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Arditi M, Crother TR. pDCs drive immunopathology by sensing oxidized mitochondrial DNA. Nat Immunol 2025:10.1038/s41590-025-02193-9. [PMID: 40528030 DOI: 10.1038/s41590-025-02193-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/20/2025]
Affiliation(s)
- Moshe Arditi
- Division of Infectious Diseases and Immunology, Department of Pediatrics, Guerin Children's at Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Timothy R Crother
- Division of Infectious Diseases and Immunology, Department of Pediatrics, Guerin Children's at Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Department of Biomedical Sciences, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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von Bubnoff D, Schmitt C, Goldinger SM, Schadendorf D, Kähler KC, Hafner C, Kramer N, Fröhlich W, Dummer R, Berking C, Schliep S, Kirchberger MC, Heinzerling L. Prognostic and predictive value of IDO expression in metastatic melanoma treated with Ipilimumab. PLoS One 2025; 20:e0321937. [PMID: 40334245 PMCID: PMC12058187 DOI: 10.1371/journal.pone.0321937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 03/11/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND The tumor microenvironment is crucial for prognosis and response to immunotherapy in several tumor entities. METHODS In a multicenter retrospective study, a total of 86 tumor samples from patients with metastatic melanoma were evaluated for baseline expression of indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PD-L1). Expression patterns of IDO and PD-L1 on tumor cells and antigen-presenting cells (APCs) as determined by immunohistochemical (IHC) staining of paraffin-embedded tissue sections were correlated with response to ipilimumab and overall survival (OS). Statistical analysis was performed using the Spearman correlation, the Mann-Whitney test and Kaplan-Meier estimator. RESULTS IDO expression in tumor cells or APCs was not predictive for treatment response. The median OS was 26 months in IDO-positive and IDO-negative patients, regardless of IDO expression in tumor cells or APCs. A correlation of IHC expression scores of IDO and PD-L1 could not be documented. CONCLUSION The exact role of IDO in creating an immunosuppressive tumor environment and its reversal needs to be further elucidated.
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Affiliation(s)
| | - Christina Schmitt
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - Simone M. Goldinger
- Department of Dermatology, University Hospital of Zurich, Zürich, Switzerland
| | - Dirk Schadendorf
- Department of Dermatology, University Hospital Essen, Essen, Germany
| | - Katharina C. Kähler
- Department of Dermatology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Christian Hafner
- Department of Dermatology, University Hospital Regensburg, Regensburg, Germany
| | - Nora Kramer
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
| | - Waltraud Fröhlich
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Reinhard Dummer
- Department of Dermatology, University Hospital of Zurich, Zürich, Switzerland
| | - Carola Berking
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Stefan Schliep
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Michael C. Kirchberger
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
| | - Lucie Heinzerling
- Department of Dermatology and Allergy, University Hospital, LMU Munich, Munich, Germany
- Department of Dermatology, Universitätsklinikum Erlangen and Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany
- Comprehensive Cancer Center Erlangen-European Metropolitan Area of Nuremberg (CCC ER-EMN), Erlangen, Germany
- Deutsches Zentrum Immuntherapie, Erlangen, Germany
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3
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Liu Y, Liu Z, Li D, He X, Xiang L, Li B, Zhang C. Emerging role of regulatory T cells in the immunopathogenesis of vitiligo and implications for treatment. Br J Dermatol 2025; 192:796-806. [PMID: 39673777 DOI: 10.1093/bjd/ljae472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 11/28/2024] [Accepted: 11/28/2024] [Indexed: 12/16/2024]
Abstract
Vitiligo is an autoimmune skin disease that targets pigment-producing melanocytes and results in depigmentation. This disfiguring condition frequently affects visible areas of the body and therefore causes a heavy psychological burden and a decreased quality of life. Although it remains intractable, the ever-growing understanding of its immunopathogenesis has dramatically shaped the treatment paradigm for vitiligo. With the impact of autoreactive cytotoxic T cells explained extensively, accumulating evidence suggests the unique role of regulatory T cells (Tregs) in the immune microenvironment of vitiligo. We systematically reviewed Treg deficiency, instability, reduced vitality and dysfunction in people with vitiligo, combined with novel findings regarding Treg function modulation in autoimmune backgrounds, including metabolic alteration, post-translational modifications and interaction with other immune cells. We further summarized classic and advanced Treg-targeted therapeutics in vitiligo practice and research. Herein, we share up-to-date knowledge of Tregs in vitiligo, providing insights into novel Treg-based therapeutic strategies.
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Affiliation(s)
- Yang Liu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Ziqi Liu
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Dan Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China
| | - Xuanxuan He
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Leihong Xiang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
| | - Bin Li
- Shanghai Institute of Immunology, Shanghai Jiao Tong University, Shanghai, China
| | - Chengfeng Zhang
- Department of Dermatology, Huashan Hospital, Fudan University, Shanghai, China
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4
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Xu J, Yu Y, Li S, Qiu F. Global Trends in Research of Amino Acid Metabolism in T Lymphocytes in Recent 15 Years: A Bibliometric Analysis. J Immunol Res 2025; 2025:3393342. [PMID: 39950085 PMCID: PMC11824865 DOI: 10.1155/jimr/3393342] [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: 07/03/2024] [Accepted: 12/20/2024] [Indexed: 02/16/2025] Open
Abstract
Amino acid metabolism in T cells determines the therapeutic efficacy of T-cell-targeting drugs. To assess the direction of amino acid metabolism in T cells and construct related knowledge structure, we performed a bibliometric analysis aiming at amino acid metabolism in T cells utilizing studies publicized in recent 15 years. Three hundred thirty-seven related studies were downloaded from the Web of Science Core Collection (WoSCC), and the information on countries, institutes, and authors was collected and analyzed. In addition, the present research status and future trends were explored according to the results yielded from the analysis of cited references and keywords. This study revealed that publications regarding amino acid metabolism in T cells gradually increased each year. The USA is the top producer and most influential country in this field. Recent research has focused on the correlation between the metabolism of several amino acids and regulatory T cells (Tregs) and CD8+ T cells. Overall, this research offers a comprehensive exhibition on the field of amino acid metabolism in T cells, which will help researchers to study this domain more effectively and intuitively.
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Affiliation(s)
- Jiaona Xu
- Department of Rehabilitation, Hangzhou Geriatric Hospital, Hangzhou 310022, China
| | - Yinan Yu
- Department of Rehabilitation, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou 310006, China
| | - Shijie Li
- Department of General Surgery, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310018, China
| | - Fanghui Qiu
- Department of Rehabilitation, Hangzhou Geriatric Hospital, Hangzhou 310022, China
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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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Mendiratta M, Mendiratta M, Ganguly S, Rai S, Gupta R, Kumar L, Bakhshi S, Dadhwal V, Pushpam D, Malik PS, Pramanik R, Aggarwal M, Gupta AK, Dhawan R, Seth T, Mahapatra M, Nayak B, Singh TD, Kumar S, Mir RA, Kaur G, GuruRao H, Singh M, Prasad CP, Prakash H, Mohanty S, Sahoo RK. Concurrent hypoxia and apoptosis imparts immune programming potential in mesenchymal stem cells: Lesson from acute graft-versus-host-disease model. Stem Cell Res Ther 2024; 15:381. [PMID: 39468660 PMCID: PMC11520827 DOI: 10.1186/s13287-024-03947-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 09/18/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have emerged as promising candidates for immune modulation in various diseases that are associated with dysregulated immune responses like Graft-versus-Host-Disease (GVHD). MSCs are pleiotropic and the fate of MSCs following administration is a major determinant of their therapeutic efficacy. METHODS Human MSCs were derived from bone marrow (BM) and Wharton's Jelly (WJ) and preconditioned through exposure to hypoxia and induction of apoptosis, either sequentially or simultaneously. The immune programming potential of preconditioned MSCs was evaluated by assessing their effects on T cell proliferation, induction of Tregs, programming of effector T-cell towards Th2 phenotype, macrophage polarization in the direct co-culture of MSCs and aGVHD patients-derived PBMNCs. Additionally, efferocytosis of MSCs and relative change in the expression of immunomodulatory soluble factors were examined. RESULTS Our study demonstrated that hypoxia preconditioned apoptotic MSCs (BM-MSCs, WJ-MSCs) bear more immune programming ability in a cellular model of acute Graft-versus-Host-Disease (aGVHD). Our findings revealed that WJ-MSCsHYP+APO were superior to BM-MSCsHYP+APO for immune regulation. These induced the differentiation of CD4+T-cell into Tregs, enhanced Th2 effector responses, and simultaneously mitigated Th1- and Th17 responses. Additionally, this approach led to the polarization of M1 macrophages toward an M2 phenotype. CONCLUSION Our study highlights the potential of WJ-MSCs conditioned with hypoxia and apoptosis concurrently, as a promising therapeutic strategy for aGVHD. It underscores the importance of considering MSC apoptosis in optimizing MSCs-based cellular therapy protocols for enhanced therapeutic efficacy in aGvHD.
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Affiliation(s)
- Mohini Mendiratta
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Meenakshi Mendiratta
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Shuvadeep Ganguly
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sandeep Rai
- Laboratory Oncology Unit, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Ritu Gupta
- Laboratory Oncology Unit, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Lalit Kumar
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sameer Bakhshi
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Vatsla Dadhwal
- Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Deepam Pushpam
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Prabhat Singh Malik
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Raja Pramanik
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Mukul Aggarwal
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Aditya Kumar Gupta
- Department of Pediatric Oncology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Rishi Dhawan
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Tulika Seth
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Manoranjan Mahapatra
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Baibaswata Nayak
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Thoudam Debraj Singh
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Sachin Kumar
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Riyaz Ahmed Mir
- Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Gurvinder Kaur
- Laboratory Oncology Unit, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Hariprasad GuruRao
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Mayank Singh
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Chandra Prakash Prasad
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India
| | - Hridayesh Prakash
- Amity Centre for Translational Research, Amity University, Sector - 125, Noida, 201313, India.
| | - Sujata Mohanty
- Stem Cell Facility (DBT-Centre of Excellence for Stem Cell Research), All India Institute of Medical Sciences, New Delhi, 110029, India.
| | - Ranjit Kumar Sahoo
- Department of Medical Oncology, Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India.
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Altintas O, MacArthur MR. General control nonderepressible 2 (GCN2) as a therapeutic target in age-related diseases. FRONTIERS IN AGING 2024; 5:1447370. [PMID: 39319345 PMCID: PMC11420162 DOI: 10.3389/fragi.2024.1447370] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Accepted: 08/28/2024] [Indexed: 09/26/2024]
Abstract
The function of General Control Nonderepressible 2 (GCN2), an evolutionary-conserved component of the integrated stress response (ISR), has been well-documented across organisms from yeast to mammals. Recently GCN2 has also gained attention for its role in health and disease states. In this review, we provide a brief overview of GCN2, including its structure, activation mechanisms and interacting partners, and explore its potential significance as a therapeutic target in various age-related diseases including neurodegeneration, inflammatory disorders and cancer. Finally, we summarize the barriers to effectively targeting GCN2 for the treatment of disease and to promote a healthier aging process.
