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Perfilyeva YV, Kali A, Aben DS, Abdusattarova YR, Lushova AV, Ostapchuk YO, Tleulieva R, Perfilyeva AV, Sharipov KO, Davlyatshin TI, Abdolla N. Effect of calcitriol on myeloid-derived suppressor cells in physiological aging. J Steroid Biochem Mol Biol 2025; 251:106768. [PMID: 40316223 DOI: 10.1016/j.jsbmb.2025.106768] [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: 01/27/2025] [Revised: 03/17/2025] [Accepted: 04/29/2025] [Indexed: 05/04/2025]
Abstract
The active hormonal form of vitamin D, 1,25(OH)2D, regulates many components of the immune system and previous research shows that 1,25(OH)2D reduces the number and suppressive activity of MDSCs in tumors. This study aimed to evaluate the effects of calcitriol treatment on MDSCs in aged mice. We showed that aged BALB/c and CD1 mice exhibited increased levels of CD11b+Gr1+ cells in both the spleen and bone marrow compared to young mice. These cells displayed a less mature phenotype marked by reduced F4/80 expression and demonstrated robust T cell suppressive activity, as evidenced by their ability to inhibit the production of IFNγ and TNFα. Treatment of aged mice with calcitriol, administered twice weekly at a dose equivalent to 1 µg/kg for 4 weeks, significantly increased the population of CD11b+Gr1+ cells in the spleen, but not in the bone marrow of the animals, and promoted their differentiation into a more mature phenotype characterized by elevated F4/80 expression. In addition, calcitriol-treated aged mice exhibited significantly improved T cell responses, as indicated by increased IFNγ production upon specific antigen stimulation compared to the control group of mice. In vitro, calcitriol treatment of bone marrow-derived MDSCs similarly enhanced F4/80 expression without altering other markers such as CD11b, CD11c, or MHCII, and led to reduced expression of reactive oxygen species by these cells. Our study highlights the consistency of MDSC expansion across inbred and outbred mouse strains and supports the immunomodulatory role of calcitriol in promoting MDSC maturation and alleviating immune suppression in aging.
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Affiliation(s)
- Yuliya V Perfilyeva
- M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan; Almaty Branch of the National Center for Biotechnology, Central Reference Laboratory, 14 Zhahanger St., Almaty 050054, Kazakhstan
| | - Aikyn Kali
- M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan
| | - Diana S Aben
- M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan
| | - Yulduz R Abdusattarova
- M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan
| | - Anzhelika V Lushova
- M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan; Almaty Branch of the National Center for Biotechnology, Central Reference Laboratory, 14 Zhahanger St., Almaty 050054, Kazakhstan; Al-Farabi Kazakh National University, 71 Al-Farabi Avenue, Almaty 050040, Kazakhstan
| | - Yekaterina O Ostapchuk
- M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan; Almaty Branch of the National Center for Biotechnology, Central Reference Laboratory, 14 Zhahanger St., Almaty 050054, Kazakhstan
| | - Raikhan Tleulieva
- M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan
| | | | - Kamalidin O Sharipov
- M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan
| | - Timur I Davlyatshin
- Clinical diagnostic laboratory 'Omikron 3D', 24 Amanzhol St., Almaty 050052, Kazakhstan
| | - Nurshat Abdolla
- M.A. Aitkhozhin Institute of Molecular Biology and Biochemistry, 86 Dosmukhamedov St., Almaty 050012, Kazakhstan; Almaty Branch of the National Center for Biotechnology, Central Reference Laboratory, 14 Zhahanger St., Almaty 050054, Kazakhstan.
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2
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Li S, Zhang J, Wei W, Zhang Z, Huang W, Xia L. The important role of myeloid-derived suppressor cells: From hepatitis to liver cancer. Biochim Biophys Acta Rev Cancer 2025; 1880:189329. [PMID: 40262654 DOI: 10.1016/j.bbcan.2025.189329] [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: 09/26/2024] [Revised: 04/15/2025] [Accepted: 04/15/2025] [Indexed: 04/24/2025]
Abstract
Liver homeostasis is coordinated by crosstalk between resident and infiltrating inflammatory cells. Liver disease creates a dynamic inflammatory microenvironment characterized by aberrant metabolism and continuous hepatic regeneration, making it an important risk factor for hepatocellular carcinoma (HCC) as well as liver failure. Recent studies have revealed a critical heterogeneous population of myeloid-derived suppressor cells (MDSCs), which influence liver disease progression and malignancy by dynamically regulating the immune microenvironment. MDSCs play an important role in preventing excessive immune responses in the liver. However, MDSCs are also associated with the promotion of liver injury and liver cancer progression. The plasticity of MDSCs in liver disease is a unique challenge for therapeutic intervention strategies and requires a deeper understanding of the underlying mechanisms. Here, we review the role of MDSCs in the establishment and progression of liver disease and highlight the evidence for MDSCs as a priority target for current and future therapeutic strategies. We explore the fate of MDSCs from hepatitis to liver cancer, providing recent insights into potential targets for clinical intervention.
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Affiliation(s)
- Siwen Li
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Jiaqian Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wang Wei
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhicheng Zhang
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
| | - Wenjie Huang
- Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Clinical Medicine Research Center for Hepatic Surgery of Hubei Province, Key Laboratory of Organ Transplantation, Ministry of Education and Ministry of Public Health, Wuhan, Hubei 430030, China.
| | - Limin Xia
- Department of Gastroenterology, Institute of Liver and Gastrointestinal Diseases, Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
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3
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Wang W, Cao C, Pandian VD, Ye H, Chen H, Zhang L. Mac-1 regulates disease stage-specific immunosuppression via the nitric oxide pathway in autoimmune disease. SCIENCE ADVANCES 2025; 11:eads3728. [PMID: 40344054 PMCID: PMC12063669 DOI: 10.1126/sciadv.ads3728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/11/2024] [Accepted: 04/03/2025] [Indexed: 05/11/2025]
Abstract
Integrin Mac-1 plays a critical role in the development of multiple sclerosis (MS); however, the underlying mechanism is not fully understood. Here, we developed a myeloid-specific Mac-1-deficient mouse. Using an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we report that Mac-1 on myeloid cells is key to disease development. Our data reveal that myeloid-specific Mac-1 significantly increases EAE severity and hinders disease regression. Loss of Mac-1 increases Gr-1+ cells in peripheral tissues and the CNS and preferably accelerates the transition of Ly6Chi monocytes from a pro-inflammatory to an immunosuppressive phenotype in a disease stage-dependent manner. Mechanistically, our results demonstrate that Mac-1 suppresses interferon-γ production and prevents monocytes from acquiring immunosuppressive functions by reducing the expression of iNOS, IDO, and CD84. Administration of a NOS-specific inhibitor in Mac-1-deficient EAE mice abolishes disease regression. These insights could help develop Mac-1-targeting strategies for better treatment of MS.
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MESH Headings
- Animals
- Mice
- Encephalomyelitis, Autoimmune, Experimental/immunology
- Encephalomyelitis, Autoimmune, Experimental/metabolism
- Encephalomyelitis, Autoimmune, Experimental/pathology
- Encephalomyelitis, Autoimmune, Experimental/genetics
- Nitric Oxide/metabolism
- Macrophage-1 Antigen/metabolism
- Macrophage-1 Antigen/genetics
- Disease Models, Animal
- Mice, Knockout
- Multiple Sclerosis/immunology
- Multiple Sclerosis/metabolism
- Multiple Sclerosis/pathology
- Signal Transduction
- Monocytes/metabolism
- Monocytes/immunology
- Mice, Inbred C57BL
- Immune Tolerance
- Female
- Autoimmune Diseases/metabolism
- Autoimmune Diseases/immunology
- Autoimmune Diseases/pathology
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Affiliation(s)
- Wei Wang
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Chunzhang Cao
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Vishnuprabu Durairaj Pandian
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Haofeng Ye
- Johns Hopkins Advanced Academic Programs, Johns Hopkins University of Arts and Sciences, Baltimore, MD, USA
| | - Hongxia Chen
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
| | - Li Zhang
- Department of Physiology, Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Baltimore, MD, USA
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Zhong H, Zhou S, Yin S, Qiu Y, Liu B, Yu H. Tumor microenvironment as niche constructed by cancer stem cells: Breaking the ecosystem to combat cancer. J Adv Res 2025; 71:279-296. [PMID: 38866179 DOI: 10.1016/j.jare.2024.06.014] [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: 04/08/2024] [Revised: 05/27/2024] [Accepted: 06/09/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) are a distinct subpopulation of cancer cells with the capacity to constantly self-renew and differentiate, and they are the main driver in the progression of cancer resistance and relapse. The tumor microenvironment (TME) constructed by CSCs is the "soil" adapted to tumor growth, helping CSCs evade immune killing, enhance their chemical resistance, and promote cancer progression. AIM OF REVIEW We aim to elaborate the tight connection between CSCs and immunosuppressive components of the TME. We attempt to summarize and provide a therapeutic strategy to eradicate CSCs based on the destruction of the tumor ecological niche. KEY SCIENTIFIC CONCEPTS OF REVIEW This review is focused on three main key concepts. First, we highlight that CSCs recruit and transform normal cells to construct the TME, which further provides ecological niche support for CSCs. Second, we describe the main characteristics of the immunosuppressive components of the TME, targeting strategies and summarize the progress of corresponding drugs in clinical trials. Third, we explore the multilevel insights of the TME to serve as an ecological niche for CSCs.
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Affiliation(s)
- Hao Zhong
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, China
| | - Shiyue Zhou
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, China
| | - Shuangshuang Yin
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, China
| | - Yuling Qiu
- School of Pharmacy, Tianjin Medical University, Tianjin, China.
| | - Bo Liu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, China.
| | - Haiyang Yu
- State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China; Haihe Laboratory of Modern Chinese Medicine, Tianjin, China.
