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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13
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Arinola GO, Abdullahi I, Rahamon SK, Fasasi ZB, Adedeji OO, Kehinde A, Bakare AA. Activities of plasma indoleamine-2, 3-dioxygenase (IDO) enzyme in Nigerian patients with lung diseases: basis for tryptophan supplementation or IDO inhibitor use. THE EGYPTIAN JOURNAL OF BRONCHOLOGY 2023; 17:2. [PMCID: PMC9828369 DOI: 10.1186/s43168-022-00174-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Background Clinical trial of IDO inhibitor or uses of micro-nutrient supplements during management of diseases is commonly done without having adequate basis for the practise. Tryptophan (Trp) is an essential amino acid needed for T-lymphocyte function, and indoleamine-2,3-dioxygenase (IDO) is a potent immunoregulatory molecule that catalyses the rate-limiting step of Trp degradation in the kynurenine (Kyn) pathway. Materials and methods Human IDO in the plasma samples was measured using ELISA in patients with non-infectious (asthma) and infectious diseases (pulmonary tuberculosis and COVID-19) compared with corresponding un-infected controls. Results Mean IDO activity in COVID-19 patients was significantly higher compared with corresponding control (p = 0.001) while mean IDO activity in pulmonary tuberculosis patients was non-significantly higher compared with corresponding control (p = 0.520), and mean IDO activity in asthma patients was non-significantly lower compared with corresponding control (p = 0.102). Conclusion Our data suggest that IDO activity as an innate immune factor is increased in infectious lung diseases (COVID-19 and pulmonary tuberculosis) but reduced in non-infectious disease (asthma) and that use of tryptophan supplementation or IDO inhibitor may not be necessary in all lung diseases.
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Affiliation(s)
- Ganiyu Olatunbosun Arinola
- grid.9582.60000 0004 1794 5983Department of Immunology, University of Ibadan and University College Hospital, Ibadan, Nigeria
| | - Issa Abdullahi
- grid.9582.60000 0004 1794 5983Department of Zoology, University of Ibadan, Ibadan, Nigeria
| | - Sheu Kadiri Rahamon
- grid.9582.60000 0004 1794 5983Department of Immunology, University of Ibadan and University College Hospital, Ibadan, Nigeria
| | - Zainab Bolanle Fasasi
- grid.9582.60000 0004 1794 5983Department of Zoology, University of Ibadan, Ibadan, Nigeria
| | | | - Adigun Kehinde
- grid.412438.80000 0004 1764 5403Department of Family Medicine, University College Hospital, Ibadan, Nigeria
| | - Adekunle Akeem Bakare
- grid.9582.60000 0004 1794 5983Department of Zoology, University of Ibadan, Ibadan, Nigeria
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14
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The Tumor Microenvironment of Hepatocellular Carcinoma: Untying an Intricate Immunological Network. Cancers (Basel) 2022; 14:cancers14246151. [PMID: 36551635 PMCID: PMC9776867 DOI: 10.3390/cancers14246151] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/06/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022] Open
Abstract
HCC, the most prevalent form of primary liver cancer, is prototypically an inflammation-driven cancer developing after years of inflammatory insults. Consequently, the hepatic microenvironment is a site of complex immunological activities. Moreover, the tolerogenic nature of the liver can act as a barrier to anti-tumor immunity, fostering cancer progression and resistance to immunotherapies based on immune checkpoint inhibitors (ICB). In addition to being a site of primary carcinogenesis, many cancer types have high tropism for the liver, and patients diagnosed with liver metastasis have a dismal prognosis. Therefore, understanding the immunological networks characterizing the tumor microenvironment (TME) of HCC will deepen our understanding of liver immunity, and it will underpin the dominant mechanisms controlling both spontaneous and therapy-induced anti-tumor immune responses. Herein, we discuss the contributions of the cellular and molecular components of the liver immune contexture during HCC onset and progression by underscoring how the balance between antagonistic immune responses can recast the properties of the TME and the response to ICB.
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15
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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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16
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Dwivedi M, Tiwari S, Kemp EH, Begum R. Implications of regulatory T cells in anti-cancer immunity: from pathogenesis to therapeutics. Heliyon 2022; 8:e10450. [PMID: 36082331 PMCID: PMC9445387 DOI: 10.1016/j.heliyon.2022.e10450] [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: 03/22/2022] [Revised: 05/08/2022] [Accepted: 08/22/2022] [Indexed: 11/25/2022] Open
Abstract
Regulatory T cells (Tregs) play an essential role in maintaining immune tolerance and suppressing inflammation. However, Tregs present major hurdle in eliciting potent anti-cancer immune responses. Therefore, curbing the activity of Tregs represents a novel and efficient way towards successful immunotherapy of cancer. Moreover, there is an emerging interest in harnessing Treg-based strategies for augmenting anti-cancer immunity in different types of the disease. This review summarises the crucial mechanisms of Tregs' mediated suppression of anti-cancer immunity and strategies to suppress or to alter such Tregs to improve the immune response against tumors. Highlighting important clinical studies, the review also describes current Treg-based therapeutic interventions in cancer, and discusses Treg-suppression by molecular targeting, which may emerge as an effective cancer immunotherapy and as an alternative to detrimental chemotherapeutic agents.
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Affiliation(s)
- Mitesh Dwivedi
- C. G. Bhakta Institute of Biotechnology, Faculty of Science, Uka Tarsadia University, Tarsadi, Surat, Gujarat, 394350, India
| | - Sanjay Tiwari
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Raebareli, Lucknow, 226002, Uttar Pradesh, India
| | - E. Helen Kemp
- Department of Oncology and Metabolism, Faculty of Medicine, Dentistry and Health, University of Sheffield, Sheffield, S10 2RX, UK
| | - Rasheedunnisa Begum
- Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, 390 002, Gujarat, India
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17
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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: 92] [Impact Index Per Article: 30.7] [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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18
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Dendritic cells in systemic lupus erythematosus: From pathogenesis to therapeutic applications. J Autoimmun 2022; 132:102856. [DOI: 10.1016/j.jaut.2022.102856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 06/15/2022] [Indexed: 11/18/2022]
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19
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Esmaeili SA, Hajavi J. The role of indoleamine 2,3-dioxygenase in allergic disorders. Mol Biol Rep 2022; 49:3297-3306. [PMID: 35028850 DOI: 10.1007/s11033-021-07067-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 12/08/2021] [Indexed: 01/08/2023]
Abstract
The amino acid tryptophan (TRP) is critical for the expansion and survival of cells. During the past few years, the manipulation of tryptophan metabolism via indoleamine 2,3 dioxygenase (IDO) has been presented as a significant regulatory mechanism for tolerance stimulation and the regulation of immune responses. Currently, a considerable number of studies suggest that the role of IDO in T helper 2 (Th2) cell regulation may be different from that of T helper 1 (Th1) immune responses. IDO acts as an immunosuppressive tolerogenic enzyme to decrease allergic responses through the stimulation of the Kynurenine-IDO pathway, the subsequent reduction of TRP, and the promotion of Kynurenine products. Kynurenine products motivate T-cell apoptosis and anergy, the propagation of Treg and Th17 cells, and the aberration of the Th1/Th2 response. We suggest that the IDO-kynurenine pathway can function as a negative reaction round for Th1 cells; however, it may play a different role in upregulating principal Th2 immune responses. In this review, we intend to integrate novel results on this pathway in correlation with allergic diseases.
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Affiliation(s)
- Seyed-Alireza Esmaeili
- Immunology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Jafar Hajavi
- Department of Basic Sciences, Faculty of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Science, 9691793718, Gonabad, Iran.
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20
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Chakraborty S, Carnazza M, Jarboe T, DeSouza N, Li XM, Moscatello A, Geliebter J, Tiwari RK. Disruption of Cell-Cell Communication in Anaplastic Thyroid Cancer as an Immunotherapeutic Opportunity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1350:33-66. [PMID: 34888843 DOI: 10.1007/978-3-030-83282-7_2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. About 44,280 new cases of thyroid cancer (12,150 in men and 32,130 in women) are estimated to be diagnosed in 2021, with an estimated death toll of around 2200. Although most thyroid tumors are treatable and associated with a favorable outcome, anaplastic thyroid cancer (ATC) is extremely aggressive with a grim prognosis of 6-9 months post-diagnosis. A large contributing factor to this aggressive nature is that ATC is completely refractory to mainstream therapies. Analysis of the tumor microenvironment (TME) associated with ATC can relay insight to the pathological realm that encompasses tumors and aids in cancer progression and proliferation. The TME is defined as a complex niche that surrounds a tumor and involves a plethora of cellular components whose secretions can modulate the environment in order to favor tumor progression. The cellular heterogeneity of the TME contributes to its dynamic function due to the presence of both immune and nonimmune resident, infiltrating, and interacting cell types. Associated immune cells discussed in this chapter include macrophages, dendritic cells (DCs), natural killer (NK) cells, and tumor-infiltrating lymphocytes (TILs). Nonimmune cells also play a role in the establishment and proliferation of the TME, including neuroendocrine (NE) cells, adipocytes, endothelial cells (ECs), mesenchymal stem cells (MSCs), and fibroblasts. The dynamic nature of the TME contributes greatly to cancer progression.Recent work has found ATC tissues to be defined by a T cell-inflamed "hot" tumor immune microenvironment (TIME) as evidenced by presence of CD3+ and CD8+ T cells. These tumor types are amenable to immune checkpoint blockade (ICB) therapy. This therapeutic avenue, as of 2021, has remained unexplored in ATC. New studies should seek to explore the therapeutic feasibility of a combination therapy, through the use of a small molecule inhibitor with ICB in ATC. Screening of in vitro model systems representative of papillary, anaplastic, and follicular thyroid cancer explored the expression of 29 immune checkpoint molecules. There are higher expressions of HVEM, BTLA, and CD160 in ATC cell lines when compared to the other TC subtypes. The expression level of HVEM was more than 30-fold higher in ATC compared to the others, on average. HVEM is a member of tumor necrosis factor (TNF) receptor superfamily, which acts as a bidirectional switch through interaction with BTLA, CD160, and LIGHT, in a cis or trans manner. Given the T cell-inflamed hot TIME in ATC, expression of HVEM on tumor cells was suggestive of a possibility for complex crosstalk of HVEM with inflammatory cytokines. Altogether, there is emerging evidence of a T cell-inflamed TIME in ATC along with the expression of immune checkpoint proteins HVEM, BTLA, and CD160 in ATC. This can open doors for combination therapies using small molecule inhibitors targeting downstream effectors of MAPK pathway and antagonistic antibodies targeting the HVEM/BTLA axis as a potentially viable therapeutic avenue for ATC patients. With this being stated, the development of adaptive resistance to targeted therapies is inevitable; therefore, using a combination therapy that targets the TIME can serve as a preemptive tactic against the characteristic therapeutic resistance that is seen in ATC. The dynamic nature of the TME, including the immune cells, nonimmune cells, and acellular components, can serve as viable targets for combination therapy in ATC. Understanding the complex interactions of these associated cells and the paradigm in which their secretions and components can serve as immunomodulators are critical points of understanding when trying to develop therapeutics specifically tailored for the anaplastic thyroid carcinoma microenvironment.