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Affiliation(s)
- Ozlem Altintas
- Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
| | - Michael R. MacArthur
- Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland
- Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, United States
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8
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Khan A, Roy P, Ley K. Breaking tolerance: the autoimmune aspect of atherosclerosis. Nat Rev Immunol 2024; 24:670-679. [PMID: 38472321 PMCID: PMC11682649 DOI: 10.1038/s41577-024-01010-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/12/2024] [Indexed: 03/14/2024]
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is a chronic inflammatory disease of the arterial walls and is characterized by the accumulation of lipoproteins that are insufficiently cleared by phagocytes. Following the initiation of atherosclerosis, the pathological progression is accelerated by engagement of the adaptive immune system. Atherosclerosis triggers the breakdown of tolerance to self-components. This loss of tolerance is reflected in defective expression of immune checkpoint molecules, dysfunctional antigen presentation, and aberrations in T cell populations - most notably in regulatory T (Treg) cells - and in the production of autoantibodies. The breakdown of tolerance to self-proteins that is observed in ASCVD may be linked to the conversion of Treg cells to 'exTreg' cells because many Treg cells in ASCVD express T cell receptors that are specific for self-epitopes. Alternatively, or in addition, breakdown of tolerance may trigger the activation of naive T cells, resulting in the clonal expansion of T cell populations with pro-inflammatory and cytotoxic effector phenotypes. In this Perspective, we review the evidence that atherosclerosis is associated with a breakdown of tolerance to self-antigens, discuss possible immunological mechanisms and identify knowledge gaps to map out future research. Rational approaches aimed at re-establishing immune tolerance may become game changers in treating ASCVD and in preventing its downstream sequelae, which include heart attacks and strokes.
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Affiliation(s)
- Amir Khan
- Immunology Center of Georgia, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Payel Roy
- Immunology Center of Georgia, Medical College of Georgia at Augusta University, Augusta, GA, USA
| | - Klaus Ley
- Immunology Center of Georgia, Medical College of Georgia at Augusta University, Augusta, GA, USA.
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Shen R, Ding Y, Dong Q, Wang Y, Yu J, Pan C, Cai Y, Li Z, Zhang J, Yu K, Zeng Q. IL-4-Induced Gene 1: A Potential Player in Myocardial Infarction. Rev Cardiovasc Med 2024; 25:337. [PMID: 39355609 PMCID: PMC11440439 DOI: 10.31083/j.rcm2509337] [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: 03/18/2024] [Revised: 04/18/2024] [Accepted: 05/06/2024] [Indexed: 10/03/2024] Open
Abstract
Myocardial infarction (MI), a severe outcome of cardiovascular disease, poses a serious threat to human health. Uncontrolled inflammation and excessive cardiomyocyte death, following an infarction event, significantly contribute to both the mortality rate and complications associated with MI. The protein IL-4-induced gene 1 (IL4I1 or FIG1) serves as a natural inhibitor of innate and adaptive immunity, playing a crucial role in CD4+ T cell differentiation, macrophage polarization, and ferroptosis inhibition. Previous studies have linked IL4I1 to acute MI. This review summarizes evidence from both basic and clinical research, highlighting IL4I1 as a critical immunoregulatory enzyme that not only regulates inflammatory responses, but also potentially mitigates MI-induced damage.
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Affiliation(s)
- Rui Shen
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Yan Ding
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Qian Dong
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Yue Wang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Jian Yu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Chengliang Pan
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Yifan Cai
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Zhiyang Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Jiangmei Zhang
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Kunwu Yu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
| | - Qiutang Zeng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
- Hubei Provincial Engineering Research Center of Immunological Diagnosis and Therapy for Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022 Wuhan, Hubei, China
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10
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Grobben Y. Targeting amino acid-metabolizing enzymes for cancer immunotherapy. Front Immunol 2024; 15:1440269. [PMID: 39211039 PMCID: PMC11359565 DOI: 10.3389/fimmu.2024.1440269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Despite the immune system's role in the detection and eradication of abnormal cells, cancer cells often evade elimination by exploitation of various immune escape mechanisms. Among these mechanisms is the ability of cancer cells to upregulate amino acid-metabolizing enzymes, or to induce these enzymes in tumor-infiltrating immunosuppressive cells. Amino acids are fundamental cellular nutrients required for a variety of physiological processes, and their inadequacy can severely impact immune cell function. Amino acid-derived metabolites can additionally dampen the anti-tumor immune response by means of their immunosuppressive activities, whilst some can also promote tumor growth directly. Based on their evident role in tumor immune escape, the amino acid-metabolizing enzymes glutaminase 1 (GLS1), arginase 1 (ARG1), inducible nitric oxide synthase (iNOS), indoleamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase (TDO) and interleukin 4 induced 1 (IL4I1) each serve as a promising target for immunotherapeutic intervention. This review summarizes and discusses the involvement of these enzymes in cancer, their effect on the anti-tumor immune response and the recent progress made in the preclinical and clinical evaluation of inhibitors targeting these enzymes.
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11
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Song X, Chen R, Li J, Zhu Y, Jiao J, Liu H, Chen Z, Geng J. Fragile Treg cells: Traitors in immune homeostasis? Pharmacol Res 2024; 206:107297. [PMID: 38977207 DOI: 10.1016/j.phrs.2024.107297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Revised: 06/18/2024] [Accepted: 07/04/2024] [Indexed: 07/10/2024]
Abstract
Regulatory T (Treg) cells play a key role in maintaining immune tolerance and tissue homeostasis. However, in some disease microenvironments, Treg cells exhibit fragility, which manifests as preserved FoxP3 expression accompanied by inflammation and loss of immunosuppression. Fragile Treg cells are formatively, phenotypically and functionally diverse in various diseases, further complicating the role of Treg cells in the immunotherapeutic response and offering novel targets for disease treatment by modulating specific Treg subsets. In this review, we summarize findings on fragile Treg cells to provide a framework for characterizing the formation and role of fragile Treg cells in different diseases, and we discuss how this information may guide the development of more specific Treg-targeted immunotherapies.
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Affiliation(s)
- Xiyu Song
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
| | - Ruo Chen
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
| | - Jiaxin Li
- Student Brigade of Basic Medicine School, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
| | - Yumeng Zhu
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
| | - Jianhua Jiao
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
| | - Hongjiao Liu
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
| | - Zhinan Chen
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China.
| | - Jiejie Geng
- National Translational Science Center for Molecular Medicine & Department of Cell Biology, Fourth Military Medical University, Xi'an, Shaanxi 710032, PR China; State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, PR China.
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12
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Spiga M, Martini E, Maffia MC, Ciceri F, Ruggiero E, Potenza A, Bonini C. Harnessing the tumor microenvironment to boost adoptive T cell therapy with engineered lymphocytes for solid tumors. Semin Immunopathol 2024; 46:8. [PMID: 39060547 DOI: 10.1007/s00281-024-01011-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/18/2024] [Indexed: 07/28/2024]
Abstract
Adoptive cell therapy (ACT) using Chimeric Antigen Receptor (CAR) and T Cell Receptor (TCR) engineered T cells represents an innovative therapeutic approach for the treatment of hematological malignancies, yet its application for solid tumors is still suboptimal. The tumor microenvironment (TME) places several challenges to overcome for a satisfactory therapeutic effect, such as physical barriers (fibrotic capsule and stroma), and inhibitory signals impeding T cell function. Some of these obstacles can be faced by combining ACT with other anti-tumor approaches, such as chemo/radiotherapy and checkpoint inhibitors. On the other hand, cutting edge technological tools offer the opportunity to overcome and, in some cases, take advantage of TME intrinsic characteristics to boost ACT efficacy. These include: the exploitation of chemokine gradients and integrin expression for preferential T-cell homing and extravasation; metabolic changes that have direct or indirect effects on TCR-T and CAR-T cells by increasing antigen presentation and reshaping T cell phenotype; introduction of additional synthetic receptors on TCR-T and CAR-T cells with the aim of increasing T cells survival and fitness.
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Affiliation(s)
- Martina Spiga
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Elisa Martini
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Maria Chiara Maffia
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Fabio Ciceri
- Vita-Salute San Raffaele University, Milan, Italy
- Hematology and Bone Marrow Transplant Unit, IRCCS San Raffaele Hospital, Milan, Italy
| | - Eliana Ruggiero
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Alessia Potenza
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Chiara Bonini
- Experimental Hematology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- Vita-Salute San Raffaele University, Milan, Italy.
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13
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Tevetoğlu F, Çomunoğlu N, Yener HM. The impact of the tumor immune microenvironment and tumor-infiltrating lymphocyte subgroups on laryngeal cancer prognosis. Sci Prog 2024; 107:368504241266087. [PMID: 39044316 PMCID: PMC11271122 DOI: 10.1177/00368504241266087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/25/2024]
Abstract
The absence of improvement in survival rates across various cancers, including laryngeal cancer, has led to an increasing interest in understanding the immune response to cancer. In head and neck cancers, immune modulatory mechanisms such as immune microenvironment and immune infiltration are important in cancer pathogenesis. This study aims to explore the distribution of tumor-infiltrating lymphocyte (TIL) subgroups in the immune microenvironment and evaluate their impact on tumor histopathological characteristics and prognosis. The study included 50 patients who underwent laryngectomy for laryngeal squamous cell carcinoma, in Istanbul University - Cerrahpaşa, Faculty of Medicine Department of Otorhinolaryngology, between January 2016 and January 2018. Pathology specimens were evaluated using immunohistochemistry to assess the expressions of the CD3, CD20, CD8, CD4, CD25, and FoxP3 markers, identifying subgroups of TILs. The investigation aimed to uncover how these subgroups influence tumor histopathological features and survival outcomes. The high infiltration of CD3, CD20, and CD4 had a positive impact on disease-specific survival, disease-free survival, and recurrence-free survival. In addition, overall survival was positively affected by high CD3 and CD4 infiltrations. However, no significant relationship was observed between the expressions of CD8, FoxP3, and CD25 and any of the survival parameters. The infiltration of CD3, CD20, and CD4 positive cells indicative of a robust antitumoral immune response-emerged as favorable prognostic factors in laryngeal cancer. These findings suggest that enhancing the infiltration of CD3, CD20, and CD4 lymphocytes could be a therapeutic strategy worth exploring in clinical trials.
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Affiliation(s)
- Fırat Tevetoğlu
- Otorhinolaryngology Department, Marmara University Pendik Training and Research Hospital, Istanbul, Türkiye
- Otorhinolaryngology Department, Istanbul University – Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Türkiye
| | - Nil Çomunoğlu
- Pathology Department, Istanbul University – Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Türkiye
| | - Haydar Murat Yener
- Otorhinolaryngology Department, Istanbul University – Cerrahpasa, Cerrahpasa Medical Faculty, Istanbul, Türkiye
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14
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Weisbrod LJ, Thiraviyam A, Vengoji R, Shonka N, Jain M, Ho W, Batra SK, Salehi A. Diffuse intrinsic pontine glioma (DIPG): A review of current and emerging treatment strategies. Cancer Lett 2024; 590:216876. [PMID: 38609002 PMCID: PMC11231989 DOI: 10.1016/j.canlet.2024.216876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 04/04/2024] [Accepted: 04/05/2024] [Indexed: 04/14/2024]
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a childhood malignancy of the brainstem with a dismal prognosis. Despite recent advances in its understanding at the molecular level, the prognosis of DIPG has remained unchanged. This article aims to review the current understanding of the genetic pathophysiology of DIPG and to highlight promising therapeutic targets. Various DIPG treatment strategies have been investigated in pre-clinical studies, several of which have shown promise and have been subsequently translated into ongoing clinical trials. Ultimately, a multifaceted therapeutic approach that targets cell-intrinsic alterations, the micro-environment, and augments the immune system will likely be necessary to eradicate DIPG.
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Affiliation(s)
- Luke J Weisbrod
- Department of Neurosurgery, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Anand Thiraviyam
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Nicole Shonka
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Winson Ho
- Department of Neurosurgery, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Afshin Salehi
- Department of Neurosurgery, University of Nebraska Medical Center, Omaha, NE, 68198-5870, USA; Division of Pediatric Neurosurgery, Children's Nebraska, Omaha, NE, 68114, USA.