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5
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Feng Z, Wang L, Li Y, Wei Y, Zhou Y, Wang S, Zhang X, Jiang C, Liao X, Kang Y, Xiao F, Zhang W. CD47-amyloid-β-CD74 signaling triggers adaptive immunosuppression in sepsis. EMBO Rep 2025; 26:2683-2714. [PMID: 40185975 PMCID: PMC12116991 DOI: 10.1038/s44319-025-00442-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 03/18/2025] [Accepted: 03/26/2025] [Indexed: 04/07/2025] Open
Abstract
Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. However, how this dysregulation occurs remains to be elucidated. In this study, we use single-cell RNA sequencing (scRNA-seq) and conventional RNA-seq to analyze the immune landscape of sepsis and observe that adaptive immunity is acutely and strongly suppressed. This systemic immunosuppression occurs not only in the peripheral blood but also in all other immune compartments, including the spleen, lymph nodes, and bone marrow. Clinical data show that these adaptive immunity-related genes may have the potential to be used to distinguish patients with sepsis from those with common infections. CD47 is found to play a pivotal role in this immunosuppression by inducing the production of amyloid-β (Aβ), which interacts with CD74 on B cells, leading to B-cell suppression and subsequent adaptive immunosuppression. Blocking CD47-Aβ signaling significantly reduces organ injury and improves the survival rate of septic mice by restoring phagocytic cell functions and alleviating B-cell suppression and adaptive immunosuppression.
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Affiliation(s)
- Zhongxue Feng
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lijun Wang
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yang Li
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yonggang Wei
- Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yueyue Zhou
- Frontier Medical Center, Xin Chuan Road, Zhong He Street, 610212, Chengdu, Sichuan, China
| | - Siying Wang
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaoqi Zhang
- Department of Orthodontics, State Key laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Chunling Jiang
- Department of Anesthesiology, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China
| | - Xuelian Liao
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yan Kang
- Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Fei Xiao
- Department of Intensive Care Unit of Gynecology and Obstetrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Wei Zhang
- Institute of Critical Care Medicine, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
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Guimarães-DE-Oliveira JC, Diniz-Lima I, Ferreira-Dos-Santos IM, Silva-Junior EBDA, Covre LP, Freire-DE-Lima M, Fonseca LMDA, Morrot A, Freire-DE-Lima L, Mendonça-Previato L, Previato JO, Guedes HLDEM, Decote-Ricardo D, Freire-DE-Lima CG. Recruitment of Polymorphonuclear Myeloid-Derived Suppressor Cells During Cryptococcus neoformans Infection. AN ACAD BRAS CIENC 2025; 97:e20240985. [PMID: 40243766 DOI: 10.1590/0001-3765202520240985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 12/02/2024] [Indexed: 04/18/2025] Open
Abstract
Cryptococcosis is a disease originating in the lungs, often seen in immunosuppressed patients. In severe cases, it can lead to meningoencephalitis and can be fatal. Biochemical studies have shown that the capsule of Cryptococcus neoformans is predominantly composed of glucuronoxylomannan (GXM), with glucuronoxylomannogalactan (GXMGal) present in smaller amounts. These polysaccharides have different effects on the immune system, with GXM mainly having anti-inflammatory properties, while GXMGal is more pro-inflammatory. Myeloid-derived suppressor cells (MDSCs) are a diverse group of immature myeloid cells, including progenitor cells and precursors of macrophages, granulocytes, and dendritic cells at different stages of development. MDSCs are known to suppress immune responses in various diseases, including bacterial and fungal infections, through mechanisms such as the inhibition of T cell proliferation. In this study, we show that infection with either B3501 or CAP67 strains results in the accumulation of granulocytic MDSC precursors in bronchoalveolar cavities. The MDSCs recruited by the B3501 strain suppress T cell proliferation, while those recruited by the CAP67 strain do not. Furthermore, we observed the expression of PD-L1 on these MDSCs, suggesting a potential mechanism of immunosuppression during infection. These findings reveal how the polysaccharides of C. neoformans might weaken the host's immune defense.
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Affiliation(s)
- Joyce C Guimarães-DE-Oliveira
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Israel Diniz-Lima
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Idália M Ferreira-Dos-Santos
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Elias B DA Silva-Junior
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Luciana P Covre
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
- Universidade Federal do Espírito Santo, Núcleo de Doenças Infecciosas, Avenida Marechal Campos, 1468, Bonfim, 29047-105 Vitória, ES, Brazil
| | - Matheus Freire-DE-Lima
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Leonardo M DA Fonseca
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
- Universidade Castelo Branco, Curso de Medicina, Avenida de Santa Cruz, 1631, 21710-255 Rio de Janeiro, RJ, Brazil
| | - Alexandre Morrot
- Instituto Oswaldo Cruz (FIOCRUZ), Avenida Brasil, 4365, Manguinhos, 21045-900 Rio de Janeiro, RJ, Brazil
- Universidade Federal do Rio de Janeiro, Faculdade de Medicina, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Leonardo Freire-DE-Lima
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Lucia Mendonça-Previato
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Jose O Previato
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Herbert L DE Matos Guedes
- Instituto Oswaldo Cruz (FIOCRUZ), Avenida Brasil, 4365, Manguinhos, 21045-900 Rio de Janeiro, RJ, Brazil
- Universidade Federal do Rio de Janeiro, Instituto de Microbiologia Professor Paulo de Goes, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
| | - Debora Decote-Ricardo
- Universidade Federal Rural do Rio de Janeiro, Instituto de Veterinária, BR 465, Km 07, 23890-000 Seropédica, RJ, Brazil
| | - Celio Geraldo Freire-DE-Lima
- Universidade Federal do Rio de Janeiro, Instituto de Biofísica Carlos Chagas Filho, Avenida Carlos Chagas Filho, 373, 21944-970 Rio de Janeiro, RJ, Brazil
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Zhu Y, Cao S. Unraveling the Complexities of Myeloid-Derived Suppressor Cells in Inflammatory Bowel Disease. Int J Mol Sci 2025; 26:3291. [PMID: 40244120 PMCID: PMC11989781 DOI: 10.3390/ijms26073291] [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: 03/03/2025] [Revised: 03/25/2025] [Accepted: 03/28/2025] [Indexed: 04/18/2025] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) regulate immune responses in many pathological conditions, one of which is inflammatory bowel disease (IBD), an incurable chronic disorder of the digestive tract and beyond. The pathophysiology of IBD remains unclear, likely involving aberrant innate and adaptive immunity. Studies have reported altered population of MDSCs in patients with IBD. However, their distribution varies among patients and different preclinical models of IBD. The expansion and activation of MDSCs are likely driven by various stimuli during intestinal inflammation, but the in-depth mechanisms remain poorly understood. The role of MDSCs in the pathogenesis of IBD appears to be paradoxical. In addition to intestinal inflammation, suppressive MDSCs may promote colitis-to-colon cancer transition. In this Review, we summarize recent progresses on the features, activation, and roles of MDSCs in the development of IBD and IBD-associated colon cancer.
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Affiliation(s)
| | - Siyan Cao
- Division of Gastroenterology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA;
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8
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Liu X, Kang X, Kang H, Yan H. The immunosuppressive role of MDSCs in HCC: mechanisms and therapeutic opportunities. Cell Commun Signal 2025; 23:155. [PMID: 40148954 PMCID: PMC11951757 DOI: 10.1186/s12964-025-02170-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 03/23/2025] [Indexed: 03/29/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is a prevalent malignancy with a significant global burden. Despite substantial advancements in HCC treatment in recent years, therapeutic efficacy remains constrained by immune evasion mechanisms within the tumor microenvironment (TME). Myeloid-derived suppressor cells (MDSCs), as critical immunosuppressive elements of the TME, have garnered increasing attention for their role in tumor progression. Recent studies emphasize their central involvement in promoting immune evasion, tolerance, and immunosuppression in HCC. This review examines the contributions of MDSCs to HCC pathogenesis, elucidates their underlying mechanisms, and discusses ongoing clinical trials, emphasizing their potential as therapeutic targets for improving clinical outcomes.
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Affiliation(s)
- Xiling Liu
- School of Public Health, Hebei Medical University, Shijiazhuang, 050017, China
- Hebei Key Laboratory of Immune Mechanism of Major Infectious Diseases and New Technology of Diagnosis and Treatment, The Fifth Hospital of Shijiazhuang, Shijiazhuang, 050021, China
| | - Xichun Kang
- Beijing Fangshan District Center for Disease Control and Prevention, Beijing, 102488, China
| | - Haiyan Kang
- Hebei Key Laboratory of Immune Mechanism of Major Infectious Diseases and New Technology of Diagnosis and Treatment, The Fifth Hospital of Shijiazhuang, Shijiazhuang, 050021, China
- Department of the Sixth Infection, The Fifth Hospital of Shijiazhuang, Shijiazhuang, 050021, China
| | - Huimin Yan
- School of Public Health, Hebei Medical University, Shijiazhuang, 050017, China.
- Hebei Key Laboratory of Immune Mechanism of Major Infectious Diseases and New Technology of Diagnosis and Treatment, The Fifth Hospital of Shijiazhuang, Shijiazhuang, 050021, China.
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9
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Vermeersch G, Gouwy M, Proost P, Struyf S, Devos T. Neutrophils in BCR::ABL1 negative MPN: Contributors or bystanders of fibrosis? Blood Rev 2025:101285. [PMID: 40133166 DOI: 10.1016/j.blre.2025.101285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 02/20/2025] [Accepted: 03/20/2025] [Indexed: 03/27/2025]
Abstract
BCR::ABL1 negative myeloproliferative neoplasms (MPNs) are a heterogenous group of disorders characterized by clonal proliferation of hematopoietic stem and progenitor cells (HSPCs) within the bone marrow. Although the identification of somatic key driver mutations significantly increased both understanding and diagnostic accuracy of MPNs, many questions about the exact pathophysiology remain unanswered. Increased neutrophil count at diagnosis is a well-recognized predictor of worse disease evolution and survival, nonetheless the exact role of neutrophilic granulocytes within MPN pathophysiology is almost unexplored. As the majority of these cells are residing within the bone marrow, they represent a non-negligible entity within the bone marrow niche and its homeostasis. This review describes how neutrophils might contribute to the development of the inflammatory bone marrow niche, and hereby also fibrosis, associated with MPNs. The versatile functions and effects in different contexts emphasize the necessity for future research oriented to bone marrow in addition to peripheral blood.