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Affiliation(s)
- Sanjukta Chakraborty
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA.,Weill Cornell Medicine, New York, NY, USA
| | - Michelle Carnazza
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA
| | - Tara Jarboe
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA
| | - Nicole DeSouza
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA
| | - Xiu-Min Li
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA
| | | | - Jan Geliebter
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA
| | - Raj K Tiwari
- Department of Pathology, Microbiology, and Immunology, New York Medical College, Valhalla, NY, USA.
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21
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Deng J, Lu C, Zhao Q, Chen K, Ma S, Li Z. The Th17/Treg cell balance: crosstalk among the immune system, bone and microbes in periodontitis. J Periodontal Res 2021; 57:246-255. [PMID: 34878170 DOI: 10.1111/jre.12958] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 10/04/2021] [Accepted: 11/08/2021] [Indexed: 12/14/2022]
Abstract
Periodontopathic bacteria constantly stimulate the host, which causes an immune response, leading to host-induced periodontal tissue damage. The complex interaction and imbalance between Th17 and Treg cells may be critical in the pathogenesis of periodontitis. Furthermore, the RANKL/RANK/OPG system plays a significant role in periodontitis bone metabolism, and its relationship with the Th17/Treg cell imbalance may be a bridge between periodontal bone metabolism and the immune system. This article reviews the literature related to the Th17/Treg cell imbalance mediated by pathogenic periodontal microbes, and its mechanism involving RANKL/RANK/OPG in periodontitis bone metabolism, in an effort to provide new ideas for the study of the immunopathological mechanism of periodontitis.
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Affiliation(s)
- Jianwen Deng
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University, Department of Stomatology, College of stomatology, Jinan University, Guangzhou, China
| | - Chunting Lu
- Science and Education Office, The First Affiliated Hospital, Jinan University, Guangzhou, China
| | - Qingtong Zhao
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University, Department of Stomatology, College of stomatology, Jinan University, Guangzhou, China
| | - Kexiao Chen
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University, Department of Stomatology, College of stomatology, Jinan University, Guangzhou, China
| | - Shuyuan Ma
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University, Department of Stomatology, College of stomatology, Jinan University, Guangzhou, China
| | - Zejian Li
- Clinical Research Platform for Interdiscipline of Stomatology, The First Affiliated Hospital of Jinan University, Department of Stomatology, College of stomatology, Jinan University, Guangzhou, China.,Chaoshan Hospital, The First Affiliated Hospital of Jinan University, Jinan University, Chaozhou, China
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22
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Watari K, Konnai S, Okagawa T, Maekawa N, Sajiki Y, Kato Y, Suzuki Y, Murata S, Ohashi K. Enhancement of interleukin-2 production by bovine peripheral blood mononuclear cells treated with the combination of anti-programmed death-ligand 1 and cytotoxic T lymphocyte antigen 4 chimeric monoclonal antibodies. J Vet Med Sci 2021; 84:6-15. [PMID: 34789592 PMCID: PMC8810316 DOI: 10.1292/jvms.21-0552] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Our previous studies demonstrate the therapeutic efficacy against bovine diseases of an anti-bovine programmed death-ligand 1 (PD-L1) chimeric antibody. In humans, PD-1 and PD-L1 antibodies are more effective when combined with an antibody targeting cytotoxic T lymphocyte antigen 4 (CTLA-4) and these combination therapies are therefore clinically used. Here we generated an anti-bovine CTLA-4 chimeric antibody (chAb) to enhance the therapeutic efficacy of the PD-L1 antibody. We further analyzed the effects of dual blockade of CTLA-4 and PD-1 pathways on T-cell responses. The established anti-bovine CTLA-4 chAb showed comparable blocking activity on the binding of bovine CTLA-4 to CD80 and CD86 as the anti-bovine CTLA-4 mouse monoclonal antibody. Anti-bovine CTLA-4 chAb also significantly increased IL-2 production from bovine peripheral blood mononuclear cells (PBMCs). Further, the combination of anti-CTLA-4 chAb with anti-PD-L1 chAb significantly upregulated IL-2 production by PBMCs. These results suggest that the combination of antibodies have higher potential to enhance immune responses against pathogens compared with single administration.
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Affiliation(s)
- Kei Watari
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University
| | - Satoru Konnai
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University.,Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
| | - Tomohiro Okagawa
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
| | - Naoya Maekawa
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
| | - Yamato Sajiki
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine
| | - Yasuhiko Suzuki
- Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University.,Division of Bioresources, International Institute for Zoonosis Control, Hokkaido University.,Global Station for Zoonosis Control, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University
| | - Shiro Murata
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University.,Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
| | - Kazuhiko Ohashi
- Department of Disease Control, Faculty of Veterinary Medicine, Hokkaido University.,Department of Advanced Pharmaceutics, Faculty of Veterinary Medicine, Hokkaido University
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23
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Sharma MD, Pacholczyk R, Shi H, Berrong ZJ, Zakharia Y, Greco A, Chang CSS, Eathiraj S, Kennedy E, Cash T, Bollag RJ, Kolhe R, Sadek R, McGaha TL, Rodriguez P, Mandula J, Blazar BR, Johnson TS, Munn DH. Inhibition of the BTK-IDO-mTOR axis promotes differentiation of monocyte-lineage dendritic cells and enhances anti-tumor T cell immunity. Immunity 2021; 54:2354-2371.e8. [PMID: 34614413 PMCID: PMC8516719 DOI: 10.1016/j.immuni.2021.09.005] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 04/19/2021] [Accepted: 09/09/2021] [Indexed: 01/04/2023]
Abstract
Monocytic-lineage inflammatory Ly6c+CD103+ dendritic cells (DCs) promote antitumor immunity, but these DCs are infrequent in tumors, even upon chemotherapy. Here, we examined how targeting pathways that inhibit the differentiation of inflammatory myeloid cells affect antitumor immunity. Pharmacologic inhibition of Bruton's tyrosine kinase (BTK) and the tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) or deletion of Btk or Ido1 allowed robust differentiation of inflammatory Ly6c+CD103+ DCs during chemotherapy, promoting antitumor T cell responses and inhibiting tumor growth. Immature Ly6c+c-kit+ precursor cells had epigenetic profiles similar to conventional DC precursors; deletion of Btk or Ido1 promoted differentiation of these cells. Mechanistically, a BTK-IDO axis inhibited a tryptophan-sensitive differentiation pathway driven by GATOR2 and mTORC1, and disruption of the GATOR2 in monocyte-lineage precursors prevented differentiation into inflammatory DCs in vivo. IDO-expressing DCs and monocytic cells were present across a range of human tumors. Thus, a BTK-IDO axis represses differentiation of inflammatory DCs during chemotherapy, with implications for targeted therapies.
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Affiliation(s)
- Madhav D Sharma
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Rafal Pacholczyk
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Huidong Shi
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Zuzana J Berrong
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Yousef Zakharia
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Austin Greco
- Department of Internal Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - Chang-Sheng S Chang
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Georgia Cancer Center, Bioinformatics Shared Resource, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | | | | | - Thomas Cash
- Department of Pediatrics, Emory University, Atlanta, GA 30322, USA
| | - Roni J Bollag
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Ravindra Kolhe
- Department of Pathology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Ramses Sadek
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Tracy L McGaha
- Department of Immunology, University of Toronto, Toronto, ON M5G 2M9, Canada
| | - Paulo Rodriguez
- Immunology Department, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Jessica Mandula
- Immunology Department, Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Bruce R Blazar
- Department of Pediatrics and Division of Blood and Marrow Transplantation, University of Minnesota, Minneapolis, MN 55455, USA
| | - Theodore S Johnson
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - David H Munn
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA; Department of Pediatrics, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
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24
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Eftekhar SP, Yazdanpanah N, Rezaei N. Immune checkpoint inhibitors and cardiotoxicity: possible mechanisms, manifestations, diagnosis and management. Expert Rev Anticancer Ther 2021; 21:1211-1228. [PMID: 34511008 DOI: 10.1080/14737140.2021.1979396] [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: 01/22/2023]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs) are a new class of anticancer drugs that enhance the immune system function and activate T cells against cancerous cells. Although cardiac complications are not common, they could be accompanied with high morbidity and mortality. AREAS COVERED Regarding the importance of cardiac complications and their subsequent burden on individuals and the healthcare system, this review attempts to discuss the mechanism, diagnosis, and management of myocarditis, besides recapitulating the possible mechanism of other cardiac adverse events. Moreover, we briefly discuss the concurrent administration of other chemotherapeutic agents. EXPERT OPINION Due to insufficient knowledge concerning the physiopathology of immune-related adverse events (irAEs) and their potential further complications, cardiovascular complications in particular and in the context of this paper's focus, cooperation of oncologists, immunologists, and cardiologists is necessary for the management of patients. Experimental approaches such as using corticosteroids are becoming a part of guidelines for managing cardiac irAEs. However, a unique algorithm for diagnosis and management is necessary, especially in myocarditis cases. Furthermore, more studies are required to resolve current challenges, including prevention of myocarditis, concurrent administration of other chemotherapeutic agents, and re-introducing patients with ICIs.