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15
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Stroope C, Nettersheim FS, Coon B, Finney AC, Schwartz MA, Ley K, Rom O, Yurdagul A. Dysregulated cellular metabolism in atherosclerosis: mediators and therapeutic opportunities. Nat Metab 2024; 6:617-638. [PMID: 38532071 PMCID: PMC11055680 DOI: 10.1038/s42255-024-01015-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 02/20/2024] [Indexed: 03/28/2024]
Abstract
Accumulating evidence over the past decades has revealed an intricate relationship between dysregulation of cellular metabolism and the progression of atherosclerotic cardiovascular disease. However, an integrated understanding of dysregulated cellular metabolism in atherosclerotic cardiovascular disease and its potential value as a therapeutic target is missing. In this Review, we (1) summarize recent advances concerning the role of metabolic dysregulation during atherosclerosis progression in lesional cells, including endothelial cells, vascular smooth muscle cells, macrophages and T cells; (2) explore the complexity of metabolic cross-talk between these lesional cells; (3) highlight emerging technologies that promise to illuminate unknown aspects of metabolism in atherosclerosis; and (4) suggest strategies for targeting these underexplored metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas with a potential new generation of cardiovascular therapeutics.
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Affiliation(s)
- Chad Stroope
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Felix Sebastian Nettersheim
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Department of Cardiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Brian Coon
- Yale Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Cardiovascular Biology Research Program, OMRF, Oklahoma City, OK, USA
- Department of Cell Biology, Oklahoma University Health Sciences Center, Oklahoma City, OK, USA
| | - Alexandra C Finney
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Martin A Schwartz
- Yale Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Departments of Cell Biology and Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Klaus Ley
- La Jolla Institute for Immunology, La Jolla, CA, USA
- Department of Bioengineering, University of California, San Diego, San Diego, CA, USA
- Immunology Center of Georgia (IMMCG), Augusta University Immunology Center of Georgia, Augusta, GA, USA
| | - Oren Rom
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Arif Yurdagul
- Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
- Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
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16
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Liu X, Chen L, Peng W, Deng H, Ni H, Tong H, Hu H, Wang S, Qian J, Liang A, Chen K. Th17/Treg balance: the bloom and wane in the pathophysiology of sepsis. Front Immunol 2024; 15:1356869. [PMID: 38558800 PMCID: PMC10978743 DOI: 10.3389/fimmu.2024.1356869] [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: 12/16/2023] [Accepted: 02/20/2024] [Indexed: 04/04/2024] Open
Abstract
Sepsis is a multi-organ dysfunction characterized by an unregulated host response to infection. It is associated with high morbidity, rapid disease progression, and high mortality. Current therapies mainly focus on symptomatic treatment, such as blood volume supplementation and antibiotic use, but their effectiveness is limited. Th17/Treg balance, based on its inflammatory property, plays a crucial role in determining the direction of the inflammatory response and the regression of organ damage in sepsis patients. This review provides a summary of the changes in T-helper (Th) 17 cell and regulatory T (Treg) cell differentiation and function during sepsis, the heterogeneity of Th17/Treg balance in the inflammatory response, and the relationship between Th17/Treg balance and organ damage. Th17/Treg balance exerts significant control over the bloom and wanes in host inflammatory response throughout sepsis.
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Affiliation(s)
- Xinyong Liu
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Longwang Chen
- Emergency Department, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wei Peng
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hongsheng Deng
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hongying Ni
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hongjie Tong
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Hangbo Hu
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Shengchao Wang
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Jin Qian
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Andong Liang
- Nursing Faculty, School of Medicine, Jinhua Polytechnic, Jinhua, China
| | - Kun Chen
- Department of Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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17
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Raynor JL, Chi H. Nutrients: Signal 4 in T cell immunity. J Exp Med 2024; 221:e20221839. [PMID: 38411744 PMCID: PMC10899091 DOI: 10.1084/jem.20221839] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/30/2024] [Accepted: 02/02/2024] [Indexed: 02/28/2024] Open
Abstract
T cells are integral in mediating adaptive immunity to infection, autoimmunity, and cancer. Upon immune challenge, T cells exit from a quiescent state, followed by clonal expansion and effector differentiation. These processes are shaped by three established immune signals, namely antigen stimulation (Signal 1), costimulation (Signal 2), and cytokines (Signal 3). Emerging findings reveal that nutrients, including glucose, amino acids, and lipids, are crucial regulators of T cell responses and interplay with Signals 1-3, highlighting nutrients as Signal 4 to license T cell immunity. Here, we first summarize the functional importance of Signal 4 and the underlying mechanisms of nutrient transport, sensing, and signaling in orchestrating T cell activation and quiescence exit. We also discuss the roles of nutrients in programming T cell differentiation and functional fitness and how nutrients can be targeted to improve disease therapy. Understanding how T cells respond to Signal 4 nutrients in microenvironments will provide insights into context-dependent functions of adaptive immunity and therapeutic interventions.
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Affiliation(s)
- Jana L Raynor
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Hongbo Chi
- Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA
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18
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Yang K, Yi T. Tumor cell stemness in gastrointestinal cancer: regulation and targeted therapy. Front Mol Biosci 2024; 10:1297611. [PMID: 38455361 PMCID: PMC10918437 DOI: 10.3389/fmolb.2023.1297611] [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: 09/20/2023] [Accepted: 11/14/2023] [Indexed: 03/09/2024] Open
Abstract
The cancer stem cells are a rare group of self-renewable cancer cells capable of the initiation, progression, metastasis and recurrence of tumors, and also a key contributor to the therapeutic resistance. Thus, understanding the molecular mechanism of tumor stemness regulation, especially in the gastrointestinal (GI) cancers, is of great importance for targeting CSC and designing novel therapeutic strategies. This review aims to elucidate current advancements in the understanding of CSC regulation, including CSC biomarkers, signaling pathways, and non-coding RNAs. We will also provide a comprehensive view on how the tumor microenvironment (TME) display an overall tumor-promoting effect, including the recruitment and impact of cancer-associated fibroblasts (CAFs), the establishment of an immunosuppressive milieu, and the induction of angiogenesis and hypoxia. Lastly, this review consolidates mainstream novel therapeutic interventions targeting CSC stemness regulation.
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Affiliation(s)
- Kangqi Yang
- School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Tuo Yi
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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19
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Liao JH, He Q, Huang ZW, Yu XB, Yang JY, Zhang Y, Song WJ, Luo J, Tao QW. Network pharmacology-based strategy to investigate the mechanisms of artemisinin in treating primary Sjögren's syndrome. BMC Immunol 2024; 25:16. [PMID: 38347480 PMCID: PMC10860289 DOI: 10.1186/s12865-024-00605-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 01/31/2024] [Indexed: 02/15/2024] Open
Abstract
OBJECTIVE The study aimed to explore the mechanism of artemisinin in treating primary Sjögren's syndrome (pSS) based on network pharmacology and experimental validation. METHODS Relevant targets of the artemisinin and pSS-related targets were integrated by public databases online. An artemisinin-pSS network was constructed by Cytoscape. The genes of artemisinin regulating pSS were imported into STRING database to construct a protein-protein interaction (PPI) network in order to predict the key targets. The enrichment analyses were performed to predict the crucial mechanism and pathway of artemisinin against pSS. The active component of artemisinin underwent molecular docking with the key proteins. Artemisinin was administered intragastrically to SS-like NOD/Ltj mice to validate the efficacy and critical mechanisms. RESULTS Network Pharmacology analysis revealed that artemisinin corresponded to 412 targets, and pSS related to 1495 genes. There were 40 intersection genes between artemisinin and pSS. KEGG indicated that therapeutic effects of artemisinin on pSS involves IL-17 signaling pathway, HIF-1 signaling pathway, apoptosis signaling pathway, Th17 cell differentiation, PI3K-Akt signaling pathway, and MAPK signaling pathway. Molecular docking results further showed that the artemisinin molecule had higher binding energy by combining with the key nodes in IL-17 signaling pathway. In vivo experiments suggested artemisinin can restored salivary gland secretory function and improve the level of glandular damage of NOD/Ltj mice. It contributed to the increase of regulatory T cells (Tregs) and the downregulated secretion of IL-17 in NOD/Ltj model. CONCLUSION The treatment of pSS with artemisinin is closely related to modulating the balance of Tregs and Th17 cells via T cell differentiation.
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Affiliation(s)
- Jia-He Liao
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Qian He
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Zi-Wei Huang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Xin-Bo Yu
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Jian-Ying Yang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Yan Zhang
- Graduate School, Beijing University of Chinese Medicine, Beijing, China
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China
| | - Wei-Jiang Song
- Traditional Chinese Medicine Department, Peking University Third Hospital, Beijing, China
| | - Jing Luo
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China.
- Beijing Key Laboratory of Immune Inflammatory Disease, China-Japan Friendship Hospital, Beijing, China.
| | - Qing-Wen Tao
- Traditional Chinese Medicine Department of Rheumatism, China-Japan Friendship Hospital, Beijing, China.
- Beijing Key Laboratory of Immune Inflammatory Disease, China-Japan Friendship Hospital, Beijing, China.
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20
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Zhang Z, Guo J, Jia R. Treg plasticity and human diseases. Inflamm Res 2023; 72:2181-2197. [PMID: 37878023 DOI: 10.1007/s00011-023-01808-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 10/08/2023] [Accepted: 10/11/2023] [Indexed: 10/26/2023] Open
Abstract
INTRODUCTION As a subset of CD4+ T cells, regulatory T cells (Tregs) with the characteristic expression of transcription factor FOXP3 play a key role in maintaining self-tolerance and regulating immune responses. However, in some inflammatory circumstances, Tregs can express cytokines of other T help (Th) cells by internal reprogramming, which is called Treg plasticity. These reprogrammed Tregs with impaired suppressive ability contribute to the progression of diseases by secreting pro-inflammatory cytokines. However, in the tumor microenvironment (TME), such changes in phenotype rarely occur in Tregs, on the contrary, Tregs usually display a stronger suppressive function and inhibit anti-tumor immunity. It is important to understand the mechanisms of Treg plasticity in inflammatory diseases and cancers. OBJECTIVES In this review, we summarize the characteristics of different Th-like Tregs and discuss the potential mechanisms of these changes in phenotype. Furthermore, we summarize the Treg plasticity in human diseases and discuss the effects of these changes in phenotype on disease progression, as well as the potential application of drugs or reagents that regulate Treg plasticity in human diseases. CONCLUSIONS Treg plasticity is associated with inflammatory diseases and cancers. Regulating Treg plasticity is a promising direction for the treatment of inflammatory diseases and cancers.
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Affiliation(s)
- Zheng Zhang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
| | - Jihua Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
- Department of Endodontics, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China
| | - Rong Jia
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Wuhan, 430072, China.