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Affiliation(s)
- Gaël Vermeersch
- Department of Hematology, University Hospitals Leuven, 3000 Leuven, Belgium; Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium.
| | - Mieke Gouwy
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium
| | - Paul Proost
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium
| | - Timothy Devos
- Department of Hematology, University Hospitals Leuven, 3000 Leuven, Belgium; Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, 3000 Leuven, Belgium
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10
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Marwedel B, De May H, Anderson L, Medina LY, Kennedy E, Flores E, O'Rourke J, Olewine M, Lagutina I, Fitzpatrick L, Shultz F, Kusewitt DF, Bartee E, Adams S, Noureddine A, Serda RE. TLR Agonist Nano Immune Therapy Clears Peritoneal and Systemic Ovarian Cancer. Adv Healthc Mater 2025; 14:e2402966. [PMID: 39478634 PMCID: PMC11912102 DOI: 10.1002/adhm.202402966] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 10/18/2024] [Indexed: 03/18/2025]
Abstract
Intraperitoneal (IP) administration of immunogenic mesoporous silica nanoparticles (iMSN) in a mouse model of metastatic ovarian cancer promotes the development of tumor-specific CD8+ T cells and protective immunity. IP delivery of iMSN functionalized with the Toll-like receptor (TLR) agonists polyethyleneimine (PEI), CpG oligonucleotide, and monophosphoryl lipid A (MPLA) stimulated rapid uptake by all peritoneal myeloid subsets. Myeloid cells quickly transported iMSN to milky spots and fat-associated lymphoid clusters (FALCs) present in tumor-burdened adipose tissues, leading to a reduction in suppressive T cells and an increase in activated memory T cells. Two doses of iMSN cleared or reduced ovarian and colorectal cancer and protected against future tumor engraftment. In contrast, subcutaneous (SC) and intravenous (IV) delivery of iMSN were without therapeutic effect in mice with peritoneal metastases, supporting the need for activation of regional immune cells. Remarkably, intraperitoneal delivery of iMSN cleared subcutaneously implanted ovarian cancer, supporting homing of antigen specific T cells to extraperitoneal tumor sites.
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Affiliation(s)
- Ben Marwedel
- Department of Internal MedicineUniversity of New Mexico Health Science CenterAlbuquerqueNM87131USA
| | - Henning De May
- Department of Obstetrics & GynecologyUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNM87131USA
| | - Lauren Anderson
- Department of Internal MedicineUniversity of New Mexico Health Science CenterAlbuquerqueNM87131USA
| | - Lorél Y. Medina
- Department of Internal MedicineUniversity of New Mexico Health Science CenterAlbuquerqueNM87131USA
| | - Ellie Kennedy
- Department of Internal MedicineUniversity of New Mexico Health Science CenterAlbuquerqueNM87131USA
| | - Erica Flores
- Department of Internal MedicineUniversity of New Mexico Health Science CenterAlbuquerqueNM87131USA
| | | | - Marian Olewine
- Chemical and Biological EngineeringUniversity of New MexicoAlbuquerqueNM87131USA
| | - Irina Lagutina
- Animal Models Shared ResourceUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNM87131USA
| | - Lillian Fitzpatrick
- Animal Models Shared ResourceUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNM87131USA
| | - Fred Shultz
- Human Tissue Repository & Tissue AnalysisUniversity of New Mexico Comprehensive Cancer CenterUniversity of New MexicoAlbuquerqueNM87131USA
- Department of PathologyUniversity of New Mexico Health Science CenterAlbuquerqueNMUSA
| | - Donna F. Kusewitt
- Human Tissue Repository & Tissue AnalysisUniversity of New Mexico Comprehensive Cancer CenterUniversity of New MexicoAlbuquerqueNM87131USA
- Department of PathologyUniversity of New Mexico Health Science CenterAlbuquerqueNMUSA
| | - Eric Bartee
- Department of Internal MedicineUniversity of New Mexico Health Science CenterAlbuquerqueNM87131USA
| | - Sarah Adams
- Department of Obstetrics & GynecologyUniversity of New Mexico Comprehensive Cancer CenterAlbuquerqueNM87131USA
| | - Achraf Noureddine
- Chemical and Biological EngineeringUniversity of New MexicoAlbuquerqueNM87131USA
| | - Rita E. Serda
- Department of Internal MedicineUniversity of New Mexico Health Science CenterAlbuquerqueNM87131USA
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11
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Brauner J, Wilt A, Montgomery CP, Bline K. The role of myeloid-derived suppressor cells in children. Front Pediatr 2025; 13:1525143. [PMID: 40083432 PMCID: PMC11903755 DOI: 10.3389/fped.2025.1525143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 02/05/2025] [Indexed: 03/16/2025] Open
Abstract
Myeloid-derived suppressor cells (MDSC) were first recognized over twenty years ago as a key immunomodulatory cell population. Since their initial identification, a growing body of literature points to the importance of MDSC as a heterogeneous, immunosuppressive cell population and as a therapeutic target in adults with cancer. MDSC are potent suppressors of T cells and Natural Killer (NK) cells and can be helpful or harmful to the host depending on the pathophysiology. For example, MDSC are beneficial in pregnancy and prevent spontaneous abortion by promoting maternal-fetal tolerance. Increased MDSC are also associated with improved outcomes in patients with graft vs. host disease by decreasing T cell-driven inflammation. However, MDSC can also be harmful and are known to be pathologic in adults with cancer and chronic infections by promoting tumor escape and impairing pathogen clearance, respectively. Despite the widespread recognition of the importance of MDSC and their immune suppression effects in adults, much less is known regarding the role of MDSC in children. Research investigating MDSC in children lags significantly behind adult studies. In fact, while over 5,000 publications on PubMed discuss MDSC in immune regulation, fewer than 50 of these publications focus specifically on their role in children. This review aims to summarize the existing literature on the role of MDSC in children and identify important directions for future research, including targeting these cells in the pediatric population to improve clinical outcomes.
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Affiliation(s)
- Jordan Brauner
- Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
| | - Anna Wilt
- University of Minnesota Health Sciences, University of Minnesota Medical Center, Minneapolis, MN, United States
| | | | - Katherine Bline
- Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
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12
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Karadima E, Chavakis T, Alexaki VI. Arginine metabolism in myeloid cells in health and disease. Semin Immunopathol 2025; 47:11. [PMID: 39863828 PMCID: PMC11762783 DOI: 10.1007/s00281-025-01038-9] [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: 04/22/2024] [Accepted: 01/15/2025] [Indexed: 01/27/2025]
Abstract
Metabolic flexibility is key for the function of myeloid cells. Arginine metabolism is integral to the regulation of myeloid cell responses. Nitric oxide (NO) production from arginine is vital for the antimicrobial and pro-inflammatory responses. Conversely, the arginase 1 (ARG1)-dependent switch between the branch of NO production and polyamine synthesis downregulates inflammation and promotes recovery of tissue homeostasis. Creatine metabolism is key for energy supply and proline metabolism is required for collagen synthesis. Myeloid ARG1 also regulates extracellular arginine availability and T cell responses in parasitic diseases and cancer. Cancer, surgery, sepsis and persistent inflammation in chronic inflammatory diseases, such as neuroinflammatory diseases or arthritis, are associated with dysregulation of arginine metabolism in myeloid cells. Here, we review current knowledge on arginine metabolism in different myeloid cell types, such as macrophages, neutrophils, microglia, osteoclasts, tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs) and myeloid-derived suppressor cells (MDSCs). A deeper understanding of the function of arginine metabolism in myeloid cells will improve our knowledge on the pathology of several diseases and may set the platform for novel therapeutic applications.
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Affiliation(s)
- Eleftheria Karadima
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Triantafyllos Chavakis
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany
| | - Vasileia Ismini Alexaki
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.
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13
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He S, Zheng L, Qi C. Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and their targeting in cancer therapy. Mol Cancer 2025; 24:5. [PMID: 39780248 PMCID: PMC11707952 DOI: 10.1186/s12943-024-02208-3] [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: 09/26/2024] [Accepted: 12/24/2024] [Indexed: 01/11/2025] Open
Abstract
The advent of immunotherapy represents a significant breakthrough in cancer treatment, with immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 demonstrating remarkable therapeutic efficacy. However, patient responses to immunotherapy vary significantly, with immunosuppression within the tumor microenvironment (TME) being a critical factor influencing this variability. Immunosuppression plays a pivotal role in regulating cancer progression, metastasis, and reducing the success rates of immunotherapy. Myeloid-derived suppressor cells (MDSCs), due to their potent immunosuppressive capabilities, emerged as major negative regulators within the TME, facilitating tumor immune evasion by modulating various immune cells. In addition to their immunosuppressive functions, MDSCs also promote tumor growth and metastasis through non-immunological mechanisms, such as angiogenesis and the formation of pre-metastatic niches. Consequently, MDSCs in the TME are key regulators of cancer immune responses and potential therapeutic targets in cancer treatment. This review describes the origins and phenotypes of MDSCs, their biological roles in tumor progression, and regulatory mechanisms, with a focus on current therapeutic approaches targeting tumor-associated MDSCs. Furthermore, the synergistic effects of targeting MDSCs in combination with immunotherapy are explored, aiming to provide new insights and directions for cancer therapy.