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Affiliation(s)
- Seyed Parsa Eftekhar
- School of Medicine, Babol University of Medical Sciences, Babol, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (Niima), Universal Scientific Education and Research Network (Usern), Babol, Iran
| | - Niloufar Yazdanpanah
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (Niima), Universal Scientific Education and Research Network (Usern), Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (Niima), Universal Scientific Education and Research Network (Usern), Tehran, Iran.,Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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25
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Krupa A, Kowalska I. The Kynurenine Pathway-New Linkage between Innate and Adaptive Immunity in Autoimmune Endocrinopathies. Int J Mol Sci 2021; 22:9879. [PMID: 34576041 PMCID: PMC8469440 DOI: 10.3390/ijms22189879] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 09/09/2021] [Accepted: 09/10/2021] [Indexed: 12/18/2022] Open
Abstract
The kynurenine pathway (KP) is highly regulated in the immune system, where it promotes immunosuppression in response to infection or inflammation. Indoleamine 2,3-dioxygenase 1 (IDO1), the main enzyme of KP, has a broad spectrum of activity on immune cells regulation, controlling the balance between stimulation and suppression of the immune system at sites of local inflammation, relevant to a wide range of autoimmune and inflammatory diseases. Various autoimmune diseases, among them endocrinopathies, have been identified to date, but despite significant progress in their diagnosis and treatment, they are still associated with significant complications, morbidity, and mortality. The precise cellular and molecular mechanisms leading to the onset and development of autoimmune disease remain poorly clarified so far. In breaking of tolerance, the cells of the innate immunity provide a decisive microenvironment that regulates immune cells' differentiation, leading to activation of adaptive immunity. The current review provided a comprehensive presentation of the known role of IDO1 and KP activation in the regulation of the innate and adaptive arms of the immune system. Significant attention has been paid to the immunoregulatory role of IDO1 in the most prevalent, organ-specific autoimmune endocrinopathies-type 1 diabetes mellitus (T1DM) and autoimmune thyroiditis.
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Affiliation(s)
- Anna Krupa
- Department of Internal Medicine and Metabolic Diseases, Medical University of Bialystok, M. Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland
| | - Irina Kowalska
- Department of Internal Medicine and Metabolic Diseases, Medical University of Bialystok, M. Sklodowskiej-Curie 24A, 15-276 Bialystok, Poland
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26
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Carvajal Alegria G, Cornec D, Saraux A, Devauchelle-Pensec V, Jamin C, Hillion S, Pers JO, Pochard P. Abatacept Promotes Regulatory B Cell Functions, Enhancing Their Ability to Reduce the Th1 Response in Rheumatoid Arthritis Patients through the Production of IL-10 and TGF-β. THE JOURNAL OF IMMUNOLOGY 2021; 207:470-482. [PMID: 34244295 DOI: 10.4049/jimmunol.2000455] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 05/14/2021] [Indexed: 11/19/2022]
Abstract
Abatacept mimics natural CD152 and competes with CD28 for binding to CD80/CD86 on APC, such as B cells, thereby preventing T cell activation. However, its potential impact on B cells has not been identified. The aim of this study was to assess whether abatacept can potentiate the immunoregulatory properties of B cells in vitro and in patients with rheumatoid arthritis (RA). T and B cells from healthy controls were purified. The suppressor properties of B cells in the presence of abatacept or control IgG1 were evaluated based on the ability of these cells to inhibit the polyclonal expansion (anti-CD3/CD28 stimulation) of T cells or their differentiation into Th1 or Th17 cells. Similar analyses were also performed with cells from RA patients before and 3 mo after abatacept initiation. Abatacept significantly potentiated regulatory B cell regulatory functions by enhancing their ability to produce IL-10 and TGF-β, resulting in the increased generation of regulatory T cells and limited T cell proliferation and differentiation into Th1 and Th17 cells. Interestingly, B cells isolated from patients that received a 3-mo treatment with abatacept had an increased ability to reduce T cell functions, confirming the above observations. Abatacept binding to CD80/CD86 induces and promotes regulatory B cell functions by enhancing the ability of these cells to produce IL-10 and TGF-β in vitro and in RA patients.
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Affiliation(s)
- Guillermo Carvajal Alegria
- UMR 1227 "Lymphocytes B et Autoimmunité," Université de Brest, INSERM, LabEx IGO, Brest, France; and CHU de Brest, Brest, France
| | - Divi Cornec
- UMR 1227 "Lymphocytes B et Autoimmunité," Université de Brest, INSERM, LabEx IGO, Brest, France; and CHU de Brest, Brest, France
| | - Alain Saraux
- UMR 1227 "Lymphocytes B et Autoimmunité," Université de Brest, INSERM, LabEx IGO, Brest, France; and CHU de Brest, Brest, France
| | - Valérie Devauchelle-Pensec
- UMR 1227 "Lymphocytes B et Autoimmunité," Université de Brest, INSERM, LabEx IGO, Brest, France; and CHU de Brest, Brest, France
| | - Christophe Jamin
- UMR 1227 "Lymphocytes B et Autoimmunité," Université de Brest, INSERM, LabEx IGO, Brest, France; and CHU de Brest, Brest, France
| | - Sophie Hillion
- UMR 1227 "Lymphocytes B et Autoimmunité," Université de Brest, INSERM, LabEx IGO, Brest, France; and CHU de Brest, Brest, France
| | - Jacques-Olivier Pers
- UMR 1227 "Lymphocytes B et Autoimmunité," Université de Brest, INSERM, LabEx IGO, Brest, France; and CHU de Brest, Brest, France
| | - Pierre Pochard
- UMR 1227 "Lymphocytes B et Autoimmunité," Université de Brest, INSERM, LabEx IGO, Brest, France; and CHU de Brest, Brest, France
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27
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Nagy NA, de Haas AM, Geijtenbeek TBH, van Ree R, Tas SW, van Kooyk Y, de Jong EC. Therapeutic Liposomal Vaccines for Dendritic Cell Activation or Tolerance. Front Immunol 2021; 12:674048. [PMID: 34054859 PMCID: PMC8155586 DOI: 10.3389/fimmu.2021.674048] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/26/2021] [Indexed: 12/15/2022] Open
Abstract
Dendritic cells (DCs) are paramount in initiating and guiding immunity towards a state of activation or tolerance. This bidirectional capacity of DCs sets them at the center stage for treatment of cancer and autoimmune or allergic conditions. Accordingly, many clinical studies use ex vivo DC vaccination as a strategy to boost anti-tumor immunity or to suppress immunity by including vitamin D3, NF-κB inhibitors or retinoic acid to create tolerogenic DCs. As harvesting DCs from patients and differentiating these cells in vitro is a costly and cumbersome process, in vivo targeting of DCs has huge potential as nanoparticulate platforms equipped with activating or tolerogenic adjuvants can modulate DCs in their natural environment. There is a rapid expansion of the choices of nanoparticles and activation- or tolerance-promoting adjuvants for a therapeutic vaccine platform. In this review we highlight the most recent nanomedical approaches aimed at inducing immune activation or tolerance via targeting DCs, together with novel fundamental insights into the mechanisms inherent to fostering anti-tumor or tolerogenic immunity.
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Affiliation(s)
- Noémi Anna Nagy
- Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Aram M. de Haas
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Teunis B. H. Geijtenbeek
- Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
| | - Ronald van Ree
- Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
- Department of Otorhinolaryngology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Sander W. Tas
- Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
- Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Center, Amsterdam Rheumatology and Immunology Center, University of Amsterdam, Amsterdam, Netherlands
| | - Yvette van Kooyk
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Center, Cancer Center Amsterdam, Amsterdam Institute for Infection and Immunity, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Esther C. de Jong
- Department of Experimental Immunology, Amsterdam University Medical Center, Amsterdam Institute for Infection and Immunity, University of Amsterdam, Amsterdam, Netherlands
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28
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Wyatt M, Greathouse KL. Targeting Dietary and Microbial Tryptophan-Indole Metabolism as Therapeutic Approaches to Colon Cancer. Nutrients 2021; 13:1189. [PMID: 33916690 PMCID: PMC8066279 DOI: 10.3390/nu13041189] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 12/15/2022] Open
Abstract
Tryptophan metabolism, via the kynurenine (Kyn) pathway, and microbial transformation of tryptophan to indolic compounds are fundamental for host health; both of which are altered in colon carcinogenesis. Alterations in tryptophan metabolism begin early in colon carcinogenesis as an adaptive mechanism for the tumor to escape immune surveillance and metastasize. The microbial community is a key part of the tumor microenvironment and influences cancer initiation, promotion and treatment response. A growing awareness of the impact of the microbiome on tryptophan (Trp) metabolism in the context of carcinogenesis has prompted this review. We first compare the different metabolic pathways of Trp under normal cellular physiology to colon carcinogenesis, in both the host cells and the microbiome. Second, we review how the microbiome, specifically indoles, influence host tryptophan pathways under normal and oncogenic metabolism. We conclude by proposing several dietary, microbial and drug therapeutic modalities that can be utilized in combination to abrogate tumorigenesis.