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21
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Mahanti K, Bhattacharyya S. Rough neighborhood: Intricacies of cancer stem cells and infiltrating immune cell interaction in tumor microenvironment and potential in therapeutic targeting. Transl Res 2023; 265:S1931-5244(23)00176-7. [PMID: 39491179 DOI: 10.1016/j.trsl.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Revised: 10/25/2023] [Accepted: 10/25/2023] [Indexed: 11/05/2024]
Abstract
Ongoing research on cellular heterogeneity of Cancer stem cells (CSCs) and its synergistic involvement with tumor milieu reveals enormous complexity, resulting in diverse hindrance in immune therapy. CSCs has captured attention for their contribution in shaping of tumor microenvironment and as target for therapeutic intervention. Recent studies have highlighted cell-extrinsic and intrinsic mechanisms of reciprocal interaction between tumor stroma constituents and CSCs. Therapeutic targeting requires an in-depth understanding of the underlying mechanisms involved with the rate limiting factors in tumor aggressiveness and pinpoint role of CSCs. Some of the major constituents of tumor microenvironment includes resident and infiltrating immune cell, both innate and adaptive. Some of these immune cells play crucial role as adjustors of tumor immune response. Tumor-adjustor immune cell interaction confer plasticity and features enabling tumor growth and metastasis in one hand and on the other hand blunts anti-tumor immunity. Detail understanding of CSC and TME resident immune cells interaction can shape new avenues for cancer immune therapy. In this review, we have tried to summarize the development of knowledge on cellular, molecular and functional interaction between CSCs and tumor microenvironment immune cells, highlighting immune-mediated therapeutic strategies aimed at CSCs. We also discussed developing a potential CSC and TME targeted therapeutic avenue.
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Affiliation(s)
- Krishna Mahanti
- Immunobiology and Translational medicine laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia, 723104, West Bengal India
| | - Sankar Bhattacharyya
- Immunobiology and Translational medicine laboratory, Department of Zoology, Sidho Kanho Birsha University, Purulia, 723104, West Bengal India.
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22
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Ming B, Zhu Y, Zhong J, Dong L. Regulatory T cells: a new therapeutic link for Sjögren syndrome? Rheumatology (Oxford) 2023; 62:2963-2970. [PMID: 36790059 DOI: 10.1093/rheumatology/kead070] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 01/21/2023] [Accepted: 01/29/2023] [Indexed: 02/16/2023] Open
Abstract
Great advancements have been made in understanding the pathogenesis of SS, but there remain unmet needs for effective and targeted treatments. Glandular and extraglandular dysfunction in SS is associated with autoimmune lymphocytic infiltration that invades the epithelial structures of affected organs. Regulatory T (Treg) cells are a subset of CD4+ T lymphocytes that maintain self-tolerance during physiological conditions. Besides inhibiting excessive inflammation and autoimmune response by targeting various immune cell subsets and tissues, Treg cells have also been shown to promote tissue repair and regeneration in pathogenic milieus. The changes of quantity and function of Treg cells in various autoimmune and chronic inflammatory disorders have been reported, owing to their effects on immune regulation. Here we summarize the recent findings from murine models and clinical data about the dysfunction of Treg cells in SS pathogenesis and discuss the therapeutic strategies of direct or indirect targeting of Treg cells in SS. Understanding the current knowledge of Treg cells in the development of SS will be important to elucidate disease pathogenesis and may guide research for successful therapeutic intervention in this disease.
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Affiliation(s)
- Bingxia Ming
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yaowu Zhu
- Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jixin Zhong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lingli Dong
- Department of Rheumatology and Immunology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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23
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Guo Y, Wang R, Shi J, Yang C, Ma P, Min J, Zhao T, Hua L, Song Y, Li J, Su H. Machine learning-based integration develops a metabolism-derived consensus model for improving immunotherapy in pancreatic cancer. J Immunother Cancer 2023; 11:e007466. [PMID: 37739440 PMCID: PMC10533800 DOI: 10.1136/jitc-2023-007466] [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] [Accepted: 08/31/2023] [Indexed: 09/24/2023] Open
Abstract
BACKGROUND Pancreatic cancer (PAC) is one of the most malignant cancer types and immunotherapy has emerged as a promising treatment option. PAC cells undergo metabolic reprogramming, which is thought to modulate the tumor microenvironment (TME) and affect immunotherapy outcomes. However, the metabolic landscape of PAC and its association with the TME remains largely unexplored. METHODS We characterized the metabolic landscape of PAC based on 112 metabolic pathways and constructed a novel metabolism-related signature (MBS) using data from 1,188 patients with PAC. We evaluated the predictive performance of MBS for immunotherapy outcomes in 11 immunotherapy cohorts from both bulk-RNA and single-cell perspectives. We validated our results using immunohistochemistry, western blotting, colony-formation assays, and an in-house cohort. RESULTS MBS was found to be negatively associated with antitumor immunity, while positively correlated with cancer stemness, intratumoral heterogeneity, and immune resistant pathways. Notably, MBS outperformed other acknowledged signatures for predicting immunotherapy response in multiple immunotherapy cohorts. Additionally, MBS was a powerful and robust biomarker for predicting prognosis compared with 66 published signatures. Further, we identified dasatinib and epothilone B as potential therapeutic options for MBS-high patients, which were validated through experiments. CONCLUSIONS Our study provides insights into the mechanisms of immunotherapy resistance in PAC and introduces MBS as a robust metabolism-based indicator for predicting response to immunotherapy and prognosis in patients with PAC. These findings have significant implications for the development of personalized treatment strategies in patients with PAC and highlight the importance of considering metabolic pathways and immune infiltration in TME regulation.
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Affiliation(s)
- Yongdong Guo
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Ronglin Wang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Jingjie Shi
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Cheng Yang
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Peixiang Ma
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Jie Min
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Ting Zhao
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Lei Hua
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Yang Song
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Junqiang Li
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
| | - Haichuan Su
- Department of Oncology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China
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24
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Chen SY, Cao JL, Li KP, Wan S, Yang L. BIN1 in cancer: biomarker and therapeutic target. J Cancer Res Clin Oncol 2023; 149:7933-7944. [PMID: 36890396 DOI: 10.1007/s00432-023-04673-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/28/2023] [Indexed: 03/10/2023]
Abstract
BACKGROUND The bridging integrator 1 (BIN1) protein was originally identified as a pro-apoptotic tumor suppressor that binds to and inhibits oncogenic MYC transcription factors. BIN1 has complex physiological functions participating in endocytosis, membrane cycling, cytoskeletal regulation, DNA repair deficiency, cell-cycle arrest, and apoptosis. The expression of BIN1 is closely related to the development of various diseases such as cancer, Alzheimer's disease, myopathy, heart failure, and inflammation. PURPOSE Because BIN1 is commonly expressed in terminally differentiated normal tissues and is usually undetectable in refractory or metastatic cancer tissues, this differential expression has led us to focus on human cancers associated with BIN1. In this review, we discuss the potential pathological mechanisms of BIN1 during cancer development and its feasibility as a prognostic marker and therapeutic target for related diseases based on recent findings on its molecular, cellular, and physiological roles. CONCLUSION BIN1 is a tumor suppressor that regulates cancer development through a series of signals in tumor progression and microenvironment. It also makes BIN1 a feasible early diagnostic or prognostic marker for cancer.
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Affiliation(s)
- Si-Yu Chen
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Jin-Long Cao
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Kun-Peng Li
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Shun Wan
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Li Yang
- Department of Urology, The Second Hospital of Lanzhou University, Lanzhou, China.
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25
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Kumar V, Bauer C, Stewart JH. Targeting cGAS/STING signaling-mediated myeloid immune cell dysfunction in TIME. J Biomed Sci 2023; 30:48. [PMID: 37380989 PMCID: PMC10304357 DOI: 10.1186/s12929-023-00942-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/14/2023] [Indexed: 06/30/2023] Open
Abstract
Myeloid immune cells (MICs) are potent innate immune cells serving as first responders to invading pathogens and internal changes to cellular homeostasis. Cancer is a stage of altered cellular homeostasis that can originate in response to different pathogens, chemical carcinogens, and internal genetic/epigenetic changes. MICs express several pattern recognition receptors (PRRs) on their membranes, cytosol, and organelles, recognizing systemic, tissue, and organ-specific altered homeostasis. cGAS/STING signaling is a cytosolic PRR system for identifying cytosolic double-stranded DNA (dsDNA) in a sequence-independent but size-dependent manner. The longer the cytosolic dsDNA size, the stronger the cGAS/STING signaling activation with increased type 1 interferon (IFN) and NF-κB-dependent cytokines and chemokines' generation. The present article discusses tumor-supportive changes occurring in the tumor microenvironment (TME) or tumor immune microenvironment (TIME) MICs, specifically emphasizing cGAS/STING signaling-dependent alteration. The article further discusses utilizing MIC-specific cGAS/STING signaling modulation as critical tumor immunotherapy to alter TIME.
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Affiliation(s)
- Vijay Kumar
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Science Center (LSUHSC), 1700 Tulane Avenue, New Orleans, LA, 70012, USA.
| | - Caitlin Bauer
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Science Center (LSUHSC), 1700 Tulane Avenue, New Orleans, LA, 70012, USA
| | - John H Stewart
- Department of Interdisciplinary Oncology, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Science Center (LSUHSC), 1700 Tulane Avenue, New Orleans, LA, 70012, USA.
- Louisiana Children's Medical Center Cancer Center, Stanley S. Scott Cancer Center, School of Medicine, Louisiana State University Health Science Center (LSUHSC), 1700 Tulane Avenue, New Orleans, LA, 70012, USA.
- Surgery, Section of Surgical Oncology, Louisiana State University New Orleans-Louisiana Children's Medical Center Cancer Center, Louisiana State University Health Science Center (LSUHSC), 1700 Tulane Avenue, New Orleans, LA, 70012, USA.
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26
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Santos-Ribeiro D, Lecocq M, de Beukelaer M, Verleden S, Bouzin C, Ambroise J, Dorfmuller P, Yakoub Y, Huaux F, Quarck R, Karmouty-Quintana H, Ghigna MR, Bignard J, Nadaud S, Soubrier F, Horman S, Perros F, Godinas L, Pilette C. Disruption of GCN2 Pathway Aggravates Vascular and Parenchymal Remodeling during Pulmonary Fibrosis. Am J Respir Cell Mol Biol 2023; 68:326-338. [PMID: 36476191 PMCID: PMC12042145 DOI: 10.1165/rcmb.2021-0541oc] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 12/06/2022] [Indexed: 12/12/2022] Open
Abstract
Pulmonary fibrosis (PF) and pulmonary hypertension (PH) are chronic diseases of the pulmonary parenchyma and circulation, respectively, which may coexist, but underlying mechanisms remain elusive. Mutations in the GCN2 (general control nonderepressible 2) gene (EIF2AK4 [eukaryotic translation initiation factor 2 alpha kinase 4]) were recently associated with pulmonary veno-occlusive disease. The aim of this study is to explore the involvement of the GCN2/eIF2α (eukaryotic initiation factor 2α) pathway in the development of PH during PF, in both human disease and in a laboratory animal model. Lung tissue from patients with PF with or without PH was collected at the time of lung transplantation, and control tissue was obtained from tumor resection surgery. Experimental lung disease was induced in either male wild-type or EIF2AK4-mutated Sprague-Dawley rats, randomly receiving a single intratracheal instillation of bleomycin or saline. Hemodynamic studies and organ collection were performed 3 weeks after instillation. Only significant results (P < 0.05) are presented. In PF lung tissue, GCN2 protein expression was decreased compared with control tissue. GCN2 expression was reduced in CD31+ endothelial cells. In line with human data, GCN2 protein expression was decreased in the lung of bleomycin rats compared with saline. EIF2AK4-mutated rats treated with bleomycin showed increased parenchymal fibrosis (hydroxyproline concentrations) and vascular remodeling (media wall thickness) as well as increased right ventricular systolic pressure compared with wild-type animals. Our data show that GCN2 is dysregulated in both humans and in an animal model of combined PF and PH. The possibility of a causative implication of GCN2 dysregulation in PF and/or PH development should be further studied.