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Affiliation(s)
- Shuyan He
- Department of Tumor Center, The Affiliated Jiangyin Hospital of Nantong University, Jiangyin, Jiangsu, China
| | - Lu Zheng
- Clinical Medical Research Center, The Third Affiliated Hospital of Soochow University, Changzhou, 213003, China
| | - Chunjian Qi
- Laboratory of Oncology, Basic Research Center, The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou, Jiangsu, China.
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14
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Rajkumari S, Singh J, Agrawal U, Agrawal S. Myeloid-derived suppressor cells in cancer: Current knowledge and future perspectives. Int Immunopharmacol 2024; 142:112949. [PMID: 39236460 DOI: 10.1016/j.intimp.2024.112949] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 08/12/2024] [Accepted: 08/13/2024] [Indexed: 09/07/2024]
Abstract
MDSCs (myeloid-derived suppressor cells) are crucial for immune system evasion in cancer. They accumulate in peripheral blood and tumor microenvironment, suppressing immune cells like T-cells, natural killer cells and dendritic cells. They promote tumor angiogenesis and metastasis by secreting cytokines and growth factors and contribute to a tumor-promoting environment. The accumulation of MDSCs in cancer patients has been linked to poor prognosis and resistance to various cancer therapies. Targeting MDSCs and their immunosuppressive mechanisms may improve treatment outcomes and enhance immune surveillance by developing drugs that inhibit MDSC function, by preventing their accumulation and by disrupting the tumor-promoting environment. This review presents a detailed overview of the MDSC research in cancer with regulation of their development and function. The relevance of MDSC as a prognostic and predictive biomarker in different types of cancers, along with recent advancements on the therapeutic approaches to target MDSCs are discussed in detail.
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Affiliation(s)
- Sunanda Rajkumari
- ICMR National Institute of Medical Statistics, Ansari Nagar, New Delhi 110029, India
| | - Jaspreet Singh
- ICMR National Institute of Pathology, Safdarjung Hospital Campus, Ansari Nagar, New Delhi 110029, India
| | - Usha Agrawal
- Asian Institute of Public Health University (AIPH) University, 1001 Haridamada, Jatani, Near IIT Bhubaneswar, Bhubaneswar 751002, India
| | - Sandeep Agrawal
- Discovery Research Division, Indian Council of Medical Research, Ansari Nagar, New Delhi 110029, India.
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15
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Xu Q, Liu H, Ye Y, Wuren T, Ge RL. Effects of different hypoxia exposure on myeloid-derived suppressor cells in mice. Exp Mol Pathol 2024; 140:104932. [PMID: 39305701 DOI: 10.1016/j.yexmp.2024.104932] [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: 12/27/2023] [Revised: 08/20/2024] [Accepted: 09/16/2024] [Indexed: 12/20/2024]
Abstract
For many people living at high altitudes for long or short periods of time, hypoxia is a challenge affecting many aspects of the body, including the immune system. Recently, myeloid-derived suppressor cells (MDSCs) have emerged as an immune cell population that plays an important role in several pathological conditions. However, to the best of our knowledge, there are no data regarding the behavior of MDSCs under hypoxic conditions. Therefore, the aim of this study is to investigate the monocytic type (M)- and polymorphonuclear type (PMN)-MDSC ratios in different hypoxic conditions to reveal the relationship between MDSCs and high-altitude hypoxia, as well as to determine whether MDSCs are involved in the regulation of the immune balance under hypoxic conditions as immunosuppressive factors. For the first time, we showed that MDSC abundance varies under different lengths of hypoxic exposure. We found that acute normobaric hypoxia led to an initial increase in the number of M-MDSCs, which decreased within 30 d. Both M- and PMN-MDSC ratios initially decreased under hypobaric hypoxia conditions within 30 d, but after 6 months in the real high altitude environment, M-MDSC ratio increased significantly. In summary, our data suggest that different hypoxic conditions influence MDSCs in mice, thereby contributing to a better understanding of the process of hypoxia adaptation and the occurrence and development of high-altitude disease.
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Affiliation(s)
- Qiying Xu
- Key Laboratory for Application of High-Altitude Medicine, Qinghai University, Xining, China; Research Center for High Altitude Medicine, Qinghai University, Xining, China; Department of Gynecology, Affiliated Hospital of Qinghai University, Xining, China
| | - Huifang Liu
- Key Laboratory for Application of High-Altitude Medicine, Qinghai University, Xining, China; Research Center for High Altitude Medicine, Qinghai University, Xining, China; Department of Gynecology, Affiliated Hospital of Qinghai University, Xining, China
| | - Yi Ye
- Key Laboratory for Application of High-Altitude Medicine, Qinghai University, Xining, China; Research Center for High Altitude Medicine, Qinghai University, Xining, China
| | - Tana Wuren
- Key Laboratory for Application of High-Altitude Medicine, Qinghai University, Xining, China; Research Center for High Altitude Medicine, Qinghai University, Xining, China.
| | - Ri-Li Ge
- Key Laboratory for Application of High-Altitude Medicine, Qinghai University, Xining, China; Research Center for High Altitude Medicine, Qinghai University, Xining, China.
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16
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Song C, Tong T, Dai B, Zhu Y, Chen E, Zhang M, Zhang W. Osteoimmunology in bone malignancies: a symphony with evil. JOURNAL OF THE NATIONAL CANCER CENTER 2024; 4:354-368. [PMID: 39735445 PMCID: PMC11674455 DOI: 10.1016/j.jncc.2024.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 09/11/2024] [Accepted: 09/11/2024] [Indexed: 12/31/2024] Open
Abstract
Bone marrow is pivotal for normal hematopoiesis and immune responses, yet it is often compromised by malignancies. The bone microenvironment (BME), composed of bone and immune cells, maintains skeletal integrity and blood production. The emergence of primary or metastatic tumors in the skeletal system results in severe complications and contributes significantly to cancer-related mortality. These tumors set off a series of interactions among cancer, bone, and immune cells, and disrupt the BME locally or distantly. However, the drivers, participants, and underlying molecules of these interactions are not fully understood. This review explores the crosstalk between bone metabolism and immune responses, synthesizing current knowledge on the intersection of cancer and osteoimmune biology. It outlines how bone marrow immune cells can either facilitate or hinder tumor progression by interacting with bone cells and pinpoints the molecules responsible for immunosuppression within bone tumors. Moreover, it discusses how primary tumors remotely alter the BME, leading to systemic immune suppression in cancer patients. This knowledge provides critical rationales for emerging immunotherapies in the treatment of bone-related tumors. Taken together, by summarizing the intricate relationship between tumor cells and the BME, this review aims to deepen the understanding of the diversity, complexity, and dynamics at play during bone tumor progression. Ultimately, it highlights the potential of targeting bone-tumor interactions to correct aberrant immune functions, thereby inhibiting tumor growth and metastasis.
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Affiliation(s)
- Churui Song
- Department of Breast Surgery and Oncology, Cancer Institute, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Tie Tong
- Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Biqi Dai
- Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Yue Zhu
- Life Sciences Institute, Zhejiang University, Hangzhou, China
| | - Elina Chen
- College of Natural Sciences, University of Texas at Austin, 110 Inner Campus Drive, Austin, USA
| | - Min Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Weijie Zhang
- Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, and Department of Orthopaedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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17
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Wang J, He Y, Hu F, Hu C, Sun Y, Yang K, Yang S. Metabolic Reprogramming of Immune Cells in the Tumor Microenvironment. Int J Mol Sci 2024; 25:12223. [PMID: 39596288 PMCID: PMC11594648 DOI: 10.3390/ijms252212223] [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: 10/15/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Metabolic reprogramming of immune cells within the tumor microenvironment (TME) plays a pivotal role in shaping tumor progression and responses to therapy. The intricate interplay between tumor cells and immune cells within this ecosystem influences their metabolic landscapes, thereby modulating the immune evasion tactics employed by tumors and the efficacy of immunotherapeutic interventions. This review delves into the metabolic reprogramming that occurs in tumor cells and a spectrum of immune cells, including T cells, macrophages, dendritic cells, and myeloid-derived suppressor cells (MDSCs), within the TME. The metabolic shifts in these cell types span alterations in glucose, lipid, and amino acid metabolism. Such metabolic reconfigurations can profoundly influence immune cell function and the mechanisms by which tumors evade immune surveillance. Gaining a comprehensive understanding of the metabolic reprogramming of immune cells in the TME is essential for devising novel cancer therapeutic strategies. By targeting the metabolic states of immune cells, it is possible to augment their anti-tumor activities, presenting new opportunities for immunotherapeutic approaches. These strategies hold promise for enhancing treatment outcomes and circumventing the emergence of drug resistance.
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Affiliation(s)
| | | | | | | | | | - Kun Yang
- Department of Immunology, The Fourth Military Medical University, Xi’an 710032, China; (J.W.); (Y.H.); (F.H.); (C.H.); (Y.S.)
| | - Shuya Yang
- Department of Immunology, The Fourth Military Medical University, Xi’an 710032, China; (J.W.); (Y.H.); (F.H.); (C.H.); (Y.S.)