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Affiliation(s)
- Madhur Wyatt
- Human Health, Performance and Recreation, Robbins College of Health and Human Sciences, Baylor University, Waco, TX 76798-7346, USA;
| | - K. Leigh Greathouse
- Human Science and Design, Robbins College of Health and Human Sciences, Baylor University, Waco, TX 76798-7346, USA
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29
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Liu M, Yu Y, Hu S. A review on applications of abatacept in systemic rheumatic diseases. Int Immunopharmacol 2021; 96:107612. [PMID: 33823429 DOI: 10.1016/j.intimp.2021.107612] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Revised: 03/11/2021] [Accepted: 03/22/2021] [Indexed: 12/26/2022]
Abstract
Abatacept is a CTLA-4Ig fusion protein that selectively modulates the CD80/CD86:CD28 costimulatory pathway required for full T-cell activation. The FDA has approved it to be used to treat adult rheumatoid arthritis, juvenile idiopathic arthritis, and adult active psoriatic arthritis. Considering the vital pathogenic role of the CTLA-4 pathway in autoimmune diseases, abatacept could efficiently treat other systemic rheumatic diseases. Here we reviewed the published literature to profile the perspectives about the off-label uses of abatacept, especially in those refractory cases with inadequate responses to conventional therapies and biologic agents. Abatacept can be a promising therapeutic option and contribute to reducing hormone dependence and correlated adverse events.
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Affiliation(s)
- Min Liu
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yikai Yu
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shaoxian Hu
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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30
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Zulpaite R, Miknevicius P, Leber B, Strupas K, Stiegler P, Schemmer P. Tryptophan Metabolism via Kynurenine Pathway: Role in Solid Organ Transplantation. Int J Mol Sci 2021; 22:1921. [PMID: 33671985 PMCID: PMC7919278 DOI: 10.3390/ijms22041921] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 01/01/2023] Open
Abstract
Solid organ transplantation is a gold standard treatment for patients suffering from an end-stage organ disease. Patient and graft survival have vastly improved during the last couple of decades; however, the field of transplantation still encounters several unique challenges, such as a shortage of transplantable organs and increasing pool of extended criteria donor (ECD) organs, which are extremely prone to ischemia-reperfusion injury (IRI), risk of graft rejection and challenges in immune regulation. Moreover, accurate and specific biomarkers, which can timely predict allograft dysfunction and/or rejection, are lacking. The essential amino acid tryptophan and, especially, its metabolites via the kynurenine pathway has been widely studied as a contributor and a therapeutic target in various diseases, such as neuropsychiatric, autoimmune disorders, allergies, infections and malignancies. The tryptophan-kynurenine pathway has also gained interest in solid organ transplantation and a variety of experimental studies investigating its role both in IRI and immune regulation after allograft implantation was first published. In this review, the current evidence regarding the role of tryptophan and its metabolites in solid organ transplantation is presented, giving insights into molecular mechanisms and into therapeutic and diagnostic/prognostic possibilities.
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Affiliation(s)
- Ruta Zulpaite
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Auenbruggerpl. 2, 8036 Graz, Austria; (R.Z.); (P.M.); (B.L.); (P.S.)
- Faculty of Medicine, Vilnius University, M. K. Ciurlionio 21, 03101 Vilnius, Lithuania;
| | - Povilas Miknevicius
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Auenbruggerpl. 2, 8036 Graz, Austria; (R.Z.); (P.M.); (B.L.); (P.S.)
- Faculty of Medicine, Vilnius University, M. K. Ciurlionio 21, 03101 Vilnius, Lithuania;
| | - Bettina Leber
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Auenbruggerpl. 2, 8036 Graz, Austria; (R.Z.); (P.M.); (B.L.); (P.S.)
| | - Kestutis Strupas
- Faculty of Medicine, Vilnius University, M. K. Ciurlionio 21, 03101 Vilnius, Lithuania;
| | - Philipp Stiegler
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Auenbruggerpl. 2, 8036 Graz, Austria; (R.Z.); (P.M.); (B.L.); (P.S.)
| | - Peter Schemmer
- General, Visceral and Transplant Surgery, Department of Surgery, Medical University of Graz, Auenbruggerpl. 2, 8036 Graz, Austria; (R.Z.); (P.M.); (B.L.); (P.S.)
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31
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Zelante T, Choera T, Beauvais A, Fallarino F, Paolicelli G, Pieraccini G, Pieroni M, Galosi C, Beato C, De Luca A, Boscaro F, Romoli R, Liu X, Warris A, Verweij PE, Ballard E, Borghi M, Pariano M, Costantino G, Calvitti M, Vacca C, Oikonomou V, Gargaro M, Wong AYW, Boon L, den Hartog M, Spáčil Z, Puccetti P, Latgè JP, Keller NP, Romani L. Aspergillus fumigatus tryptophan metabolic route differently affects host immunity. Cell Rep 2021; 34:108673. [PMID: 33503414 PMCID: PMC7844877 DOI: 10.1016/j.celrep.2020.108673] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 10/20/2020] [Accepted: 12/30/2020] [Indexed: 12/28/2022] Open
Abstract
Indoleamine 2,3-dioxygenases (IDOs) degrade l-tryptophan to kynurenines and drive the de novo synthesis of nicotinamide adenine dinucleotide. Unsurprisingly, various invertebrates, vertebrates, and even fungi produce IDO. In mammals, IDO1 also serves as a homeostatic regulator, modulating immune response to infection via local tryptophan deprivation, active catabolite production, and non-enzymatic cell signaling. Whether fungal Idos have pleiotropic functions that impact on host-fungal physiology is unclear. Here, we show that Aspergillus fumigatus possesses three ido genes that are expressed under conditions of hypoxia or tryptophan abundance. Loss of these genes results in increased fungal pathogenicity and inflammation in a mouse model of aspergillosis, driven by an alternative tryptophan degradation pathway to indole derivatives and the host aryl hydrocarbon receptor. Fungal tryptophan metabolic pathways thus cooperate with the host xenobiotic response to shape host-microbe interactions in local tissue microenvironments.
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Affiliation(s)
- Teresa Zelante
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy.
| | - Tsokyi Choera
- Department of Medical Microbiology and Immunology, Department of Bacteriology, University of Wisconsin, Madison, WI, USA
| | - Anne Beauvais
- Unitè des Aspergillus, Pasteur Institute, 75724 Paris, France
| | - Francesca Fallarino
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Giuseppe Paolicelli
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Giuseppe Pieraccini
- Mass Spectrometry Centre (CISM), University of Florence, 50019 Florence, Italy
| | - Marco Pieroni
- P4T group, Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy
| | - Claudia Galosi
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Claudia Beato
- Interdepartmental Centre for Measures (CIM) "G. Casnati," University of Parma, Parco Area delle Scienze 23/A, 43124 Parma, Italy
| | - Antonella De Luca
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Francesca Boscaro
- Mass Spectrometry Centre (CISM), University of Florence, 50019 Florence, Italy
| | - Riccardo Romoli
- Mass Spectrometry Centre (CISM), University of Florence, 50019 Florence, Italy
| | - Xin Liu
- Department of Medical Microbiology and Immunology, Department of Bacteriology, University of Wisconsin, Madison, WI, USA
| | - Adilia Warris
- MRC Centre for Medical Mycology, Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK
| | - Paul E Verweij
- Department of Medical Microbiology, Centre of Expertise in Mycology, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Eloise Ballard
- MRC Centre for Medical Mycology, Aberdeen Fungal Group, Institute of Medical Sciences, University of Aberdeen, Aberdeen AB25 2ZD, UK
| | - Monica Borghi
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Marilena Pariano
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Gabriele Costantino
- P4T group, Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy
| | - Mario Calvitti
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Carmine Vacca
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Vasilis Oikonomou
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Marco Gargaro
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Alicia Yoke Wei Wong
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore, Singapore
| | | | | | - Zdeněk Spáčil
- Research Centre for Toxic Compounds in the Environment (RECETOX), Brno, Czech Republic
| | - Paolo Puccetti
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
| | - Jean-Paul Latgè
- Unitè des Aspergillus, Pasteur Institute, 75724 Paris, France
| | - Nancy P Keller
- Department of Medical Microbiology and Immunology, Department of Bacteriology, University of Wisconsin, Madison, WI, USA
| | - Luigina Romani
- Department of Medicine and Surgery, University of Perugia, 06132 Perugia, Italy
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Liu XH, Zhai XY. Role of tryptophan metabolism in cancers and therapeutic implications. Biochimie 2021; 182:131-139. [PMID: 33460767 DOI: 10.1016/j.biochi.2021.01.005] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 01/08/2021] [Accepted: 01/10/2021] [Indexed: 12/15/2022]
Abstract
Tryptophan (Trp) metabolism is associated with diverse biological processes, including nerve conduction, inflammation, and the immune response. The majority of free Trp is broken down through the kynurenine (Kyn) pathway (KP), in which indoleamine-2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) catalyze the rate-limiting step. Clinical studies have demonstrated that Trp metabolism promotes tumor progression due to modulation of the immunosuppressive microenvironment through multiple mechanisms. In this process, IDO-expressing dendritic cells (DCs) exhibit tolerogenic potential and orchestrate T cell immune responses. Various signaling molecules control IDO expression, initiating the immunoregulatory pathway of Trp catabolism. Based on these characteristics, KP enzymes and catabolites are emerging as significant prognostic indicators and potential therapeutic targets of cancer. The physiological and oncologic roles of Trp metabolism are briefly summarized here, along with great challenges for treatment strategies.
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Affiliation(s)
- Xiao-Han Liu
- Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, Liaoning, 110122, China
| | - Xiao-Yue Zhai
- Department of Histology and Embryology, Basic Medical College, China Medical University, Shenyang, Liaoning, 110122, China.