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Affiliation(s)
| | | | | | - Stijn Verleden
- Laboratory of Respiratory Diseases & Thoracic Surgery, Department of Chronic Diseases and Metabolism, and
| | | | | | - Peter Dorfmuller
- Department of Pathology, University of Giessen and Marburg Lung Center, Justus-Liebig University Giessen, German Center for Lung Research, Giessen, Germany
| | - Yousef Yakoub
- Louvain Center for Toxicology and Applied Pharmacology, and
| | - François Huaux
- Louvain Center for Toxicology and Applied Pharmacology, and
| | - Rozenn Quarck
- Clinical Department of Respiratory Diseases, University Hospitals - University of Leuven, Leuven, Belgium
| | - Harry Karmouty-Quintana
- Department of Biochemistry and Molecular Biology and
- Division of Critical Care and
- Division of Pulmonary and Sleep Medicine, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Maria-Rosa Ghigna
- Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
- Département de Pathologie and
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
| | | | - Sophie Nadaud
- UMR_S 1166-ICAN, INSERM, Sorbonne Université, Paris, France
| | | | - Sandrine Horman
- Cardiovascular Research Unit, Institute of Experimental and Clinical Research, Catholic University of Louvain, Brussels, Belgium
| | - Frederic Perros
- Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France
- INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France
- Assistance Publique-Hôpitaux de Paris, Centre de Référence de l'Hypertension Pulmonaire, Service de Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
- Laboratoire CarMeN, UMR INSERM U1060/INRA U1397, Université Claude Bernard Lyon1, Pierre-Bénite and Bron, France; and
| | - Laurent Godinas
- Clinical Department of Respiratory Diseases, University Hospitals - University of Leuven, Leuven, Belgium
| | - Charles Pilette
- Pneumology, ENT and Dermatology
- Département de Pneumologie, Cliniques Universitaires St-Luc, Brussels, Belgium
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27
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Oparaugo NC, Ouyang K, Nguyen NPN, Nelson AM, Agak GW. Human Regulatory T Cells: Understanding the Role of Tregs in Select Autoimmune Skin Diseases and Post-Transplant Nonmelanoma Skin Cancers. Int J Mol Sci 2023; 24:1527. [PMID: 36675037 PMCID: PMC9864298 DOI: 10.3390/ijms24021527] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 01/04/2023] [Accepted: 01/09/2023] [Indexed: 01/15/2023] Open
Abstract
Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity.
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Affiliation(s)
- Nicole Chizara Oparaugo
- David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
- Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Kelsey Ouyang
- Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA
| | | | - Amanda M. Nelson
- Department of Dermatology, Penn State University College of Medicine, Hershey, PA 17033, USA
| | - George W. Agak
- Division of Dermatology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
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28
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Hassan WA, ElBanna AK, Noufal N, El-Assmy M, Lotfy H, Ali RI. Significance of tumor-associated neutrophils, lymphocytes, and neutrophil-to-lymphocyte ratio in non-invasive and invasive bladder urothelial carcinoma. J Pathol Transl Med 2023; 57:88-94. [PMID: 36623816 PMCID: PMC10028012 DOI: 10.4132/jptm.2022.11.06] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/06/2022] [Indexed: 01/11/2023] Open
Abstract
Background Tumor-infiltrating neutrophils and lymphocytes play essential roles in promoting or combating various neoplasms. This study aimed to investigate the association between tumor-infiltrating neutrophils and lymphocytes and the neutrophil-to-lymphocyte ratio in the progression of urothelial carcinoma. Methods A total of 106 patients diagnosed with urothelial carcinoma were was. Pathological examination for tumor grade and stage and for tumor-infiltrating neutrophils, both CD4 and CD8+ T lymphocytes, as well as the neutrophil- to-lymphocyte ratio were evaluated. Results The presence of neutrophils and the neutrophil-to-lymphocyte ratio correlated with high-grade urothelial neoplasms. In both low- and high-grade tumors, the lymphocytes increased during progression from a non-invasive neoplasm to an early-invasive neoplasm. CD8+ T lymphocytes increased in low-grade non-muscle-invasive tumors compared to non-invasive tumors. Additionally, there was a significant decrease in CD8+ T lymphocytes during progression to muscle-invasive tumors. Conclusions Our results suggest that tumor-infiltrating neutrophils and CD8+ T lymphocytes have a significant effect on tumor grade and progression.
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Affiliation(s)
- Wael Abdo Hassan
- Department of Pathology, Faculty of Medicine, Suez Canal University, El Sheikh Zayed, Egypt
- Department of Basic Sciences, College of Medicine, Suliman Al Rajhi University, Al Bukairiyah, Saudi Arabia
| | - Ahmed Kamal ElBanna
- Department of Basic Sciences, College of Medicine, Suliman Al Rajhi University, Al Bukairiyah, Saudi Arabia
- Department of Anatomy, Faculty of Medicine, Al-Azhar University, Cairo, Egypt
| | - Noha Noufal
- Department of Pathology, Faculty of Medicine, Suez Canal University, El Sheikh Zayed, Egypt
- Department of Basic Medical Sciences, College of Medicine, Dar Al Uloom University, Riyadh, Saudi Arabia
| | - Mohamed El-Assmy
- Department of Clinical Sciences, Suliman Al Rajhi University, Bukayriah, Saudi Arabia
| | - Hany Lotfy
- Department of Basic Sciences, College of Medicine, Suliman Al Rajhi University, Al Bukairiyah, Saudi Arabia
- Department of Microbiology and Immunology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Rehab Ibrahim Ali
- Department of Pathology, College of Medicine, Jouf University, Al-Jawf, Saudi Arabia
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29
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Perez-Castro L, Garcia R, Venkateswaran N, Barnes S, Conacci-Sorrell M. Tryptophan and its metabolites in normal physiology and cancer etiology. FEBS J 2023; 290:7-27. [PMID: 34687129 PMCID: PMC9883803 DOI: 10.1111/febs.16245] [Citation(s) in RCA: 54] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/10/2021] [Accepted: 10/21/2021] [Indexed: 02/06/2023]
Abstract
Within the growing field of amino acid metabolism, tryptophan (Trp) catabolism is an area of increasing interest. Trp is essential for protein synthesis, and its metabolism gives rise to biologically active catabolites including serotonin and numerous metabolites in the kynurenine (Kyn) pathway. In normal tissues, the production of Trp metabolites is directly regulated by the tissue-specific expression of Trp-metabolizing enzymes. Alterations of these enzymes in cancers can shift the balance and lead to an increased production of specific byproducts that can function as oncometabolites. For example, increased expression of the enzyme indoleamine 2,3-dioxygenase, which converts Trp into Kyn, leads to an increase in Kyn levels in numerous cancers. Kyn functions as an oncometabolite in cancer cells by promoting the activity of the transcription factor aryl hydrocarbon receptor, which regulates progrowth genes. Moreover, Kyn also inhibits T-cell activity and thus allows cancer cells to evade clearance by the immune system. Therefore, targeting the Kyn pathway has become a therapeutic focus as a novel means to abrogate tumor growth and immune resistance. This review summarizes the biological role and regulation of Trp metabolism and its catabolites with an emphasis on tumor cell growth and immune evasion and outlines areas for future research focus.
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Affiliation(s)
- Lizbeth Perez-Castro
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Roy Garcia
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Niranjan Venkateswaran
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Spencer Barnes
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Maralice Conacci-Sorrell
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
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30
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Mao W. Overcoming current challenges to T-cell receptor therapy via metabolic targeting to increase antitumor efficacy, durability, and tolerability. Front Immunol 2022; 13:1056622. [PMID: 36479131 PMCID: PMC9720167 DOI: 10.3389/fimmu.2022.1056622] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 10/31/2022] [Indexed: 11/22/2022] Open
Abstract
The antitumor potential of personalized immunotherapy, including adoptive T-cell therapy, has been shown in both preclinical and clinical studies. Combining cell therapy with targeted metabolic interventions can further enhance therapeutic outcomes in terms of magnitude and durability. The ability of a T cell receptor to recognize peptides derived from tumor neoantigens allows for a robust yet specific response against cancer cells while sparing healthy tissue. However, there exist challenges to adoptive T cell therapy such as a suppressive tumor milieu, the fitness and survival of transferred cells, and tumor escape, all of which can be targeted to further enhance the antitumor potential of T cell receptor-engineered T cell (TCR-T) therapy. Here, we explore current strategies involving metabolic reprogramming of both the tumor microenvironment and the cell product, which can lead to increased T cell proliferation, survival, and anti-tumor cytotoxicity. In addition, we highlight potential metabolic pathways and targets which can be leveraged to improve engraftment of transferred cells and obviate the need for lymphodepletion, while minimizing off-target effects. Metabolic signaling is delicately balanced, and we demonstrate the need for thoughtful and precise interventions that are tailored for the unique characteristics of each tumor. Through improved understanding of the interplay between immunometabolism, tumor resistance, and T cell signaling, we can improve current treatment regimens and open the door to potential synergistic combinations.
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31
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Lee DY, Im E, Yoon D, Lee YS, Kim GS, Kim D, Kim SH. Pivotal role of PD-1/PD-L1 immune checkpoints in immune escape and cancer progression: Their interplay with platelets and FOXP3+Tregs related molecules, clinical implications and combinational potential with phytochemicals. Semin Cancer Biol 2022; 86:1033-1057. [PMID: 33301862 DOI: 10.1016/j.semcancer.2020.12.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/25/2020] [Accepted: 12/01/2020] [Indexed: 01/27/2023]
Abstract
Immune checkpoint proteins including programmed cell death protein 1 (PD-1), its ligand PD-L1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are involved in proliferation, angiogenesis, metastasis, chemoresistance via immune escape and immune tolerance by disturbing cytotoxic T cell activation. Though many clinical trials have been completed in several cancers by using immune checkpoint inhibitors alone or in combination with other agents to date, recently multi-target therapy is considered more attractive than monotherapy, since immune checkpoint proteins work with other components such as surrounding blood vessels, dendritic cells, fibroblasts, macrophages, platelets and extracellular matrix within tumor microenvironment. Thus, in the current review, we look back on research history of immune checkpoint proteins and discuss their associations with platelets or tumor cell induced platelet aggregation (TCIPA) and FOXP3+ regulatory T cells (Tregs) related molecules involved in immune evasion and tumor progression, clinical implications of completed trial results and signaling networks by phytochemicals for combination therapy with immune checkpoint inhibitors and suggest future research perspectives.
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Affiliation(s)
- Dae Young Lee
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong, 27709, Republic of Korea
| | - Eunji Im
- College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea
| | - Dahye Yoon
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong, 27709, Republic of Korea
| | - Young-Seob Lee
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong, 27709, Republic of Korea
| | - Geum-Soog Kim
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong, 27709, Republic of Korea
| | - Donghwi Kim
- Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science, RDA, Eumseong, 27709, Republic of Korea
| | - Sung-Hoon Kim
- College of Korean Medicine, Kyung Hee University, Seoul, 02447, Republic of Korea.