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18
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Wakabayashi H, Hattori N, Uzawa A, Ito M, Hasegawa H, Mimura N, Empitu M, Aizawa M, Kuwabara S, Asanuma K, Oda S. Tryptophan-immunoadsorption plasmapheresis regulates polymorphonuclear-myeloid-derived suppressor cells and pro-inflammatory cytokines. Ther Apher Dial 2024. [PMID: 39508126 DOI: 10.1111/1744-9987.14228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2024] [Revised: 10/20/2024] [Accepted: 10/25/2024] [Indexed: 11/08/2024]
Abstract
INTRODUCTION Immunoadsorption plasmapheresis (IA) has been reported to have immunoregulatory effects, in addition to the removal of autoantibodies. This study aimed to investigate the effects of IA on the proportion of myeloid-derived suppressor cells (MDSCs) that potentially suppress autoimmune responses and regulate immunity. METHODS The study included 21 patients with autoimmune neurological diseases and 8 healthy participants. We measured polymorphonuclear (PMN)-MDSCs (CD14-CD11b+CD33+) and inflammation-related mediators before and after a single session of tryptophan-IA. We also investigated whether an increase in PMN-MDSCs after initial IA was a predictor of clinical efficacy in nine patients with myasthenia gravis based on the Quantitative Myasthenia Gravis score. RESULTS For a total of 36 times of IA procedures, the number of PMN-MDSCs significantly increased after IA. Interleukin-10, monocyte chemoattractant protein-1 and macrophage inflammatory protein-1β levels showed significant increases after IA. Despite similar severity at admission, the Quantitative Myasthenia Gravis scores at discharge were significantly lower in the group in which IA increased PMN-MDSCs to a level of 20% of peripheral blood mononuclear cells or more. CONCLUSION Tryptophan-IA regulates PMN-MDSCs and pro-inflammatory cytokines, possibly leading to suppression of autoimmune responses and tissue damage in neuroimmunological disorders.
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Affiliation(s)
- Hanae Wakabayashi
- Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Noriyuki Hattori
- Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akiyuki Uzawa
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Michihiro Ito
- Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan
| | - Hiroko Hasegawa
- Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan
| | - Naoya Mimura
- Department of Transfusion Medicine and Cell Therapy, Chiba University Hospital, Chiba, Japan
| | - Maulana Empitu
- Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Masashi Aizawa
- Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Satoshi Kuwabara
- Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Katsuhiko Asanuma
- Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shigeto Oda
- Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
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19
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Le PM, Mattapallil MJ, Caspi RR, Stepp MA, Menko AS. Immunoregulatory Properties of Immune Cells that Associate with the Lens Capsule Surface during Acute and Resolution Phases of Experimental Autoimmune Uveitis. THE AMERICAN JOURNAL OF PATHOLOGY 2024; 194:2194-2211. [PMID: 39159867 PMCID: PMC11627221 DOI: 10.1016/j.ajpath.2024.07.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Revised: 06/07/2024] [Accepted: 07/31/2024] [Indexed: 08/21/2024]
Abstract
Inflammation in the eye is tightly regulated to prevent vision impairment and irreversible blindness. Emerging evidence shows that immune cells are specifically recruited to the lens capsule in response to autoimmune uveitis, yet the potential that they have a role in regulating this inflammatory disease remained unexplored. Here, an immunolocalization approach combined with high-resolution confocal microscopy was used to investigate whether the immune cells that become stably associated with the lens capsule in the eyes of C57BL/6J mice with experimental autoimmune uveitis (EAU) have an immunoregulatory phenotype. These studies revealed that during the acute phase of uveitis, at day 18 after disease induction, the immune cells specifically recruited to the lens capsule, such as regulatory T cells [forkhead box P3 (FoxP3)+CD4+] and M2 macrophages (CD68+ arginase 1+IL-10+), included those with putative anti-inflammatory, proresolution roles. The frequency of these lens capsule-associated immunomodulatory phenotypes increased at day 35 after induction, during the resolution phase of EAU inflammation. At this later stage of resolution, most of the macrophages expressed CD206, a mannose receptor responsible for removing inflammatory molecules, in addition to arginase 1 and IL-10. These results suggest a previously unknown role for the lens as a site for recruitment of immune cells whose role is to suppress inflammation, promote resolution, and maintain remission of EAU.
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Affiliation(s)
- Phuong M Le
- Department of Pathology and Genomic Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Mary J Mattapallil
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland
| | - Rachel R Caspi
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, Maryland
| | - Mary Ann Stepp
- Department of Anatomy and Cell Biology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia; Department of Ophthalmology, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia
| | - A Sue Menko
- Department of Pathology and Genomic Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; Department of Ophthalmology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
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Lu Y, Zheng J, Lin P, Lin Y, Zheng Y, Mai Z, Chen X, Xia T, Zhao X, Cui L. Tumor Microenvironment-Derived Exosomes: A Double-Edged Sword for Advanced T Cell-Based Immunotherapy. ACS NANO 2024; 18:27230-27260. [PMID: 39319751 DOI: 10.1021/acsnano.4c09190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2024]
Abstract
The tumor microenvironment (TME) plays a crucial role in cancer progression and immune evasion, partially mediated by the activity of the TME-derived exosomes. These extracellular vesicles are pivotal in shaping immune responses through the transfer of proteins, lipids, and nucleic acids between cells, facilitating a complex interplay that promotes tumor growth and metastasis. This review delves into the dual roles of exosomes in the TME, highlighting both their immunosuppressive functions and their emerging therapeutic potential. Exosomes can inhibit T cell function and promote tumor immune escape by carrying immune-modulatory molecules, such as PD-L1, yet they also hold promise for cancer therapy as vehicles for delivering tumor antigens and costimulatory signals. Additionally, the review discusses the intricate crosstalk mediated by exosomes among various cell types within the TME, influencing both cancer progression and responses to immunotherapies. Moreover, this highlights current challenges and future directions. Collectively, elucidating the detailed mechanisms by which TME-derived exosomes mediate T cell function offers a promising avenue for revolutionizing cancer treatment. Understanding these interactions allows for the development of targeted therapies that manipulate exosomal pathways to enhance the immune system's response to tumors.
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Affiliation(s)
- Ye Lu
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Jiarong Zheng
- Department of Dentistry, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, China
| | - Pei Lin
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Yunfan Lin
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Yucheng Zheng
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Zizhao Mai
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Xu Chen
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Tian Xia
- Division of NanoMedicine, Department of Medicine, University of California Los Angeles, Los Angeles, California 90095, United States
| | - Xinyuan Zhao
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, China
| | - Li Cui
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, Guangdong 510280, China
- School of Dentistry, University of California Los Angeles, Los Angeles, California 90095, United States
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21
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Fay M, Clavijo PE, Allen CT. Heterogeneous characterization of neutrophilic cells in head and neck cancers. Head Neck 2024; 46:2591-2599. [PMID: 38622975 PMCID: PMC11473716 DOI: 10.1002/hed.27774] [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: 12/08/2023] [Revised: 03/14/2024] [Accepted: 04/07/2024] [Indexed: 04/17/2024] Open
Abstract
BACKGROUND Neutrophilic cells are among the most abundant immune populations within the head and neck tumor microenvironment (TME) and harbor multiple mechanisms of immunosuppression. Despite these important features, neutrophilic cells may be underrepresented in contemporary studies that aim to comprehensively characterize the immune landscape of the TME due to discrepancies in tissue processing and analysis techniques. Here, we review the role of pathologically activated neutrophilic cells within the TME and pitfalls of various approaches used to study their frequency and function in clinical samples. METHODS The literature was identified by searching PubMed for "immune landscape" and "tumor immune microenvironment" in combination with keywords describing solid tumor malignancies. Key publications that assessed the immune composition of solid tumors derived from human specimens were included. The tumor and blood processing methodologies in each study were reviewed in depth and correlated with the reported abundance of neutrophilic cells. RESULTS Neutrophilic cells do not survive cryopreservation, and many studies fail to identify and study neutrophilic cell populations due to cryopreservation of clinical samples for practical reasons. Additional single-cell transcriptomic studies filter out neutrophilic cells due to low transcriptional counts. CONCLUSIONS This report can help readers critically interpret studies aiming to comprehensively study the immune TME that fail to identify and characterize neutrophilic cells.
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Affiliation(s)
- Magdalena Fay
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Paul E. Clavijo
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Clint T. Allen
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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22
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Chen B, Guo L, Wang L, Wu P, Zheng X, Tan C, Xie N, Sun X, Zhou M, Huang H, Hao N, Lei Y, Yan K, Wu D, Du Y. Leveraging cell death patterns to predict metastasis in prostate adenocarcinoma and targeting PTGDS for tumor suppression. Sci Rep 2024; 14:21680. [PMID: 39289451 PMCID: PMC11408614 DOI: 10.1038/s41598-024-72985-w] [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: 03/02/2024] [Accepted: 09/12/2024] [Indexed: 09/19/2024] Open
Abstract
Metastasis is the major cause of treatment failure in patients with prostate adenocarcinoma (PRAD). Diverse programmed cell death (PCD) patterns play an important role in tumor metastasis and hold promise as predictive indicators for PRAD metastasis. Using the LASSO Cox regression method, we developed PCD score (PCDS) based on differentially expressed genes (DEGs) associated with PCD. Clinical correlation, external validation, functional enrichment analysis, mutation landscape analysis, tumor immune environment analysis, and immunotherapy analysis were conducted. The role of Prostaglandin D2 Synthase (PTGDS) in PRAD was examined through in vitro experiments, single-cell, and Mendelian randomization (MR) analysis. PCDS is elevated in patients with higher Gleason scores, higher T stage, biochemical recurrence (BCR), and higher prostate-specific antigen (PSA) levels. Individuals with higher PCDS are prone to metastasis, metastasis after BCR, BCR, and castration resistance. Moreover, PRAD patients with low PCDS responded positively to immunotherapy. Random forest analysis and Mendelian randomization analysis identified PTGDS as the top gene associated with PRAD metastasis and in vitro experiments revealed that PTGDS was considerably downregulated in PRAD cells against normal prostate cells. Furthermore, the overexpression of PTGDS was found to suppress the migration, invasion, proliferationof DU145 and LNCaP cells. To sum up, PCDS may be a useful biomarker for forecasting the possibility of metastasis, recurrence, castration resistance, and the efficacy of immunotherapy in PRAD patients. Additionally, PTGDS was identified as a viable therapeutic target for the management of PRAD.