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Engel S, Jolivel V, Kraus SHP, Zayoud M, Rosenfeld K, Tumani H, Furlan R, Kurschus FC, Waisman A, Luessi F. Laquinimod dampens IL-1β signaling and Th17-polarizing capacity of monocytes in patients with MS. NEUROLOGY-NEUROIMMUNOLOGY & NEUROINFLAMMATION 2020; 8:8/1/e908. [PMID: 33203651 PMCID: PMC7676421 DOI: 10.1212/nxi.0000000000000908] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 09/23/2020] [Indexed: 01/16/2023]
Abstract
OBJECTIVE To assess the impact of laquinimod treatment on monocytes and to investigate the underlying immunomodulatory mechanisms in MS. METHODS In this cross-sectional study, we performed in vivo and in vitro analyses of cluster of differentiation (CD14+) monocytes isolated from healthy donors (n = 15), untreated (n = 13), and laquinimod-treated patients with MS (n = 14). Their frequency and the expression of surface activation markers were assessed by flow cytometry and the viability by calcein staining. Cytokine concentrations in the supernatants of lipopolysaccharide (LPS)-stimulated monocytes were determined by flow cytometry. The messenger ribonucleic acid (mRNA) expression level of genes involved in cytokine expression was measured by quantitative PCR. The LPS-mediated nuclear factor kappa-light-chain-enhancer of activated B-cell (NF-κB) activation was determined by the quantification of the phosphorylation level of the p65 subunit. Laquinimod-treated monocytes were cocultured with CD4+ T cells, and the resulting cytokine production was analyzed by flow cytometry after intracellular cytokine staining. The interleukin (IL)-17A concentration of the supernatant was assessed by ELISA. RESULTS Laquinimod did not alter the frequency or viability of circulating monocytes, but led to an upregulation of CD86 expression. LPS-stimulated monocytes of laquinimod-treated patients with MS secreted less IL-1β following a downregulation of IL-1β gene expression. Phosphorylation levels of the NF-κB p65 subunit were reduced after laquinimod treatment, indicating a laquinimod-associated inhibition of the NF-κB pathway. T cells primed with laquinimod-treated monocytes differentiated significantly less into IL-17A-producing T helper (Th)-17 cells. CONCLUSIONS Our findings suggest that inhibited NF-κB signaling and downregulation of IL-1β expression in monocytes contributes to the immunomodulatory effects of laquinimod and that the impairment of Th17 polarization might mediate its disease-modifying activity in MS.
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Affiliation(s)
- Sinah Engel
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany
| | - Valérie Jolivel
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany
| | - Stefan H-P Kraus
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany
| | - Morad Zayoud
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany
| | - Karolina Rosenfeld
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany
| | - Hayrettin Tumani
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany
| | - Roberto Furlan
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany
| | - Florian C Kurschus
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany
| | - Ari Waisman
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany
| | - Felix Luessi
- From the Department of Neurology (S.E., V.J., S.H.-P.K., K.R., F.L.), Focus Program Translational Neuroscience (FTN), University Medical Center of the Johannes Gutenberg University of Mainz, Germany; Biopathology of Myelin (V.J.), Neuroprotection and Therapeutic Strategy, INSERM U1119, Fédération de Médecine Translationnelle de Strasbourg (FMTS), University of Strasbourg, France; Institute for Molecular Medicine (M.Z., F.C.K., A.W.), University Medical Centre of the Johannes Gutenberg University of Mainz, Germany; Sheba Cancer Research Center (M.Z.), Chaim Sheba Academic Medical Center, Ramat Gan, Israel; Department of Neurology (H.T.), University of Ulm, Germany and Specialty Clinic of Neurology Dietenbronn, Schwendi, Germany; Clinical Neuroimmunology Unit (R.F.), San Raffaele Scientific Institute, Milan, Italy; and Department of Dermatology (F.C.K.), Heidelberg University Hospital, Heidelberg, Germany.
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Wang F, Wang S, Zhou Q. The Resistance Mechanisms of Lung Cancer Immunotherapy. Front Oncol 2020; 10:568059. [PMID: 33194652 PMCID: PMC7606919 DOI: 10.3389/fonc.2020.568059] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 09/14/2020] [Indexed: 12/14/2022] Open
Abstract
Immunotherapy has revolutionized lung cancer treatment in the past decade. By reactivating the host’s immune system, immunotherapy significantly prolongs survival in some advanced lung cancer patients. However, resistance to immunotherapy is frequent, which manifests as a lack of initial response or clinical benefit to therapy (primary resistance) or tumor progression after the initial period of response (acquired resistance). Overcoming immunotherapy resistance is challenging owing to the complex and dynamic interplay among malignant cells and the defense system. This review aims to discuss the mechanisms that drive immunotherapy resistance and the innovative strategies implemented to overcome it in lung cancer.
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Affiliation(s)
- Fen Wang
- Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangdong Lung Cancer Institute, South China University of Technology, Guangzhou, China.,Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Department of Oncology, Cancer Institute of Shenzhen-PKU-HKUST Medical Center, Peking University Shenzhen Hospital, Shenzhen, China
| | - Shubin Wang
- Shenzhen Key Laboratory of Gastrointestinal Cancer Translational Research, Department of Oncology, Cancer Institute of Shenzhen-PKU-HKUST Medical Center, Peking University Shenzhen Hospital, Shenzhen, China
| | - Qing Zhou
- Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, School of Medicine, Guangdong Lung Cancer Institute, South China University of Technology, Guangzhou, China
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Meireson A, Devos M, Brochez L. IDO Expression in Cancer: Different Compartment, Different Functionality? Front Immunol 2020; 11:531491. [PMID: 33072086 PMCID: PMC7541907 DOI: 10.3389/fimmu.2020.531491] [Citation(s) in RCA: 134] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 08/25/2020] [Indexed: 12/11/2022] Open
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.
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Affiliation(s)
- Annabel Meireson
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium
| | - Michael Devos
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium
| | - Lieve Brochez
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.,Cancer Research Institute Ghent, Ghent, Belgium
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D'Arrigo P, Tufano M, Rea A, Vigorito V, Novizio N, Russo S, Romano MF, Romano S. Manipulation of the Immune System for Cancer Defeat: A Focus on the T Cell Inhibitory Checkpoint Molecules. Curr Med Chem 2020; 27:2402-2448. [PMID: 30398102 DOI: 10.2174/0929867325666181106114421] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 10/15/2018] [Accepted: 10/24/2018] [Indexed: 12/19/2022]
Abstract
The immune system actively counteracts the tumorigenesis process; a breakout of the immune system function, or its ability to recognize transformed cells, can favor cancer development. Cancer becomes able to escape from immune system control by using multiple mechanisms, which are only in part known at a cellular and molecular level. Among these mechanisms, in the last decade, the role played by the so-called "inhibitory immune checkpoints" is emerging as pivotal in preventing the tumor attack by the immune system. Physiologically, the inhibitory immune checkpoints work to maintain the self-tolerance and attenuate the tissue injury caused by pathogenic infections. Cancer cell exploits such immune-inhibitory molecules to contrast the immune intervention and induce tumor tolerance. Molecular agents that target these checkpoints represent the new frontier for cancer treatment. Despite the heterogeneity and multiplicity of molecular alterations among the tumors, the immune checkpoint targeted therapy has been shown to be helpful in selected and even histologically different types of cancer, and are currently being adopted against an increasing variety of tumors. The most frequently used is the moAb-based immunotherapy that targets the Programmed Cell Death 1 protein (PD-1), the PD-1 Ligand (PD-L1) or the cytotoxic T lymphocyte antigen-4 (CTLA4). However, new therapeutic approaches are currently in development, along with the discovery of new immune checkpoints exploited by the cancer cell. This article aims to review the inhibitory checkpoints, which are known up to now, along with the mechanisms of cancer immunoediting. An outline of the immune checkpoint targeting approaches, also including combined immunotherapies and the existing trials, is also provided. Notwithstanding the great efforts devoted by researchers in the field of biomarkers of response, to date, no validated FDA-approved immunological biomarkers exist for cancer patients. We highlight relevant studies on predictive biomarkers and attempt to discuss the challenges in this field, due to the complex and largely unknown dynamic mechanisms that drive the tumor immune tolerance.
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Affiliation(s)
- Paolo D'Arrigo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Martina Tufano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Anna Rea
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Vincenza Vigorito
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Nunzia Novizio
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Salvatore Russo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Maria Fiammetta Romano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
| | - Simona Romano
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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FoxP3 + T regulatory cells in cancer: Prognostic biomarkers and therapeutic targets. Cancer Lett 2020; 490:174-185. [PMID: 32721551 DOI: 10.1016/j.canlet.2020.07.022] [Citation(s) in RCA: 212] [Impact Index Per Article: 42.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/28/2020] [Accepted: 07/16/2020] [Indexed: 12/19/2022]
Abstract
T Regulatory cells (Tregs) can have both protective and pathological roles. They maintain immune homeostasis and inhibit immune responses in various diseases, including cancer. Proportions of Tregs in the peripheral blood of some cancer patients increase by approximately two-fold, compared to those in healthy individuals. Tregs contribute to cancer development and progression by suppressing T effector cell functions, thereby compromising tumor killing and promoting tumor growth. Highly immunosuppressive Tregs express upregulated levels of the transcription factor, Forkhead box protein P3 (FoxP3). Elevated levels of FoxP3+ Tregs within the tumor microenvironment (TME) showed a positive correlation with poor prognosis in various cancer patients. Despite the success of immunotherapy, including the use of immune checkpoint inhibitors, a significant proportion of patients show low response rates as a result of primary or acquired resistance against therapy. Some of the mechanisms which underlie the development of therapy resistance are associated with Treg suppressive function. In this review, we describe Treg contribution to cancer development/progression, and the mechanisms of Treg-mediated immunosuppression. We discuss the prognostic significance of FoxP3+ Tregs in different cancers and their potential use as prognostic biomarkers. We also describe potential therapeutic strategies to target Tregs in combination with other types of immunotherapies aiming to overcome tumor resistance and improve clinical outcomes in cancer patients. Overall, understanding the prognostic significance of FoxP3+ Tregs in various cancers and their contribution to therapy resistance could help in the development of more effective targeted therapeutic strategies to enhance the clinical outcomes in cancer patients.