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32
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Mohammadi Y, Ahmadvand S, Mirtalebi M, Ashraf MJ, Khademi B, Ghaderi A. CD45RO+TILs: cellular biomarkers for larynx squamous cell carcinoma outcome. Braz J Otorhinolaryngol 2022; 88 Suppl 4:S133-S142. [PMID: 36319566 PMCID: PMC9756076 DOI: 10.1016/j.bjorl.2022.09.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 09/22/2022] [Accepted: 10/06/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE The prognostic importance of Tumor-Infiltrating Lymphocytes (TILs) in the tumor microenvironment of various cancers is increasingly recognized. In the present study, we aimed to investigate the prognostic value of CD3+, CD4+, CD8+, and CD45RO + TILs and their relation to histopathological features in larynx squamous cell carcinoma. METHODS Formalin-Fixed and Paraffin-Embedded (FFPE) samples from 63 primary larynx squamous cell carcinoma patients were immunostained for CD3, CD4, CD8, and CD45RO expression. Positive cells in micrographs from Invasive Margin (IM) and Tumor Center (CT) of tissue specimens counted by ImageJ software and their correlation with disease outcome were analyzed. RESULTS The expression level of TILs subpopulations was associated with clinicopathological markers as well as Overall Survival (OS) and Disease-Free Survival (DFS). In multivariate analysis, high frequency of CD45RO + cells in IM were confirmed as an independent prognostic marker for DFS (p = 0.007, HR = 4.968) and OS (p = 0.007, HR = 4.957). Similar findings were observed in the multivariate analysis of the combined frequency of CD45RO+cells in IM and CT. CONCLUSION TILs are associated with patients clinicopathological features. Also, our findings indicate that CD45RO + TILs are a valuable marker for risk prediction in larynx SCC and could predict patients' outcomes.
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Affiliation(s)
- Yousef Mohammadi
- Shiraz University of Medical Sciences, School of Medicine, Department of Immunology, Shiraz, Iran; Shiraz University of Medical Sciences, School of Medicine, Shiraz Institute for Cancer Research, Shiraz, Iran
| | - Simin Ahmadvand
- Shiraz University of Medical Sciences, School of Medicine, Shiraz Institute for Cancer Research, Shiraz, Iran
| | - Maryam Mirtalebi
- Shiraz University of Medical Sciences, School of Medicine, Department of Pathology, Shiraz, Iran
| | - Mohammad Javad Ashraf
- Shiraz University of Medical Sciences, School of Medicine, Department of Pathology, Shiraz, Iran
| | - Bijan Khademi
- Shiraz University of Medical Sciences, Otolaryngology Research Center, Department of Otorhinolaryngology, Shiraz, Iran
| | - Abbas Ghaderi
- Shiraz University of Medical Sciences, School of Medicine, Department of Immunology, Shiraz, Iran; Shiraz University of Medical Sciences, School of Medicine, Shiraz Institute for Cancer Research, Shiraz, Iran.
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Pallotta MT, Rossini S, Suvieri C, Coletti A, Orabona C, Macchiarulo A, Volpi C, Grohmann U. Indoleamine 2,3-dioxygenase 1 (IDO1): an up-to-date overview of an eclectic immunoregulatory enzyme. FEBS J 2022; 289:6099-6118. [PMID: 34145969 PMCID: PMC9786828 DOI: 10.1111/febs.16086] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/04/2021] [Accepted: 06/18/2021] [Indexed: 12/30/2022]
Abstract
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the initial rate-limiting step in the degradation of the essential amino acid tryptophan along the kynurenine pathway. When discovered more than 50 years ago, IDO1 was thought to be an effector molecule capable of mediating a survival strategy based on the deprivation of bacteria and tumor cells of the essential amino acid tryptophan. Since 1998, when tryptophan catabolism was discovered to be crucially involved in the maintenance of maternal T-cell tolerance, IDO1 has become the focus of several laboratories around the world. Indeed, IDO1 is now considered as an authentic immune regulator not only in pregnancy, but also in autoimmune diseases, chronic inflammation, and tumor immunity. However, in the last years, a bulk of new information-including structural, biological, and functional evidence-on IDO1 has come to light. For instance, we now know that IDO1 has a peculiar conformational plasticity and, in addition to a complex and highly regulated catalytic activity, is capable of performing a nonenzymic function that reprograms the expression profile of immune cells toward a highly immunoregulatory phenotype. With this state-of-the-art review, we aimed at gathering the most recent information obtained for this eclectic protein as well as at highlighting the major unresolved questions.
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Affiliation(s)
| | - Sofia Rossini
- Department of Medicine and SurgeryUniversity of PerugiaItaly
| | - Chiara Suvieri
- Department of Medicine and SurgeryUniversity of PerugiaItaly
| | - Alice Coletti
- Department of Pharmaceutical SciencesUniversity of PerugiaItaly
| | - Ciriana Orabona
- Department of Medicine and SurgeryUniversity of PerugiaItaly
| | | | - Claudia Volpi
- Department of Medicine and SurgeryUniversity of PerugiaItaly
| | - Ursula Grohmann
- Department of Medicine and SurgeryUniversity of PerugiaItaly
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Plasmacytoid Dendritic Cells as a Novel Cell-Based Cancer Immunotherapy. Int J Mol Sci 2022; 23:ijms231911397. [PMID: 36232698 PMCID: PMC9570010 DOI: 10.3390/ijms231911397] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 09/21/2022] [Accepted: 09/22/2022] [Indexed: 12/15/2022] Open
Abstract
Plasmacytoid dendritic cells (pDCs) are multifaceted immune cells with a wide range of innate and adaptive immunological functions. They constitute the first line of defence against multiple viral infections and have also been reported to actively participate in antitumor immune responses. The clinical implication of the presence of pDCs in the tumor microenvironment (TME) is still ambiguous, but it is clear that pDCs possess the ability to modulate tumor-specific T cell responses and direct cytotoxic functions. Therapeutic strategies designed to exploit these qualities of pDCs to boost tumor-specific immune responses could represent an attractive alternative compared to conventional therapeutic approaches in the future, and promising antitumor effects have already been reported in phase I/II clinical trials. Here, we review the many roles of pDCs in cancer and present current advances in developing pDC-based immunotherapeutic approaches for treating cancer.
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Kudo-Saito C, Boku N, Hirano H, Shoji H. Targeting myeloid villains in the treatment with immune checkpoint inhibitors in gastrointestinal cancer. Front Immunol 2022; 13:1009701. [PMID: 36211375 PMCID: PMC9539086 DOI: 10.3389/fimmu.2022.1009701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 09/13/2022] [Indexed: 12/03/2022] Open
Abstract
Despite the clinical outcomes being extremely limited, blocking immune inhibitory checkpoint pathways has been in the spotlight as a promising strategy for treating gastrointestinal cancer. However, a distinct strategy for the successful treatment is obviously needed in the clinical settings. Myeloid cells, such as neutrophils, macrophages, dendritic cells, and mast cells, are the majority of cellular components in the human immune system, but have received relatively less attention for the practical implementation than T cells and NK cells in cancer therapy because of concentration of the interest in development of the immune checkpoint blocking antibody inhibitors (ICIs). Abnormality of myeloid cells must impact on the entire host, including immune responses, stromagenesis, and cancer cells, leading to refractory cancer. This implies that elimination and reprogramming of the tumor-supportive myeloid villains may be a breakthrough to efficiently induce potent anti-tumor immunity in cancer patients. In this review, we provide an overview of current situation of the IC-blocking therapy of gastrointestinal cancer, including gastric, colorectal, and esophageal cancers. Also, we highlight the possible oncoimmunological components involved in the mechanisms underlying the resistance to the ICI therapy, particularly focusing on myeloid cells, including unique subsets expressing IC molecules. A deeper understanding of the molecular and cellular determinants may facilitate its practical implementation of targeting myeloid villains, and improve the clinical outcomes in the ICI therapy of gastrointestinal cancer.
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Affiliation(s)
- Chie Kudo-Saito
- Department of Immune Medicine, National Cancer Center Research Institute, Tokyo, Japan
- *Correspondence: Chie Kudo-Saito,
| | - Narikazu Boku
- Department of Oncology and General Medicine, Institute of Medical Science Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hidekazu Hirano
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hirokazu Shoji
- Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
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Yang K. Regulation of Treg Cell Metabolism and Function in Non-Lymphoid Tissues. Front Immunol 2022; 13:909705. [PMID: 35720275 PMCID: PMC9200993 DOI: 10.3389/fimmu.2022.909705] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/06/2022] [Indexed: 12/12/2022] Open
Abstract
Regulator T cells (Tregs) play pivotal roles in maintaining immune tolerance and regulating immune responses against pathogens and tumors. Reprogramming of cellular metabolism has been determined as a crucial process that connects microenvironmental cues and signaling networks to influence homeostasis and function of tissue Tregs. In adaptation to a variety of non-lymphoid tissues, Tregs coordinate local immune signals and signaling networks to rewire cellular metabolic programs to sustain their suppressive function. Altered Treg metabolism in turn shapes Treg activation and function. In light of the advanced understanding of immunometabolism, manipulation of systemic metabolites has been emerging as an attractive strategy aiming to modulate metabolism and function of tissue Tregs and improve the treatment of immune-related diseases. In this review, we summarize key immune signals and metabolic programs involved in the regulation of tissue Tregs, review the mechanisms underlying the differentiation and function of Tregs in various non-lymphoid tissues, and discuss therapeutic intervention of metabolic modulators of tissue Tregs for the treatment of autoimmune diseases and cancer.
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Affiliation(s)
- Kai Yang
- Department of Pediatrics and the Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, United States
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Molnar V, Pavelić E, Vrdoljak K, Čemerin M, Klarić E, Matišić V, Bjelica R, Brlek P, Kovačić I, Tremolada C, Primorac D. Mesenchymal Stem Cell Mechanisms of Action and Clinical Effects in Osteoarthritis: A Narrative Review. Genes (Basel) 2022; 13:genes13060949. [PMID: 35741711 PMCID: PMC9222975 DOI: 10.3390/genes13060949] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/21/2022] [Accepted: 05/24/2022] [Indexed: 02/04/2023] Open
Abstract
With the insufficient satisfaction rates and high cost of operative treatment for osteoarthritis (OA), alternatives have been sought. Furthermore, the inability of current medications to arrest disease progression has led to rapidly growing clinical research relating to mesenchymal stem cells (MSCs). The availability and function of MSCs vary according to tissue source. The three primary sources include the placenta, bone marrow, and adipose tissue, all of which offer excellent safety profiles. The primary mechanisms of action are trophic and immunomodulatory effects, which prevent the further degradation of joints. However, the function and degree to which benefits are observed vary significantly based on the exosomes secreted by MSCs. Paracrine and autocrine mechanisms prevent cell apoptosis and tissue fibrosis, initiate angiogenesis, and stimulate mitosis via growth factors. MSCs have even been shown to exhibit antimicrobial effects. Clinical results incorporating clinical scores and objective radiological imaging have been promising, but a lack of standardization in isolating MSCs prevents their incorporation in current guidelines.
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Affiliation(s)
- Vilim Molnar
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
| | - Eduard Pavelić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Kristijan Vrdoljak
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Martin Čemerin
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia; (K.V.); (M.Č.)
| | - Emil Klarić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Vid Matišić
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | - Roko Bjelica
- Department of Oral Surgery, School of Dental Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Petar Brlek
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
| | | | | | - Dragan Primorac
- St. Catherine Specialty Hospital, 10000 Zagreb, Croatia; (V.M.); (E.P.); (E.K.); (V.M.); (P.B.)
- Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Split, 21000 Split, Croatia
- Faculty of Dental Medicine and Health, Josip Juraj Strossmayer University of Osijek, 31000 Osijek, Croatia
- Medical School, University of Rijeka, 51000 Rijeka, Croatia
- Medical School REGIOMED, 96450 Coburg, Germany
- Eberly College of Science, The Pennsylvania State University, University Park, PA 16802, USA
- The Henry C. Lee College of Criminal Justice and Forensic Sciences, University of New Haven, West Haven, CT 06516, USA
- Correspondence:
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Kazmi S, Khan MA, Shamma T, Altuhami A, Assiri AM, Broering DC. Therapeutic nexus of T cell immunometabolism in improving transplantation immunotherapy. Int Immunopharmacol 2022; 106:108621. [PMID: 35189469 DOI: 10.1016/j.intimp.2022.108621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 02/03/2022] [Accepted: 02/10/2022] [Indexed: 11/26/2022]
Abstract
Immunometabolism is a therapeutic strategy to tune immune cells through metabolic reprogramming, which allows immune cells to be differentiated according to their energy requirements. Recent therapeutic strategies targeting immunometabolism suggest that intracellular metabolic reprogramming controls T cell activation, proliferation, and differentiation into effector (Teff) or regulatory (Treg) cells. Immunometabolism is being studied for the treatment of inflammatory diseases, including those associated with solid organ transplantation (SOT). Here, we review immunometabolic regulation of immune cells, with a particular focus on Treg metabolic regulation and liver kinase B1 (LKB1) signaling, which stabilize Tregs and prevent inflammation-associated tissue injuries. All in all, here we discussed how targeting T cell immunometabolism modulates Teff and Treg-mediated immune responses, which can be used to boost Treg differentiation, stability, and ultimately favor immunotolerance in clinical transplants.
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Affiliation(s)
- Shadab Kazmi
- Transplant Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia.
| | - Mohammad Afzal Khan
- Transplant Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia.
| | - Talal Shamma
- Transplant Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia.
| | - Abdullah Altuhami
- Transplant Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia.
| | - Abdullah Mohammed Assiri
- Comparative Medicine Department, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.
| | - Dieter Clemens Broering
- Transplant Research and Innovation Department, Organ Transplant Centre of Excellence, King Faisal Specialist Hospital and Research Centre, Riyadh 12713, Saudi Arabia.
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Takeshita H, Yamamoto K. Tryptophan Metabolism and COVID-19-Induced Skeletal Muscle Damage: Is ACE2 a Key Regulator? Front Nutr 2022; 9:868845. [PMID: 35463998 PMCID: PMC9028463 DOI: 10.3389/fnut.2022.868845] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 03/07/2022] [Indexed: 12/15/2022] Open
Abstract
The severity of coronavirus disease 2019 (COVID-19) is characterized by systemic damage to organs, including skeletal muscle, due to excessive secretion of inflammatory cytokines. Clinical studies have suggested that the kynurenine pathway of tryptophan metabolism is selectively enhanced in patients with severe COVID-19. In addition to acting as a receptor for severe acute respiratory syndrome coronavirus 2, the causative virus of COVID-19, angiotensin converting enzyme 2 (ACE2) contributes to tryptophan absorption and inhibition of the renin-angiotensin system. In this article, we review previous studies to assess the potential for a link between tryptophan metabolism, ACE2, and skeletal muscle damage in patients with COVID-19.
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Gao R, Shi GP, Wang J. Functional Diversities of Regulatory T Cells in the Context of Cancer Immunotherapy. Front Immunol 2022; 13:833667. [PMID: 35371055 PMCID: PMC8969660 DOI: 10.3389/fimmu.2022.833667] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
Regulatory T cells (Tregs) are a subset of CD4+ T cells with their immunosuppressive activities to block abnormal or excessive immune responses to self and non-autoantigens. Tregs express the transcription factor Foxp3, maintain the immune homeostasis, and prevent the initiation of anti-tumor immune effects in various ways as their mechanisms to modulate tumor development. Recognition of different phenotypes and functions of intratumoral Tregs has offered the possibilities to develop therapeutic strategies by selectively targeting Tregs in cancers with the aim of alleviating their immunosuppressive activities from anti-tumor immune responses. Several Treg-based immunotherapeutic approaches have emerged to target cytotoxic T lymphocyte antigen-4, glucocorticoid-induced tumor necrosis factor receptor, CD25, indoleamine-2, 3-dioxygenase-1, and cytokines. These immunotherapies have yielded encouraging outcomes from preclinical studies and early-phase clinical trials. Further, dual therapy or combined therapy has been approved to be better choices than single immunotherapy, radiotherapy, or chemotherapy. In this short review article, we discuss our current understanding of the immunologic characteristics of Tregs, including Treg differentiation, development, therapeutic efficacy, and future potential of Treg-related therapies among the general cancer therapy.
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Affiliation(s)
- Ran Gao
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, China
| | - Guo-Ping Shi
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
| | - Jing Wang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, China
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Schumacher NSG, Fernandes LGR, de Lima Zollner R. Aqueous extract of Passiflora alata leaves modulates in vitro the indoleamine 2,3-dioxygenase (IDO) and CD86 expression in bone marrow-derived professional antigen-presenting cells polarizing NOD mice T cells to a Treg profile. Cytokine 2022; 152:155832. [PMID: 35202987 DOI: 10.1016/j.cyto.2022.155832] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 02/03/2022] [Accepted: 02/15/2022] [Indexed: 12/18/2022]
Abstract
Dendritic cells (DCs) and macrophages are professional antigen-presenting cells (pAPCs), numerous in the pancreas of nonobese diabetic (NOD) mice and playing an essential role in the autoimmune response of type 1 diabetes. The expression of the enzyme indoleamine 2,3-dioxygenase (IDO) is a critical factor for the tolerogenic activity of pAPCs, acting in the catabolism of tryptophan, providing metabolites that suppress the T cell effectors and induce T regulatory cells differentiation. Here we investigated the in vitro mechanisms of lyophilized aqueous extract from Passiflora alata leaves (LAEPAL) that modulates bone marrow-derived professional antigen-presenting cells (BM-pAPCs), affecting their ability to polarize T cells. A cell culture model was defined using mixed cultures of BM-pAPCs and T lymphocytes NOD mice with stressed MIN-6 cells as a source of pancreatic β cells antigens. We showed that the treatment with 300 µg/mL of LAEPAL induces a significant decrease in the CD4 and CD8 T effector lymphocytes proliferation from diabetic but not in non-diabetic mice, followed by a reduction of the IL-6 and IFN-γ cytokines release in the cell cultures supernatants. Moreover, we observed an increase of CD4+CD25+FoxP3+ Tregs in the cell cultures from diabetic mice. These results could be partially explained by the LAEPAL modulatory effects in BM-pAPCs, downregulating the CD86 co-stimulatory molecule expression, and increasing IDO-1 expression in F4/80+ BM-pAPCs. These results contribute to a better understanding of the polyphenols' immunomodulatory properties, meaning they could induce tolerogenic antigen-presenting cells, which could polarize T cells to a Treg profile and decrease the activity of CD4+ and CD8+ T effector cells.
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Affiliation(s)
- Nayara Simon Gonzalez Schumacher
- Laboratory of Translational Immunology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-888, Brazil.
| | - Luís Gustavo Romani Fernandes
- Laboratory of Translational Immunology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-888, Brazil.
| | - Ricardo de Lima Zollner
- Laboratory of Translational Immunology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas 13083-888, Brazil.
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Wilczyński JR, Nowak M. Cancer Immunoediting: Elimination, Equilibrium, and Immune Escape in Solid Tumors. EXPERIENTIA SUPPLEMENTUM (2012) 2022; 113:1-57. [PMID: 35165859 DOI: 10.1007/978-3-030-91311-3_1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Emphasizing the dynamic processes between cancer and host immune system, the initially discovered concept of cancer immunosurveillance has been replaced by the current concept of cancer immunoediting consisting of three phases: elimination, equilibrium, and escape. Solid tumors composed of both cancer and host stromal cells are an example how the three phases of cancer immunoediting functionally evolve and how tumor shaped by the host immune system gets finally resistant phenotype. The elimination, equilibrium, and escape have been described in this chapter in details, including the role of immune surveillance, cancer dormancy, disruption of the antigen-presenting machinery, tumor-infiltrating immune cells, resistance to apoptosis, as well as the function of tumor stroma, microvesicles, exosomes, and inflammation.
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Affiliation(s)
- Jacek R Wilczyński
- Department of Gynecologic Surgery and Gynecologic Oncology, Medical University of Lodz, Lodz, Poland.
| | - Marek Nowak
- Department of Operative Gynecology and Gynecologic Oncology, Polish Mother's Memorial Hospital-Research Institute, Lodz, Poland
- Department of Operative and Endoscopic Gynecology, Medical University of Lodz, Lodz, Poland
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Oberholtzer N, Quinn KM, Chakraborty P, Mehrotra S. New Developments in T Cell Immunometabolism and Implications for Cancer Immunotherapy. Cells 2022; 11:708. [PMID: 35203357 PMCID: PMC8870179 DOI: 10.3390/cells11040708] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 02/05/2022] [Accepted: 02/10/2022] [Indexed: 12/12/2022] Open
Abstract
Despite rapid advances in the field of immunotherapy, the elimination of established tumors has not been achieved. Many promising new treatments such as adoptive cell therapy (ACT) fall short, primarily due to the loss of T cell effector function or the failure of long-term T cell persistence. With the availability of new tools and advancements in technology, our understanding of metabolic processes has increased enormously in the last decade. Redundancy in metabolic pathways and overlapping targets that could address the plasticity and heterogenous phenotypes of various T cell subsets have illuminated the need for understanding immunometabolism in the context of multiple disease states, including cancer immunology. Herein, we discuss the developing field of T cell immunometabolism and its crucial relevance to improving immunotherapeutic approaches. This in-depth review details the metabolic pathways and preferences of the antitumor immune system and the state of various metabolism-targeting therapeutic approaches.
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Affiliation(s)
- Nathaniel Oberholtzer
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA; (K.M.Q.); (P.C.)
| | | | | | - Shikhar Mehrotra
- Department of Surgery, Medical University of South Carolina, Charleston, SC 29425, USA; (K.M.Q.); (P.C.)
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Hu D, Cao Q, Tong M, Ji C, Li Z, Huang W, Jin Y, Tong G, Wang Y, Li P, Zhang H. A novel defined risk signature based on pyroptosis-related genes can predict the prognosis of prostate cancer. BMC Med Genomics 2022; 15:24. [PMID: 35135561 PMCID: PMC8822680 DOI: 10.1186/s12920-022-01172-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 01/31/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Pyroptosis can not only inhibit the occurrence and development of tumors but also develop a microenvironment conducive to cancer growth. However, pyroptosis research in prostate cancer (PCa) has rarely been reported. METHODS The expression profile and corresponding clinical data were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Patients were divided into different clusters using consensus clustering analysis, and differential genes were obtained. We developed and validated a prognostic biomarker for biochemical recurrence (BCR) of PCa using univariate Cox analysis, Lasso-Cox analysis, Kaplan-Meier (K-M) survival analysis, and time-dependent receiver operating characteristics (ROC) curves. RESULTS The expression levels of most pyroptosis-related genes (PRGs) are different not only between normal and tumor tissues but also between different clusters. Cluster 2 patients have a better prognosis than cluster 1 patients, and there are significant differences in immune cell content and biological pathway between them. Based on the classification of different clusters, we constructed an eight genes signature that can independently predict the progression-free survival (PFS) rate of a patient, and this signature was validated using a GEO data set (GSE70769). Finally, we established a nomogram model with good accuracy. CONCLUSIONS In this study, PRGs were used as the starting point and based on the expression profile and clinical data, a prognostic signature with a high predictive value for biochemical recurrence (BCR) following radical prostatectomy (RP) was finally constructed, and the relationship between pyroptosis, immune microenvironment, and PCa was explored, providing important clues for future research on pyroptosis and immunity.