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Affiliation(s)
- Bohong Chen
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Li Guo
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Lihui Wang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi Province, China
| | - Peiqiang Wu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xinyu Zheng
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Congzhu Tan
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Na Xie
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Xinyue Sun
- Department of Neurology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Mingguo Zhou
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Haoxiang Huang
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China
| | - Na Hao
- Department of Breast Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 716000, Shaanxi Province, China
| | - Yangyang Lei
- Yan'an University, Yan'an, 710061, Shaanxi Province, China
| | - Kun Yan
- Department of Urology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China
| | - Dapeng Wu
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
- Department of Urology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an, 710061, Shaanxi Province, China.
| | - Yuefeng Du
- Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
- Department of Urology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, 277 Yanta Western Rd, Xi'an, 710061, Shaanxi Province, China.
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23
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Peng B, Luo Y, Xie S, Zhuang Q, Li J, Zhang P, Liu K, Zhang Y, Zhou C, Guo C, Zhou Z, Zhou J, Cai Y, Xia M, Cheng K, Ming Y. Proliferation of MDSCs may indicate a lower CD4+ T cell immune response in schistosomiasis japonica. Parasite 2024; 31:52. [PMID: 39212529 PMCID: PMC11363901 DOI: 10.1051/parasite/2024050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Accepted: 07/25/2024] [Indexed: 09/04/2024] Open
Abstract
BACKGROUND Schistosoma japonicum (S. japonicum) is the main species of Schistosoma prevalent in China. Myeloid-derived suppressor cells (MDSCs) are important immunoregulatory cells and generally expand in parasite infection, but there is little research relating to MDSCs in Schistosoma infection. METHODS Fifty-six S. japonicum-infected patients were included in this study. MDSCs and percentages and absolute cell numbers of lymphocyte subsets, including CD3+ T cells, CD4+ T cells, CD8+ T cells, B cells and natural killer (NK) cells were detected using flow cytometry. The degree of liver fibrosis was determined using color Doppler ultrasound. RESULTS Patients infected with S. japonicum had a much higher percentage of MDSCs among peripheral blood mononuclear cells (PBMCs) than the healthy control. Regarding subpopulations of MDSCs, the percentage of granulocytic myeloid-derived suppressor cells (G-MDSCs) was clearly increased. Correlation analysis showed that the absolute cell counts of T-cell subsets correlated negatively with the percentages of MDSCs and G-MDSCs among PBMCs. The percentage of G-MDSCs in PBMCs was also significantly higher in patients with liver fibrosis diagnosed by color doppler ultrasound (grade > 0), and the percentage of G-MDSCs in PBMCs and liver fibrosis grading based on ultrasound showed a positive correlation. CONCLUSION S. japonicum infection contributes to an increase in MDSCs, especially G-MDSCs, whose proliferation may inhibit the number of CD4+ T cells in peripheral blood. Meanwhile, there is a close relationship between proliferation of G-MDSCs and liver fibrosis in S. japonicum-infected patients.
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Affiliation(s)
- Bo Peng
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Yulin Luo
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Shudong Xie
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Quan Zhuang
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Junhui Li
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Pengpeng Zhang
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Kai Liu
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Yu Zhang
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Chen Zhou
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Chen Guo
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Zhaoqin Zhou
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Jie Zhou
- Schistosomiasis Control Institute of Hunan Province, Yueyang, Hunan, China - Xiangyue Hospital affiliated to Hunan Institute of Schistosomiasis Control, Yueyang, Hunan, China
| | - Yu Cai
- Xiangyue Hospital affiliated to Hunan Institute of Schistosomiasis Control, Yueyang, Hunan, China
| | - Meng Xia
- Xiangyue Hospital affiliated to Hunan Institute of Schistosomiasis Control, Yueyang, Hunan, China
| | - Ke Cheng
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
| | - Yingzi Ming
- Transplantation Center, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China - NHC Key Laboratory of Translational Research on Transplantation Medicine, Changsha, Hunan, China
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24
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Li X, Chen Y, Liang Y, Shi W. 5-Fluorouracil resistance due to sphingosine kinase 2 overexpression in colorectal cancer is associated with myeloid-derived suppressor cell-mediated immunosuppressive effects. BMC Cancer 2024; 24:983. [PMID: 39118083 PMCID: PMC11313101 DOI: 10.1186/s12885-024-12742-4] [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: 03/25/2024] [Accepted: 07/31/2024] [Indexed: 08/10/2024] Open
Abstract
PURPOSE Colorectal cancer (CRC) is one of the top five cancer-related causes of mortality globally. Acquired resistance has hindered the effectiveness of 5-fluorouracil (5-FU), the main chemotherapeutic drug used to treat CRC. Sphingosine kinase 2 (SphK2) may be a cancer treatment target and involved in 5-FU resistance. METHODS Cell growth was examined using MTT and clone formation assays for SphK2 expression. To identify immune cells in mice, flow cytometry was performed. West blotting demonstrated alterations in cell division and inflammation-related proteins. SphK2 levels and inflammation-related variables were studied using Elisa. RESULTS Due to SphK2 overexpression, immunosuppression, and 5-FU resistance are caused by the development of myeloid-derived suppressor cells (MDSCs) subsequent to IL-6/STAT3 activation and alterations in the arginase (ARG-1) protein. After therapy, the combination of SphK2 inhibitors and 5-FU can effectively suppress MDSCs while increasing CD4+ and CD8+ T cell infiltration into the tumor microenvironment, lowering tumor burden, and exhibiting a therapeutic impact on CRC. CONCLUSIONS Our findings suggest that 5-FU treatment combined with simultaneous Spkh2 inhibition by ABC294640 has anti-tumor synergistic effects by influencing multiple effects on tumor cells, T cells, and MDSCs, potentially improving the poor prognosis of colorectal cancer patients.
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Affiliation(s)
- Xiuyun Li
- Maternal and Child Health Development Research Center, Shandong Provincial Maternal and Child Health Care Hospital Affiliated to Qingdao University, Jinan, China
| | - Yungao Chen
- Human Resources Department, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yulin Liang
- School of Nursing, Peking Union Medical College, Beijing, China
| | - Wenna Shi
- Department of Pharmacy and Shandong Provincial key Traditional Chinese Medical Discipline of Clinical Chinese pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, China.
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25
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Kirti A, Simnani FZ, Jena S, Lenka SS, Kalalpitiya C, Naser SS, Singh D, Choudhury A, Sahu RN, Yadav A, Sinha A, Nandi A, Panda PK, Kaushik NK, Suar M, Verma SK. Nanoparticle-mediated metronomic chemotherapy in cancer: A paradigm of precision and persistence. Cancer Lett 2024; 594:216990. [PMID: 38801886 DOI: 10.1016/j.canlet.2024.216990] [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: 09/04/2023] [Revised: 03/05/2024] [Accepted: 05/23/2024] [Indexed: 05/29/2024]
Abstract
Current methods of cancer therapy have demonstrated enormous potential in tumor inhibition. However, a high dosage regimen of chemotherapy results in various complications which affect the normal body cells. Tumor cells also develop resistance against the prescribed drugs in the whole treatment regimen increasing the risk of cancer relapse. Metronomic chemotherapy is a modern treatment method that involves administering drugs at low doses continuously, allowing the drug sufficient time to take its effect. This method ensures that the toxicity of the drugs is to a minimum in comparison to conventional chemotherapy. Nanoparticles have shown efficacy in delivering drugs to the tumor cells in various cancer therapies. Combining nanoparticles with metronomic chemotherapy can yield better treatment results. This combination stimulates the immune system, improving cancer cells recognition by immune cells. Evidence from clinical and pre-clinical trials supports the use of metronomic delivery for drug-loaded nanoparticles. This review focuses on the functionalization of nanoparticles for improved drug delivery and inhibition of tumor growth. It emphasizes the mechanisms of metronomic chemotherapy and its conjunction with nanotechnology. Additionally, it explores tumor progression and the current methods of chemotherapy. The challenges associated with nano-based metronomic chemotherapy are outlined, paving the way for prospects in this dynamic field.
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Affiliation(s)
- Apoorv Kirti
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | | | - Snehasmita Jena
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Sudakshya S Lenka
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | | | | | - Dibyangshee Singh
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Anmol Choudhury
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Rudra Narayan Sahu
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Anu Yadav
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Adrija Sinha
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India
| | - Aditya Nandi
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India; Instituto de Investigaciones en Materiales, UNAM, 04510, CDMX, Mexico
| | - Pritam Kumar Panda
- Condensed Matter Theory Group, Materials Theory Division, Department of Physics and Astronomy, Uppsala University, Box 516, SE-751 20, Uppsala, Sweden
| | - Nagendra Kumar Kaushik
- Plasma Bioscience Research Center, Department of Electrical and Biological Physics, Kwangwoon University, Seoul, 01897, Republic of Korea.
| | - Mrutyunjay Suar
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India.
| | - Suresh K Verma
- KIIT School of Biotechnology, KIIT University, Bhubaneswar, 751024, India.
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Binder AK, Bremm F, Dörrie J, Schaft N. Non-Coding RNA in Tumor Cells and Tumor-Associated Myeloid Cells-Function and Therapeutic Potential. Int J Mol Sci 2024; 25:7275. [PMID: 39000381 PMCID: PMC11242727 DOI: 10.3390/ijms25137275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Revised: 06/19/2024] [Accepted: 06/29/2024] [Indexed: 07/16/2024] Open
Abstract
The RNA world is wide, and besides mRNA, there is a variety of other RNA types, such as non-coding (nc)RNAs, which harbor various intracellular regulatory functions. This review focuses on small interfering (si)RNA and micro (mi)RNA, which form a complex network regulating mRNA translation and, consequently, gene expression. In fact, these RNAs are critically involved in the function and phenotype of all cells in the human body, including malignant cells. In cancer, the two main targets for therapy are dysregulated cancer cells and dysfunctional immune cells. To exploit the potential of mi- or siRNA therapeutics in cancer therapy, a profound understanding of the regulatory mechanisms of RNAs and following targeted intervention is needed to re-program cancer cells and immune cell functions in vivo. The first part focuses on the function of less well-known RNAs, including siRNA and miRNA, and presents RNA-based technologies. In the second part, the therapeutic potential of these technologies in treating cancer is discussed, with particular attention on manipulating tumor-associated immune cells, especially tumor-associated myeloid cells.