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Li C, Wang X, Yuan F, Zhao Z, Zhang B, Zhang J, Li W, Liu T. MiR-669b-3p regulates CD4 + T cell function by down-regulating indoleamine-2, 3-dioxygenase. Transpl Immunol 2020; 62:101320. [PMID: 32687860 DOI: 10.1016/j.trim.2020.101320] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/14/2020] [Accepted: 07/14/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Acute rejection is a major cause of morbidity and mortality after solid organ transplantation. Therefore, optimizing treatment strategies and improving curative effect is urgent and necessary. Reliable biomarkers for acute rejection and the underlying molecular mechanisms remain to be determined. METHODS In this study, we established a mouse-to-mouse cardiac transplantation model and identified miR-669b-3p as a potential biomarker of acute rejection using a microRNA polymerase chain reaction (PCR)-based chip assay. RESULTS Further analyses showed that miR-669b-3p negatively regulated indoleamine-2,3-dioxygenase (IDO), a rate-limiting enzyme of tryptophan catabolism inhibiting T cell function. Using mixed lymphocyte reaction assay, we showed that miR-669b-3p increased proliferation stimulation index and inhibited apoptosis in CD4+ T cells. Moreover, miR-669b-3p regulated the expression of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and Interleukin 10 (IL-10) and contributed to cytokine shift towards a Th2-dominant response. CONCLUSION Our results advance the current understanding of the immune regulatory function of miRNA and shed light on the role of miR-669b-3p in CD4+ T cells, suggesting that miR-669b-3p is a potential target for acute allograft rejection.
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Affiliation(s)
- Chuan Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Xi Wang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Fang Yuan
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zhicheng Zhao
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Baotong Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Jiehong Zhang
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - WeiDong Li
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
| | - Tong Liu
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
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Biernacki T, Sandi D, Bencsik K, Vécsei L. Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives. Cells 2020; 9:cells9061564. [PMID: 32604956 PMCID: PMC7349747 DOI: 10.3390/cells9061564] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/22/2020] [Accepted: 06/23/2020] [Indexed: 12/11/2022] Open
Abstract
Over the past years, an increasing amount of evidence has emerged in support of the kynurenine pathway’s (KP) pivotal role in the pathogenesis of several neurodegenerative, psychiatric, vascular and autoimmune diseases. Different neuroactive metabolites of the KP are known to exert opposite effects on neurons, some being neuroprotective (e.g., picolinic acid, kynurenic acid, and the cofactor nicotinamide adenine dinucleotide), while others are toxic to neurons (e.g., 3-hydroxykynurenine, quinolinic acid). Not only the alterations in the levels of the metabolites but also disturbances in their ratio (quinolinic acid/kynurenic acid) have been reported in several diseases. In addition to the metabolites, the enzymes participating in the KP have been unearthed to be involved in modulation of the immune system, the energetic upkeep of neurons and have been shown to influence redox processes and inflammatory cascades, revealing a sophisticated, intertwined system. This review considers various methods through which enzymes and metabolites of the kynurenine pathway influence the immune system, the roles they play in the pathogenesis of neuroinflammatory diseases based on current evidence with a focus on their involvement in multiple sclerosis, as well as therapeutic approaches.
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Affiliation(s)
- Tamás Biernacki
- Department of Neurology, Faculty of General Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, H-6725 Szeged, Hungary; (T.B.); (D.S.); (K.B.)
| | - Dániel Sandi
- Department of Neurology, Faculty of General Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, H-6725 Szeged, Hungary; (T.B.); (D.S.); (K.B.)
| | - Krisztina Bencsik
- Department of Neurology, Faculty of General Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, H-6725 Szeged, Hungary; (T.B.); (D.S.); (K.B.)
| | - László Vécsei
- Department of Neurology, Faculty of General Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, H-6725 Szeged, Hungary; (T.B.); (D.S.); (K.B.)
- MTA—SZTE Neuroscience Research Group, H-6725 Szeged, Hungary
- Interdisciplinary Excellence Center, University of Szeged, H-6720 Szeged, Hungary
- Correspondence: ; Tel.: +36-62-545-356; Fax: +36-62-545-597
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Hurkmans DP, Tamminga M, van Es B, Peters T, Karman W, van Wijck RTA, van der Spek PJ, Tauber T, Los M, van Schetsen A, Vu T, Hiltermann TJN, Schuuring E, Aerts JGJV, Chen S, Groen HJM. Molecular data show conserved DNA locations distinguishing lung cancer subtypes and regulation of immune genes. Lung Cancer 2020; 146:341-349. [PMID: 32645666 DOI: 10.1016/j.lungcan.2020.06.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 06/03/2020] [Accepted: 06/09/2020] [Indexed: 01/22/2023]
Abstract
INTRODUCTION Non-small-cell lung cancer exhibits a range of transcriptional and epigenetic patterns that not only define distinct phenotypes, but may also govern immune related genes, which have a major impact on survival. METHODS We used open-source RNA expression and DNA methylation data of the Cancer Genome Atlas with matched non-cancerous tissue to evaluate whether these pretreatment molecular patterns also influenced genes related to the immune system and overall survival. RESULTS The distinction between lung adenocarcinoma and squamous cell carcinoma are determined by 1083 conserved methylation loci and RNA expression of 203 genes which differ for >80 % of patients between the two subtypes. Using the RNA expression profiles of 6 genes, more than 95 % of patients could be correctly classified as having either adeno or squamous cell lung cancer. Comparing tumor tissue with matched normal tissue, no differences in RNA expression were found for costimulatory and co-inhibitory genes, nor genes involved in cytokine release. However, genes involved in antigen presentation had a lower expression and a wider distribution in tumor tissue. DISCUSSION Only a small number of genes, influenced by DNA methylation, determine the lung cancer subtype. The antigen presentation of cancer cells is dysfunctional, while other T cell immune functions appear to remain intact.
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Affiliation(s)
- Daan P Hurkmans
- Erasmus University Medical Center, Departments of Pulmonary Diseases, Internal Medicine and Pathology, Bioinformatic Unit, Dr. Molewaterplein 40, 3015 GD, the Netherlands.
| | - Menno Tamminga
- University of Groningen and University Medical Center Groningen, Departments of Pulmonary Diseases and Pathology and Medical Biology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
| | - Bram van Es
- Otravo B.V., Suikersilo-West 41, 1165 MP, Amsterdam-Halfweg, the Netherlands.
| | - Tom Peters
- PricewaterhouseCoopers Advisory NV, Thomas R. Malthusstraat 5, 1066 JR, Amsterdam, the Netherlands.
| | - Wouter Karman
- PricewaterhouseCoopers Advisory NV, Thomas R. Malthusstraat 5, 1066 JR, Amsterdam, the Netherlands.
| | - Rogier T A van Wijck
- Erasmus University Medical Center, Departments of Pulmonary Diseases, Internal Medicine and Pathology, Bioinformatic Unit, Dr. Molewaterplein 40, 3015 GD, the Netherlands.
| | - Peter J van der Spek
- Erasmus University Medical Center, Departments of Pulmonary Diseases, Internal Medicine and Pathology, Bioinformatic Unit, Dr. Molewaterplein 40, 3015 GD, the Netherlands.
| | - Tjebbe Tauber
- ABN-AMRO, Foppingadreef 22, 1102 BS Amsterdam, the Netherlands.
| | - Maureen Los
- PricewaterhouseCoopers Advisory NV, Thomas R. Malthusstraat 5, 1066 JR, Amsterdam, the Netherlands.
| | - Anouk van Schetsen
- PricewaterhouseCoopers Advisory NV, Thomas R. Malthusstraat 5, 1066 JR, Amsterdam, the Netherlands.
| | - Thu Vu
- PricewaterhouseCoopers Advisory NV, Thomas R. Malthusstraat 5, 1066 JR, Amsterdam, the Netherlands.
| | - T Jeroen N Hiltermann
- University of Groningen and University Medical Center Groningen, Departments of Pulmonary Diseases and Pathology and Medical Biology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
| | - Ed Schuuring
- University of Groningen and University Medical Center Groningen, Departments of Pulmonary Diseases and Pathology and Medical Biology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
| | - Joachim G J V Aerts
- Erasmus University Medical Center, Departments of Pulmonary Diseases, Internal Medicine and Pathology, Bioinformatic Unit, Dr. Molewaterplein 40, 3015 GD, the Netherlands.
| | - Sissy Chen
- PricewaterhouseCoopers Advisory NV, Thomas R. Malthusstraat 5, 1066 JR, Amsterdam, the Netherlands.
| | - Harry J M Groen
- University of Groningen and University Medical Center Groningen, Departments of Pulmonary Diseases and Pathology and Medical Biology, Hanzeplein 1, 9713 GZ, Groningen, the Netherlands.
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Ketelhuth DFJ. The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall. Cardiovasc Res 2020; 115:1408-1415. [PMID: 30847484 DOI: 10.1093/cvr/cvz067] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2018] [Revised: 01/30/2019] [Accepted: 03/05/2019] [Indexed: 01/05/2023] Open
Abstract
Coronary heart disease and stroke, the two most common cardiovascular diseases worldwide, are triggered by complications of atherosclerosis. Atherosclerotic plaques are initiated by a maladaptive immune response triggered by accumulation of lipids in the artery wall. Hence, disease is influenced by several non-modifiable and modifiable risk factors, including dyslipidaemia, hypertension, smoking, and diabetes. Indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway of tryptophan (Trp) degradation, is modulated by inflammation and regarded as a key molecule driving immunotolerance and immunosuppressive mechanisms. A large body of evidence indicates that IDO-mediated Trp metabolism is involved directly or indirectly in atherogenesis. This review summarizes evidence from basic and clinical research showing that IDO is a major regulatory enzyme involved in the maintenance of immunohomeostasis in the vascular wall, as well as current knowledge about promising targets for the development of new anti-atherosclerotic drugs.