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Affiliation(s)
- Ding Hu
- Department of Urology, Jinzhou Medical University, The First Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Qingfei Cao
- Department of Urology, Jinzhou Medical University, The First Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Ming Tong
- Department of Urology, Jinzhou Medical University, The First Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China.
| | - Chundong Ji
- Department of Urology, Affiliated Hospital of Panzhihua University, Panzhihua, Sichuan, China.
| | - Zizhi Li
- Department of Urology, Jinzhou Medical University, The First Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Weichao Huang
- Department of Urology, Jinzhou Medical University, The First Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Yanyang Jin
- Department of Urology, Jinzhou Medical University, The First Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Guangquan Tong
- Department of Urology, Jinzhou Medical University, The First Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Yutao Wang
- Department of Urology, China Medical University, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Pengfei Li
- Department of Urology, Jinzhou Medical University, The First Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
| | - Huashan Zhang
- Department of Urology, Jinzhou Medical University, The First Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China
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Prognostic Role of Tumor Microenvironment in DLBCL and Relation to Patients’ Clinical Outcome: A Clinical and Immunohistochemical Study. Anal Cell Pathol (Amst) 2022; 2022:9993496. [PMID: 35083113 PMCID: PMC8786528 DOI: 10.1155/2022/9993496] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 12/07/2021] [Indexed: 11/29/2022] Open
Abstract
Diffuse large B cell lymphoma is the most common type of lymphoma in Egypt with an unfavorable prognosis. The tumor microenvironment is rich in immune response either T cells or macrophages. The current study is aimed at testing CD4, CD8, CD68, and MMP9 immunohistochemistry of DLBCL activities with the prognosis of the tumor. The results showed no positive relation between T cell and macrophage reaction to the tumor prognosis suggesting that this reaction is part of the tumor process and not a defense mechanism from the surrounding stroma.
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Wee HN, Liu JJ, Ching J, Kovalik JP, Lim SC. The Kynurenine Pathway in Acute Kidney Injury and Chronic Kidney Disease. Am J Nephrol 2021; 52:771-787. [PMID: 34753140 PMCID: PMC8743908 DOI: 10.1159/000519811] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 09/15/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND The kynurenine pathway (KP) is the major catabolic pathway for tryptophan degradation. The KP plays an important role as the sole de novo nicotinamide adenine dinucleotide (NAD+) biosynthetic pathway in normal human physiology and functions as a counter-regulatory mechanism to mitigate immune responses during inflammation. Although the KP has been implicated in a variety of disorders including Huntington's disease, seizures, cardiovascular disease, and osteoporosis, its role in renal diseases is seldom discussed. SUMMARY This review summarizes the roles of the KP and its metabolites in acute kidney injury (AKI) and chronic kidney disease (CKD) based on current literature evidence. Metabolomics studies demonstrated that the KP metabolites were significantly altered in patients and animal models with AKI or CKD. The diagnostic and prognostic values of the KP metabolites in AKI and CKD were highlighted in cross-sectional and longitudinal human observational studies. The biological impact of the KP on the pathophysiology of AKI and CKD has been studied in experimental models of different etiologies. In particular, the activation of the KP was found to confer protection in animal models of glomerulonephritis, and its immunomodulatory mechanism may involve the regulation of T cell subsets such as Th17 and regulatory T cells. Manipulation of the KP to increase NAD+ production or diversion toward specific KP metabolites was also found to be beneficial in animal models of AKI. Key Messages: KP metabolites are reported to be dysregulated in human observational and animal experimental studies of AKI and CKD. In AKI, the magnitude and direction of changes in the KP depend on the etiology of the damage. In CKD, KP metabolites are altered with the onset and progression of CKD all the way to advanced stages of the disease, including uremia and its related vascular complications. The activation of the KP and diversion to specific sub-branches are currently being explored as therapeutic strategies in these diseases, especially with regards to the immunomodulatory effects of certain KP metabolites. Further elucidation of the KP may hold promise for the development of biomarkers and targeted therapies for these kidney diseases.
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Affiliation(s)
| | - Jian-Jun Liu
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
| | - Jianhong Ching
- Duke-NUS Medical School, Singapore, Singapore
- KK Research Centre, KK Women's and Children's Hospital, Singapore, Singapore
| | | | - Su Chi Lim
- Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, Singapore
- Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore
- Diabetes Centre, Admiralty Medical Centre, Singapore, Singapore
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Xu XL, Deng SL, Lian ZX, Yu K. Resveratrol Targets a Variety of Oncogenic and Oncosuppressive Signaling for Ovarian Cancer Prevention and Treatment. Antioxidants (Basel) 2021; 10:antiox10111718. [PMID: 34829589 PMCID: PMC8614917 DOI: 10.3390/antiox10111718] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/21/2021] [Accepted: 10/26/2021] [Indexed: 11/16/2022] Open
Abstract
Ovarian cancer is a heterogeneous disease and is also the major cause of death among women from gynecologic malignancies. A combination of surgery and chemotherapy is the major therapy for ovarian cancer. Unfortunately, despite good response rates to initial surgery and chemotherapy, most patients relapse and have a generally poor survival rate. The present research sheds light on the therapeutic effects of multiple natural products in patients with ovarian cancer. Notably, these natural ingredients do not have adverse effects on healthy cells and tissues, indicating that natural products can serve as a safe alternative therapy for ovarian cancer. Trans-3,4,5′-Trihydroxystibene (resveratrol) is a natural product that is commonly found in the human diet and that has been shown to have anticancer effects on various human cancer cells. This review summarizes current knowledge regarding the progress of resveratrol against tumor cell proliferation, metastasis, apoptosis induction, autophagy, sensitization, and antioxidation as well as anti-inflammation. It also provides information regarding the role of resveratrol analogues in ovarian cancer. A better understanding of the role of resveratrol in ovarian cancer may provide a new array for the prevention and therapy of ovarian cancer.
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Affiliation(s)
- Xue-Ling Xu
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
| | - Shou-Long Deng
- Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing 100021, China; or
| | - Zheng-Xing Lian
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
- Correspondence: (Z.-X.L.); (K.Y.)
| | - Kun Yu
- Beijing Key Laboratory for Animal Genetic Improvement, National Engineering Laboratory for Animal Breeding, Key Laboratory of Animal Genetics and Breeding of the Ministry of Agriculture, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China;
- Correspondence: (Z.-X.L.); (K.Y.)
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Marques HS, de Brito BB, da Silva FAF, Santos MLC, de Souza JCB, Correia TML, Lopes LW, Neres NSDM, Dórea RSDM, Dantas ACS, Morbeck LLB, Lima IS, de Almeida AA, Dias MRDJ, de Melo FF. Relationship between Th17 immune response and cancer. World J Clin Oncol 2021; 12:845-867. [PMID: 34733609 PMCID: PMC8546660 DOI: 10.5306/wjco.v12.i10.845] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/21/2021] [Accepted: 09/16/2021] [Indexed: 02/06/2023] Open
Abstract
Cancer is the second leading cause of death worldwide and epidemiological projections predict growing cancer mortality rates in the next decades. Cancer has a close relationship with the immune system and, although Th17 cells are known to play roles in the immune response against microorganisms and in autoimmunity, studies have emphasized their roles in cancer pathogenesis. The Th17 immune response profile is involved in several types of cancer including urogenital, respiratory, gastrointestinal, and skin cancers. This type of immune response exerts pro and antitumor functions through several mechanisms, depending on the context of each tumor, including the protumor angiogenesis and exhaustion of T cells and the antitumor recruitment of T cells and neutrophils to the tumor microenvironment. Among other factors, the paradoxical behavior of Th17 cells in this setting has been attributed to its plasticity potential, which makes possible their conversion into other types of T cells such as Th17/Treg and Th17/Th1 cells. Interleukin (IL)-17 stands out among Th17-related cytokines since it modulates pathways and interacts with other cell profiles in the tumor microenvironment, which allow Th17 cells to prevail in tumors. Moreover, the IL-17 is able to mediate pro and antitumor processes that influence the development and progression of various cancers, being associated with variable clinical outcomes. The understanding of the relationship between the Th17 immune response and cancer as well as the singularities of carcinogenic processes in each type of tumor is crucial for the identification of new therapeutic targets.
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Affiliation(s)
- Hanna Santos Marques
- Campus Vitória da Conquista, Universidade Estadual do Sudoeste da Bahia, Vitória da Conquista 45083-900, Bahia, Brazil
| | - Breno Bittencourt de Brito
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Maria Luísa Cordeiro Santos
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Júlio César Braga de Souza
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Thiago Macêdo Lopes Correia
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Luana Weber Lopes
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Nayara Silva de Macêdo Neres
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | | | - Anna Carolina Saúde Dantas
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Lorena Lôbo Brito Morbeck
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Iasmin Souza Lima
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Amanda Alves de Almeida
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Maiara Raulina de Jesus Dias
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
| | - Fabrício Freire de Melo
- Instituto Multidisciplinar em Saúde, Universidade Federal da Bahia, Vitória da Conquista 45029-094, Bahia, Brazil
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Hofer F, Di Sario G, Musiu C, Sartoris S, De Sanctis F, Ugel S. A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment. Cells 2021; 10:cells10102700. [PMID: 34685679 PMCID: PMC8534848 DOI: 10.3390/cells10102700] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 12/19/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) constitute a plastic and heterogeneous cell population among immune cells within the tumour microenvironment (TME) that support cancer progression and resistance to therapy. During tumour progression, cancer cells modify their metabolism to sustain an increased energy demand to cope with uncontrolled cell proliferation and differentiation. This metabolic reprogramming of cancer establishes competition for nutrients between tumour cells and leukocytes and most importantly, among tumour-infiltrating immune cells. Thus, MDSCs that have emerged as one of the most decisive immune regulators of TME exhibit an increase in glycolysis and fatty acid metabolism and also an upregulation of enzymes that catabolise essential metabolites. This complex metabolic network is not only crucial for MDSC survival and accumulation in the TME but also for enhancing immunosuppressive functions toward immune effectors. In this review, we discuss recent progress in the field of MDSC-associated metabolic pathways that could facilitate therapeutic targeting of these cells during cancer progression.
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Affiliation(s)
| | | | | | | | | | - Stefano Ugel
- Correspondence: ; Tel.: +39-045-8126451; Fax: +39-045-8126455
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Hatzioannou A, Boumpas A, Papadopoulou M, Papafragkos I, Varveri A, Alissafi T, Verginis P. Regulatory T Cells in Autoimmunity and Cancer: A Duplicitous Lifestyle. Front Immunol 2021; 12:731947. [PMID: 34539668 PMCID: PMC8446642 DOI: 10.3389/fimmu.2021.731947] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 08/18/2021] [Indexed: 01/08/2023] Open
Abstract
Regulatory T (Treg) cells, possess a strategic role in the maintenance of immune homeostasis, and their function has been closely linked to development of diverse pathologies including autoimmunity and cancer. Comprehensive studies in various disease contexts revealed an increased plasticity as a characteristic of Treg cells. Although Treg cell plasticity comes in various flavors, the major categories enclose the loss of Foxp3 expression, which is the master regulator of Treg cell lineage, giving rise to “ex-Treg” cells and the “fragile” Treg cells in which FOXP3 expression is retained but accompanied by the engagement of an inflammatory program and attenuation of the suppressive activity. Treg cell plasticity possess a tremendous therapeutic potential either by inducing Treg cell de-stabilization to promote anti-tumor immunity, or re-enforcing Treg cell stability to attenuate chronic inflammation. Herein, we review the literature on the Treg cell plasticity with lessons learned in autoimmunity and cancer and discuss challenges and open questions with potential therapeutic implications.
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Affiliation(s)
- Aikaterini Hatzioannou
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Athina Boumpas
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Miranta Papadopoulou
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Iosif Papafragkos
- Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece.,Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
| | - Athina Varveri
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Themis Alissafi
- Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Panayotis Verginis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.,Center of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology - Hellas (FORTH), Heraklion, Greece.,Laboratory of Immune Regulation and Tolerance, Division of Basic Sciences, Medical School, University of Crete, Heraklion, Greece
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