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Affiliation(s)
- Amanda Katharina Binder
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Franziska Bremm
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Jan Dörrie
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
| | - Niels Schaft
- Department of Dermatology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany; (A.K.B.); (F.B.); (J.D.)
- Comprehensive Cancer Center Erlangen European Metropolitan Area of Nuremberg (CCC ER-EMN), 91054 Erlangen, Germany
- Deutsches Zentrum Immuntherapie (DZI), 91054 Erlangen, Germany
- Bavarian Cancer Research Center (BZKF), 91054 Erlangen, Germany
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27
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Nepal MR, Shah S, Kang KT. Dual roles of myeloid-derived suppressor cells in various diseases: a review. Arch Pharm Res 2024; 47:597-616. [PMID: 39008186 DOI: 10.1007/s12272-024-01504-2] [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: 10/09/2023] [Accepted: 06/30/2024] [Indexed: 07/16/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that originate from bone marrow stem cells. In pathological conditions, such as autoimmune disorders, allergies, infections, and cancer, normal myelopoiesis is altered to facilitate the formation of MDSCs. MDSCs were first shown to promote cancer initiation and progression by immunosuppression with the assistance of various chemokines and cytokines. Recently, various studies have demonstrated that MDSCs play two distinct roles depending on the physiological and pathological conditions. MDSCs have protective roles in autoimmune disorders (such as uveoretinitis, multiple sclerosis, rheumatoid arthritis, ankylosing spondylitis, type 1 diabetes, autoimmune hepatitis, inflammatory bowel disease, alopecia areata, and systemic lupus erythematosus), allergies, and organ transplantation. However, they play negative roles in infections and various cancers. Several immunosuppressive functions and mechanisms of MDSCs have been determined in different disease conditions. This review comprehensively discusses the associations between MDSCs and various pathological conditions and briefly describes therapeutic approaches.
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Affiliation(s)
- Mahesh Raj Nepal
- College of Pharmacy, Duksung Women's University, Seoul, South Korea
- Duksung Innovative Drug Center, Duksung Women's University, Seoul, South Korea
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Sajita Shah
- College of Pharmacy, Duksung Women's University, Seoul, South Korea
- Duksung Innovative Drug Center, Duksung Women's University, Seoul, South Korea
- The Comprehensive Cancer Center, Department of Radiation Oncology, Ohio State University, Columbus, OH, USA
| | - Kyu-Tae Kang
- College of Pharmacy, Duksung Women's University, Seoul, South Korea.
- Duksung Innovative Drug Center, Duksung Women's University, Seoul, South Korea.
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28
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Lasser S, Ozbay Kurt FG, Fritz L, Gutzeit N, De La Torre C, Altevogt P, Utikal J, Umansky V. Generation of Myeloid-Derived Suppressor Cells Mediated by MicroRNA-125a-5p in Melanoma. Int J Mol Sci 2024; 25:6693. [PMID: 38928399 PMCID: PMC11203613 DOI: 10.3390/ijms25126693] [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: 03/28/2024] [Revised: 06/13/2024] [Accepted: 06/13/2024] [Indexed: 06/28/2024] Open
Abstract
The ability of tumor-derived extracellular vesicles (EVs) to modulate the function of myeloid cells is widely recognized. Hence, a comprehensive understanding of the distinct components associated with EVs and the signals that they deliver to myeloid cells could provide potential approaches to impede the immunosuppression by myeloid-derived suppressor cells (MDSCs). We investigated melanoma EV-associated microRNAs (miRs) using the RET transgenic melanoma mouse model and simulated their transfer to normal myeloid cells by transfecting immature mouse myeloid cells and human monocytes. We observed elevated levels of miR-125a-5p, -125b-5p, and let-7e-5p in mouse melanoma-infiltrating MDSCs. In addition, miR-125a-5p levels in the tumor microenvironment correlated with mouse melanoma progression. The delivery of miR-125a-5p, alone or in combination with let-7e-5p and miR-99b-5p from the same genomic cluster, to normal myeloid cells resulted in their conversion to MDSC-like cells. Our findings indicate that miR-125a-5p could modulate myeloid cell activation in the melanoma microenvironment via a NF-κB-dependent mechanism.
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Affiliation(s)
- Samantha Lasser
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany; (S.L.); (F.G.O.K.); (L.F.); (N.G.); (P.A.); (J.U.)
- Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- DFKZ-Hector Cancer Institute, University Medical Center Mannheim, 68167 Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Feyza Gul Ozbay Kurt
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany; (S.L.); (F.G.O.K.); (L.F.); (N.G.); (P.A.); (J.U.)
- Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- DFKZ-Hector Cancer Institute, University Medical Center Mannheim, 68167 Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Lennart Fritz
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany; (S.L.); (F.G.O.K.); (L.F.); (N.G.); (P.A.); (J.U.)
- Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- DFKZ-Hector Cancer Institute, University Medical Center Mannheim, 68167 Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Nina Gutzeit
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany; (S.L.); (F.G.O.K.); (L.F.); (N.G.); (P.A.); (J.U.)
- Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- DFKZ-Hector Cancer Institute, University Medical Center Mannheim, 68167 Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Carolina De La Torre
- NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Peter Altevogt
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany; (S.L.); (F.G.O.K.); (L.F.); (N.G.); (P.A.); (J.U.)
- Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- DFKZ-Hector Cancer Institute, University Medical Center Mannheim, 68167 Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
| | - Jochen Utikal
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany; (S.L.); (F.G.O.K.); (L.F.); (N.G.); (P.A.); (J.U.)
- Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- DFKZ-Hector Cancer Institute, University Medical Center Mannheim, 68167 Mannheim, Germany
| | - Viktor Umansky
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, 68167 Mannheim, Germany; (S.L.); (F.G.O.K.); (L.F.); (N.G.); (P.A.); (J.U.)
- Skin Cancer Unit, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- DFKZ-Hector Cancer Institute, University Medical Center Mannheim, 68167 Mannheim, Germany
- Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany
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Perzolli A, Koedijk JB, Zwaan CM, Heidenreich O. Targeting the innate immune system in pediatric and adult AML. Leukemia 2024; 38:1191-1201. [PMID: 38459166 PMCID: PMC11147779 DOI: 10.1038/s41375-024-02217-7] [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: 01/29/2024] [Revised: 02/27/2024] [Accepted: 02/29/2024] [Indexed: 03/10/2024]
Abstract
While the introduction of T cell-based immunotherapies has improved outcomes in many cancer types, the development of immunotherapies for both adult and pediatric AML has been relatively slow and limited. In addition to the need to identify suitable target antigens, a better understanding of the immunosuppressive tumor microenvironment is necessary for the design of novel immunotherapy approaches. To date, most immune characterization studies in AML have focused on T cells, while innate immune lineages such as monocytes, granulocytes and natural killer (NK) cells, received less attention. In solid cancers, studies have shown that innate immune cells, such as macrophages, myeloid-derived suppressor cells and neutrophils are highly plastic and may differentiate into immunosuppressive cells depending on signals received in their microenvironment, while NK cells appear to be functionally impaired. Hence, an in-depth characterization of the innate immune compartment in the TME is urgently needed to guide the development of immunotherapeutic interventions for AML. In this review, we summarize the current knowledge on the innate immune compartment in AML, and we discuss how targeting its components may enhance T cell-based- and other immunotherapeutic approaches.
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Affiliation(s)
- Alicia Perzolli
- Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
- Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD, Rotterdam, The Netherlands
| | - Joost B Koedijk
- Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
- Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD, Rotterdam, The Netherlands
| | - C Michel Zwaan
- Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands
- Department of Pediatric Oncology, Erasmus MC/Sophia Children's Hospital, 3015 GD, Rotterdam, The Netherlands
| | - Olaf Heidenreich
- Princess Máxima Center for Pediatric Oncology, 3584 CS, Utrecht, The Netherlands.
- Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne, NE1 7RU, UK.
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Tang Y, Cui G, Liu H, Han Y, Cai C, Feng Z, Shen H, Zeng S. Converting "cold" to "hot": epigenetics strategies to improve immune therapy effect by regulating tumor-associated immune suppressive cells. Cancer Commun (Lond) 2024; 44:601-636. [PMID: 38715348 PMCID: PMC11194457 DOI: 10.1002/cac2.12546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 04/09/2024] [Accepted: 04/18/2024] [Indexed: 06/26/2024] Open
Abstract
Significant developments in cancer treatment have been made since the advent of immune therapies. However, there are still some patients with malignant tumors who do not benefit from immunotherapy. Tumors without immunogenicity are called "cold" tumors which are unresponsive to immunotherapy, and the opposite are "hot" tumors. Immune suppressive cells (ISCs) refer to cells which can inhibit the immune response such as tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) cells and so on. The more ISCs infiltrated, the weaker the immunogenicity of the tumor, showing the characteristics of "cold" tumor. The dysfunction of ISCs in the tumor microenvironment (TME) may play essential roles in insensitive therapeutic reaction. Previous studies have found that epigenetic mechanisms play an important role in the regulation of ISCs. Regulating ISCs may be a new approach to transforming "cold" tumors into "hot" tumors. Here, we focused on the function of ISCs in the TME and discussed how epigenetics is involved in regulating ISCs. In addition, we summarized the mechanisms by which the epigenetic drugs convert immunotherapy-insensitive tumors into immunotherapy-sensitive tumors which would be an innovative tendency for future immunotherapy in "cold" tumor.