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Affiliation(s)
- Daniel F J Ketelhuth
- Cardiovascular Medicine Unit, Center for Molecular Medicine, Department of Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.,Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, Univ. of Southern Denmark, J. B. Winsløws Vej 21(3), Odense C, Denmark
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42
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Dos Santos LM, Commodaro AG, Vasquez ARR, Kohlhoff M, de Paula Guerra DA, Coimbra RS, Martins-Filho OA, Teixeira-Carvalho A, Rizzo LV, Vieira LQ, Serra HM. Intestinal microbiota regulates tryptophan metabolism following oral infection with Toxoplasma gondii. Parasite Immunol 2020; 42:e12720. [PMID: 32275066 DOI: 10.1111/pim.12720] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Revised: 02/24/2020] [Accepted: 03/30/2020] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The intestinal microbiota plays an important role in modulating host immune responses. Oral Toxoplasma gondii infection can promote intestinal inflammation in certain mice strains. The IDO-AhR axis may control tryptophan (Trp) metabolism constituting an important immune regulatory mechanism in inflammatory settings. AIMS In the present study, we investigated the role of the intestinal microbiota on Trp metabolism during oral infection with T gondii. METHODS AND RESULTS Mice were treated with antibiotics for four weeks and then infected with T gondii by gavage. Histopathology and immune responses were evaluated 8 days after infection. We found that depletion of intestinal microbiota by antibiotics contributed to resistance against T gondii infection and led to reduced expression of AhR on dendritic and Treg cells. Mice depleted of Gram-negative bacteria presented higher levels of systemic Trp, downregulation of AhR expression and increased resistance to infection whereas depletion of Gram-positive bacteria did not affect susceptibility or expression of AhR on immune cells. CONCLUSION Our findings indicate that the intestinal microbiota can control Trp availability and provide a link between the AhR pathway and host-microbiota interaction in acute infection with T gondii.
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Affiliation(s)
- Liliane M Dos Santos
- Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Alessandra G Commodaro
- Departmento de Oftalmologia, Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil
| | - Alicia R R Vasquez
- Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Markus Kohlhoff
- Instituto René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil
| | | | - Roney S Coimbra
- Instituto René Rachou, Fundação Oswaldo Cruz-FIOCRUZ, Belo Horizonte, Brazil
| | | | | | - Luiz V Rizzo
- Instituto Israelita de Pesquisa e Ensino, São Paulo, Brazil
| | - Leda Q Vieira
- Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Horacio M Serra
- Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.,Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), CONICET, Córdoba, Argentina
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Sarawar SR, Shen J, Dias P. Insights into CD8 T Cell Activation and Exhaustion from a Mouse Gammaherpesvirus Model. Viral Immunol 2020; 33:215-224. [PMID: 32286179 PMCID: PMC7185348 DOI: 10.1089/vim.2019.0183] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
(S.R.S.) I was introduced to viral immunology while working in Peter Doherty's laboratory in the early stages of my research career, inspiring a lifelong interest in this area. During those early years under Peter's mentorship, we studied a mouse gammaherpesvirus model (murine gammaherpesvirus-68 [MHV-68]) that provided a useful small animal model for investigating the immunological control of gammaherpesvirus infection. Interestingly, while CD4 T cells were not required for acute control of MHV-68 in the lung, CD8 T cell-mediated control was progressively lost in the absence of CD4 T cell help, leading to viral recrudescence. This was one of several early studies showing that CD8 T cell control of persistent viral infections was lost in the absence of CD4 T cell help, preceding the concept of CD8 T cell exhaustion. Further studies showed that MHV-68 infection of mice offered a unique model for comparing the mechanisms of acute and long-term control of a persistent viral infection and developing strategies for reversing T cell exhaustion. Here, we provide a brief review of the literature on CD8 T cell activation and exhaustion in this model, focusing on the role of CD40 and B7 family members and including some previously unpublished data.
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Affiliation(s)
- Sally R Sarawar
- Viral Immunology, The Biomedical Research Institute of Southern California, San Diego, California
| | - Jadon Shen
- Palo Alto Veterans Institute For Research, Palo Alto, California
| | - Peter Dias
- Viral Immunology, The Biomedical Research Institute of Southern California, San Diego, California
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Jamali A, Harris DL, Blanco T, Lopez MJ, Hamrah P. Resident plasmacytoid dendritic cells patrol vessels in the naïve limbus and conjunctiva. Ocul Surf 2020; 18:277-285. [PMID: 32109562 PMCID: PMC7397780 DOI: 10.1016/j.jtos.2020.02.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 02/15/2020] [Accepted: 02/22/2020] [Indexed: 12/21/2022]
Abstract
Plasmacytoid dendritic cells (pDCs) constitute a unique population of bone marrow-derived cells that play a pivotal role in linking innate and adaptive immune responses. While peripheral tissues are typically devoid of pDCs during steady state, few tissues do host resident pDCs. In the current study, we aim to assess presence and distribution of pDCs in naïve murine limbus and bulbar conjunctiva. Immunofluorescence staining followed by confocal microscopy revealed that the naïve bulbar conjunctiva of wild-type mice hosts CD45+ CD11clow PDCA-1+ pDCs. Flow cytometry confirmed the presence of resident pDCs in the bulbar conjunctiva through multiple additional markers, and showed that they express maturation markers, the T cell co-inhibitory molecules PD-L1 and B7-H3, and minor to negligible levels of T cell co-stimulatory molecules CD40, CD86, and ICAM-1. Epi-fluorescent microscopy of DPE-GFP×RAG1-/- transgenic mice with GFP-tagged pDCs indicated lower density of pDCs in the bulbar conjunctiva compared to the limbus. Further, intravital multiphoton microscopy revealed that resident pDCs accompany the limbal vessels and patrol the intravascular space. In vitro multiphoton microscopy showed that pDCs are attracted to human umbilical vein endothelial cells and interact with them during tube formation. In conclusion, our study shows that the limbus and bulbar conjunctiva are endowed with resident pDCs during steady state, which express maturation and classic T cell co-inhibitory molecules, engulf limbal vessels, and patrol intravascular spaces.
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Affiliation(s)
- Arsia Jamali
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Deshea L Harris
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Tomas Blanco
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA
| | - Maria J Lopez
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Pedram Hamrah
- Center for Translational Ocular Immunology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Department of Ophthalmology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA; Schepens Eye Research Institute/Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Program in Immunology, School of Graduate Biomedical Sciences, Tufts University, Boston, MA, USA; Cornea Service, Tufts New England Eye Center, Boston, MA, USA.
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Figueiredo CR, Kalirai H, Sacco JJ, Azevedo RA, Duckworth A, Slupsky JR, Coulson JM, Coupland SE. Loss of BAP1 expression is associated with an immunosuppressive microenvironment in uveal melanoma, with implications for immunotherapy development. J Pathol 2020; 250:420-439. [PMID: 31960425 PMCID: PMC7216965 DOI: 10.1002/path.5384] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 12/28/2019] [Accepted: 01/14/2020] [Indexed: 12/22/2022]
Abstract
Immunotherapy using immune checkpoint inhibitors (ICIs) induces durable responses in many metastatic cancers. Metastatic uveal melanoma (mUM), typically occurring in the liver, is one of the most refractory tumours to ICIs and has dismal outcomes. Monosomy 3 (M3), polysomy 8q, and BAP1 loss in primary uveal melanoma (pUM) are associated with poor prognoses. The presence of tumour-infiltrating lymphocytes (TILs) within pUM and surrounding mUM - and some evidence of clinical responses to adoptive TIL transfer - strongly suggests that UMs are indeed immunogenic despite their low mutational burden. The mechanisms that suppress TILs in pUM and mUM are unknown. We show that BAP1 loss is correlated with upregulation of several genes associated with suppressive immune responses, some of which build an immune suppressive axis, including HLA-DR, CD38, and CD74. Further, single-cell analysis of pUM by mass cytometry confirmed the expression of these and other markers revealing important functions of infiltrating immune cells in UM, most being regulatory CD8+ T lymphocytes and tumour-associated macrophages (TAMs). Transcriptomic analysis of hepatic mUM revealed similar immune profiles to pUM with BAP1 loss, including the expression of IDO1. At the protein level, we observed TAMs and TILs entrapped within peritumoural fibrotic areas surrounding mUM, with increased expression of IDO1, PD-L1, and β-catenin (CTNNB1), suggesting tumour-driven immune exclusion and hence the immunotherapy resistance. These findings aid the understanding of how the immune response is organised in BAP1 - mUM, which will further enable functional validation of detected biomarkers and the development of focused immunotherapeutic approaches. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Carlos R Figueiredo
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
- Department of the Faculty of Medicine, MediCity Research Laboratory and Institute of BiomedicineUniversity of TurkuTurkuFinland
| | - Helen Kalirai
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
| | - Joseph J Sacco
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
- Department of Medical OncologyThe Clatterbridge Cancer CentreWirralUK
| | - Ricardo A Azevedo
- Department of Cancer BiologyThe University of Texas–MD Anderson Cancer CenterHoustonTXUSA
| | - Andrew Duckworth
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
| | - Joseph R Slupsky
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
| | - Judy M Coulson
- Department of Cellular and Molecular PhysiologyUniversity of LiverpoolLiverpoolUK
| | - Sarah E Coupland
- Department of Molecular and Clinical Cancer Medicine, ITMUniversity of LiverpoolLiverpoolUK
- Liverpool Clinical LaboratoriesRoyal Liverpool University HospitalLiverpoolUK
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Giles JL, Polak OJ, Landon J. Disease modifying drugs for rheumatological diseases: a brief history of everything. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2020; 120:313-348. [PMID: 32085884 DOI: 10.1016/bs.apcsb.2019.11.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The rheumatological diseases are a group of chronic, painful, degenerative and debilitating conditions with an increasing prevalence across the globe. The pathogenesis of these disorders is complex, overlapping and not fully understood. As such, it is difficult and time consuming to achieve correct diagnosis and complete remission for an individual patient. In this review we describe the most common forms of inflammatory arthritis and discuss how the management and treatment options for these rheumatic diseases have developed over time. We outline the successes and the limitations of current treatment regimens and discuss the economic burden of the current options. With advancements in understanding of disease mechanisms, we discuss the importance of the biologics revolution in the context of rheumatological disease and how the development of biosimilars and small molecule inhibitors will impact current treatment options in order to alleviate some of the cost burden of biological therapies. The ideal treatment strategy for the future would involve personalized and predictive medicine where by treatments can be tailored to an individual patient's needs in order to achieve fast and successful remission with no adverse events.
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Affiliation(s)
- Joanna L Giles
- MicroPharm Ltd, Newcastle Emlyn, Carmarthenshire, United Kingdom
| | - Oktawia J Polak
- MicroPharm Ltd, Newcastle Emlyn, Carmarthenshire, United Kingdom
| | - John Landon
- MicroPharm Ltd, Newcastle Emlyn, Carmarthenshire, United Kingdom
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Van Coillie S, Wiernicki B, Xu J. Molecular and Cellular Functions of CTLA-4. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1248:7-32. [PMID: 32185705 DOI: 10.1007/978-981-15-3266-5_2] [Citation(s) in RCA: 131] [Impact Index Per Article: 26.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is an inhibitory receptor belonging to the CD28 immunoglobulin subfamily, expressed primarily by T-cells. Its ligands, CD80 and CD86, are typically found on the surface of antigen-presenting cells and can either bind CD28 or CTLA-4, resulting in a costimulatory or a co-inhibitory response, respectively. Because of its dampening effect, CTLA-4 is a crucial regulator of T-cell homeostasis and self-tolerance. The mechanisms by which CTLA-4 exerts its inhibitory function can be categorized as either cell-intrinsic (affects the CTLA-4 expressing T-cell) or cell-extrinsic (affects secondary cells). Research from the last decade has shown that CTLA-4 mainly acts in a cell-extrinsic manner via its competition with CD28, CTLA-4-mediated trans-endocytosis of CD80 and CD86, and its direct tolerogenic effects on the interacting cell. Nonetheless, intrinsic CTLA-4 signaling has been implicated in T-cell motility and the regulation of CTLA-4 its subcellular localization amongst others. CTLA-4 is well recognized as a key immune checkpoint and has gained significant momentum as a therapeutic target in the field of autoimmunity and cancer. In this chapter, we describe the role of costimulation in immune response induction as well as the main mechanisms by which CTLA-4 can inhibit this process.
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Affiliation(s)
- Samya Van Coillie
- Molecular Signaling and Cell Death Unit, VIB-UGent Center for Inflammation Research, Zwijnaarde, 9052, Ghent, Belgium.
| | - Bartosz Wiernicki
- Molecular Signaling and Cell Death Unit, VIB-UGent Center for Inflammation Research, Zwijnaarde, 9052, Ghent, Belgium
| | - Jie Xu
- Institutes of Biomedical Sciences, Zhongshan-Xuhui Hospital, Fudan University, Shanghai, 200032, China.
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Mitsuiki N, Schwab C, Grimbacher B. What did we learn from CTLA-4 insufficiency on the human immune system? Immunol Rev 2019; 287:33-49. [PMID: 30565239 DOI: 10.1111/imr.12721] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 09/16/2018] [Indexed: 02/07/2023]
Abstract
Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) is a negative immune regulator constitutively expressed on regulatory T (Treg) cells and upregulated on activated T cells. CTLA-4 inhibits T cell activation by various suppressive functions including competition with CD28, regulation of the inhibitory function of Treg cells, such as transendocytosis, and the control of adhesion and motility. Intrinsic CTLA-4 signaling has been controversially discussed, but so far no distinct signaling pathway has been identified. The CTLA-4-mediated Treg suppression plays an important role in the maintenance of peripheral tolerance and the prevention of autoimmune diseases. Human CTLA-4 insufficiency is caused by heterozygous germline mutations in CTLA4 and characterized by a complex immune dysregulation syndrome. Clinical studies on CTLA4 mutation carriers showed a reduced penetrance and variable expressivity, suggesting modifying factor(s). One hundred and forty-eight CTLA4 mutation carriers have been reported; patients showed hypogammaglobulinemia, recurrent infectious diseases, various autoimmune diseases, and lymphocytic infiltration into multiple organs. The CTLA-4 expression level in Treg cells was reduced, while the frequency of Treg cells was increased in CTLA-4-insufficient patients. The transendocytosis assay is a specific functional test for the assessment of newly identified CTLA4 gene variants. Immunoglobulin substitution, corticosteroids, immunosuppressive therapy, and targeted therapy such as with CTLA-4 fusion proteins and mechanistic target of rapamycin (mTOR) inhibitors were applied; patients with life-threatening, treatment-resistant symptoms underwent hematopoietic stem cell transplantation. The fact that in humans CTLA-4 insufficiency causes severe disease taught us that the amount of CTLA-4 molecules present in/on T cells matters for immune homeostasis. However, whether the pathology-causing activated T lymphocytes in CTLA-4-insufficient patients are antigen-specific is an unsolved question. CTLA-4, in addition, has a role in autoimmune diseases and cancer. Anti-CTLA-4 drugs are employed as checkpoint inhibitors to target various forms of cancer. Thus, clinical research on human CTLA-4 insufficiency might provide us a deeper understanding of the mechanism(s) of the CTLA-4 molecule and immune dysregulation disorders.
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Affiliation(s)
- Noriko Mitsuiki
- Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Charlotte Schwab
- Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Bodo Grimbacher
- Center for Chronic Immunodeficiency (CCI), Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Calich VLG, Mamoni RL, Loures FV. Regulatory T cells in paracoccidioidomycosis. Virulence 2019; 10:810-821. [PMID: 30067137 PMCID: PMC6779406 DOI: 10.1080/21505594.2018.1483674] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2017] [Accepted: 05/26/2018] [Indexed: 12/24/2022] Open
Abstract
This review addresses the role of regulatory T cells (Tregs), which are essential for maintaining peripheral tolerance and controlling pathogen immunity, in the host response against Paracoccidioides brasiliensis, a primary fungal pathogen. A brief introduction on the general features of Treg cells summarizes their main functions, subpopulations, mechanisms of suppression and plasticity. The main aspects of immunity in the diverse forms of the P. brasiliensis infection are presented, as are the few extant studies on the relevance of Treg cells in the control of severity of the human disease. Finally, the influence of Toll-like receptors, Dectin-1, NOD-like receptor P3 (NLRP3), Myeloid differentiation factor-88 (MyD88), as well as the enzyme indoleamine 2,3 dioxygenase (IDO) on the expansion and function of Treg cells in a murine model of pulmonary paracoccidioidomycosis (PCM) is also discussed. It is demonstrated that some of these components are involved in the negative control of Treg cell expansion, whereas others positively trigger the proliferation and activity of these cells. Finally, the studies here summarized highlight the dual role of Treg cells in PCM, which can be protective by controlling excessive immunity and tissue pathology but also deleterious by inhibiting the anti-fungal immunity necessary to control fungal growth and dissemination.
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Affiliation(s)
- Vera L. G. Calich
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
| | - Ronei L. Mamoni
- Department of Morphology and Basic Pathology, Faculty of Medicine of Jundiai (FMJ), Jundiai, Brazil
- Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), São Paulo, Brazil
| | - Flávio V. Loures
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo (USP), São Paulo, Brazil
- Institute of Science and Technology (ICT), Federal University of São Paulo (UNIFESP) at São José dos Campos, São Paulo, Brazil
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50
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Bai X, Yi M, Jiao Y, Chu Q, Wu K. Blocking TGF-β Signaling To Enhance The Efficacy Of Immune Checkpoint Inhibitor. Onco Targets Ther 2019; 12:9527-9538. [PMID: 31807028 PMCID: PMC6857659 DOI: 10.2147/ott.s224013] [Citation(s) in RCA: 104] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Accepted: 10/25/2019] [Indexed: 12/20/2022] Open
Abstract
During malignant transformation, a growing body of mutations accumulate in cancer cells which not only drive cancer progression but also endow cancer cells with high immunogenicity. However, because one or multiple steps in cancer-immunity cycle are impaired, anti-cancer immune response is too weak to effectively clear cancer cells. Therefore, how to restore robust immune response to malignant cells is a hot research topic in cancer therapeutics field. In the last decade, based on the deeper understanding of cancer immunity, great signs of progress have been made in cancer immunotherapies especially immune checkpoint inhibitors (ICIs). ICIs could block negative immune co-stimulatory pathways and reactivate tumor-infiltrating lymphocytes (TILs) from exhausted status. ICIs exhibit potent anti-cancer effect and have been approved for the treatment of numerous cancer types. Parallel with durable and effective tumor control, the actual response rate of ICIs is unsatisfactory. Although a subset of patients benefit from ICIs treatment, a large proportion of patients show primary or acquired resistance. Previously intensive studies indicated that the efficacy of ICIs was determined by a series of factors including tumor mutation burden, programmed death ligand-1 (PD-L1) expression, and TILs status. Recently, it was reported that transforming growth factor-beta (TGF-β) signaling pathway participated in cancer immune escape and ICI resistance. Concurrent TGF-β blockade might be a feasible strategy to enhance the efficacy of immunotherapy and relieve ICI resistance. In this mini-review, we summarized the latest understanding of TGF-β signaling pathway and cancer immunity. Besides, we highlighted the synergistic effect of TGF-β blockade and ICIs.
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Affiliation(s)
- Xianguang Bai
- Medical School, Pingdingshan University, Pingdingshan, Henan, People's Republic of China.,Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Ming Yi
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Ying Jiao
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Kongming Wu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.,Department of Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
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