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Affiliation(s)
- Yijia Tang
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Guangzu Cui
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Haicong Liu
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Ying Han
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Changjing Cai
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Ziyang Feng
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
| | - Hong Shen
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
- National Clinical Resaerch Center for Geriatric Disorders, Xiangya Hospital, Central South UniversityChangshaHunanChina
| | - Shan Zeng
- Department of OncologyXiangya HospitalCentral South UniversityChangshaHunanP. R. China
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Möller M, Orth V, Umansky V, Hetjens S, Braun V, Reißfelder C, Hardt J, Seyfried S. Myeloid-derived suppressor cells in peripheral blood as predictive biomarkers in patients with solid tumors undergoing immune checkpoint therapy: systematic review and meta-analysis. Front Immunol 2024; 15:1403771. [PMID: 38855104 PMCID: PMC11157008 DOI: 10.3389/fimmu.2024.1403771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/09/2024] [Indexed: 06/11/2024] Open
Abstract
Background Immunotherapeutic approaches, including immune checkpoint inhibitor (ICI) therapy, are increasingly recognized for their potential. Despite notable successes, patient responses to these treatments vary significantly. The absence of reliable predictive and prognostic biomarkers hampers the ability to foresee outcomes. This meta-analysis aims to evaluate the predictive significance of circulating myeloid-derived suppressor cells (MDSC) in patients with solid tumors undergoing ICI therapy, focusing on progression-free survival (PFS) and overall survival (OS). Methods A comprehensive literature search was performed across PubMed and EMBASE from January 2007 to November 2023, utilizing keywords related to MDSC and ICI. We extracted hazard ratios (HRs) and 95% confidence intervals (CIs) directly from the publications or calculated them based on the reported data. A hazard ratio greater than 1 indicated a beneficial effect of low MDSC levels. We assessed heterogeneity and effect size through subgroup analyses. Results Our search yielded 4,023 articles, of which 17 studies involving 1,035 patients were included. The analysis revealed that patients with lower levels of circulating MDSC experienced significantly improved OS (HR=2.13 [95% CI 1.51-2.99]) and PFS (HR=1.87 [95% CI 1.29-2.72]) in response to ICI therapy. Notably, heterogeneity across these outcomes was primarily attributed to differences in polymorphonuclear MDSC (PMN-MDSC) subpopulations and varying cutoff methodologies used in the studies. The monocytic MDSC (M-MDSC) subpopulation emerged as a consistent and significant prognostic marker across various subgroup analyses, including ethnicity, tumor type, ICI target, sample size, and cutoff methodology. Conclusions Our findings suggest that standardized assessment of MDSC, particularly M-MDSC, should be integral to ICI therapy strategies. These cells hold the promise of identifying patients at risk of poor response to ICI therapy, enabling tailored treatment approaches. Further research focusing on the standardization of markers and validation of cutoff methods is crucial for integrating MDSC into clinical practice. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023420095, identifier CRD42023420095.
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Affiliation(s)
- Maximilian Möller
- Department of Surgery, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
| | - Vanessa Orth
- Department of Surgery, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
| | - Viktor Umansky
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
- Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany
- German Cancer Research Center (DKFZ)-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
| | - Svetlana Hetjens
- Department of Biometry and Statistics, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
| | - Volker Braun
- Department of Library and Information Sciences, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Christoph Reißfelder
- Department of Surgery, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
- German Cancer Research Center (DKFZ)-Hector Cancer Institute, University Medical Centre Mannheim, Mannheim, Germany
| | - Julia Hardt
- Department of Surgery, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
| | - Steffen Seyfried
- Department of Surgery, Medical Faculty Mannheim, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
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Wu LY, Park SH, Jakobsson H, Shackleton M, Möller A. Immune Regulation and Immune Therapy in Melanoma: Review with Emphasis on CD155 Signalling. Cancers (Basel) 2024; 16:1950. [PMID: 38893071 PMCID: PMC11171058 DOI: 10.3390/cancers16111950] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/16/2024] [Accepted: 05/17/2024] [Indexed: 06/21/2024] Open
Abstract
Melanoma is commonly diagnosed in a younger population than most other solid malignancies and, in Australia and most of the world, is the leading cause of skin-cancer-related death. Melanoma is a cancer type with high immunogenicity; thus, immunotherapies are used as first-line treatment for advanced melanoma patients. Although immunotherapies are working well, not all the patients are benefitting from them. A lack of a comprehensive understanding of immune regulation in the melanoma tumour microenvironment is a major challenge of patient stratification. Overexpression of CD155 has been reported as a key factor in melanoma immune regulation for the development of therapy resistance. A more thorough understanding of the actions of current immunotherapy strategies, their effects on immune cell subsets, and the roles that CD155 plays are essential for a rational design of novel targets of anti-cancer immunotherapies. In this review, we comprehensively discuss current anti-melanoma immunotherapy strategies and the immune response contribution of different cell lineages, including tumour endothelial cells, myeloid-derived suppressor cells, cytotoxic T cells, cancer-associated fibroblast, and nature killer cells. Finally, we explore the impact of CD155 and its receptors DNAM-1, TIGIT, and CD96 on immune cells, especially in the context of the melanoma tumour microenvironment and anti-cancer immunotherapies.
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Affiliation(s)
- Li-Ying Wu
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- JC STEM Lab, Department of Otorhinolaryngology, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China;
- Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Su-Ho Park
- JC STEM Lab, Department of Otorhinolaryngology, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China;
- Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
| | - Haakan Jakobsson
- Department of Medical Oncology, Paula Fox Melanoma and Cancer Centre, Alfred Health, Melbourne, VIC 3004, Australia;
| | - Mark Shackleton
- Department of Medical Oncology, Paula Fox Melanoma and Cancer Centre, Alfred Health, Melbourne, VIC 3004, Australia;
- School of Translational Medicine, Monash University, Melbourne, VIC 3004, Australia
| | - Andreas Möller
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia;
- JC STEM Lab, Department of Otorhinolaryngology, Chinese University of Hong Kong, Shatin, Hong Kong SAR, China;
- Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China
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Zhang Q, Yu T, Tan H, Shi H. Hepatic recruitment of myeloid-derived suppressor cells upon liver injury promotes both liver regeneration and fibrosis. BMC Gastroenterol 2024; 24:163. [PMID: 38745150 PMCID: PMC11092103 DOI: 10.1186/s12876-024-03245-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 04/29/2024] [Indexed: 05/16/2024] Open
Abstract
BACKGROUND The liver regeneration is a highly complicated process depending on the close cooperations between the hepatocytes and non-parenchymal cells involving various inflammatory cells. Here, we explored the role of myeloid-derived suppressor cells (MDSCs) in the processes of liver regeneration and liver fibrosis after liver injury. METHODS We established four liver injury models of mice including CCl4-induced liver injury model, bile duct ligation (BDL) model, concanavalin A (Con A)-induced hepatitis model, and lipopolysaccharide (LPS)-induced hepatitis model. The intrahepatic levels of MDSCs (CD11b+Gr-1+) after the liver injury were detected by flow cytometry. The effects of MDSCs on liver tissues were analyzed in the transwell co-culture system, in which the MDSCs cytokines including IL-10, VEGF, and TGF-β were measured by ELISA assay and followed by being blocked with specific antibodies. RESULTS The intrahepatic infiltrations of MDSCs with surface marker of CD11b+Gr-1+ remarkably increased after the establishment of four liver injury models. The blood served as the primary reservoir for hepatic recruitment of MDSCs during the liver injury, while the bone marrow appeared play a compensated role in increasing the number of MDSCs at the late stage of the inflammation. The recruited MDSCs in injured liver were mainly the M-MDSCs (CD11b+Ly6G-Ly6Chigh) featured by high expression levels of cytokines including IL-10, VEGF, and TGF-β. Co-culture of the liver tissues with MDSCs significantly promoted the proliferation of both hepatocytes and hepatic stellate cells (HSCs). CONCLUSIONS The dramatically and quickly infiltrated CD11b+Gr-1+ MDSCs in injured liver not only exerted pro-proliferative effects on hepatocytes, but also accounted for the activation of profibrotic HSCs.
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Affiliation(s)
- Qiongwen Zhang
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Ting Yu
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Huaicheng Tan
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Huashan Shi
- Department of Head and Neck Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China.
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Jiang Q, Duan J, Van Kaer L, Yang G. The Role of Myeloid-Derived Suppressor Cells in Multiple Sclerosis and Its Animal Model. Aging Dis 2024; 15:1329-1343. [PMID: 37307825 PMCID: PMC11081146 DOI: 10.14336/ad.2023.0323-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 03/23/2023] [Indexed: 06/14/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs), a heterogeneous cell population that consists of mostly immature myeloid cells, are immunoregulatory cells mainly characterized by their suppressive functions. Emerging findings have revealed the involvement of MDSCs in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). MS is an autoimmune and degenerative disease of the central nervous system characterized by demyelination, axon loss, and inflammation. Studies have reported accumulation of MDSCs in inflamed tissues and lymphoid organs of MS patients and EAE mice, and these cells display dual functions in EAE. However, the contribution of MDSCs to MS/EAE pathogenesis remains unclear. This review aims to summarize our current understanding of MDSC subsets and their possible roles in MS/EAE pathogenesis. We also discuss the potential utility and associated obstacles in employing MDSCs as biomarkers and cell-based therapies for MS.
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Affiliation(s)
- Qianling Jiang
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong, China.
| | - Jielin Duan
- Department of Allergy and Clinical Immunology, State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Luc Van Kaer
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
| | - Guan Yang
- Department of Infectious Diseases and Public Health, Jockey Club College of Veterinary Medicine and Life Sciences, City University of Hong Kong, Kowloon, Hong Kong, China.
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Mahanti K, Saha J, Sarkar D, Pramanik A, Roy Chattopadhyay N, Bhattacharyya S. Alteration of functionality and differentiation directed by changing gene expression patterns in myeloid-derived suppressor cells (MDSCs) in tumor microenvironment and bone marrow through early to terminal phase of tumor progression. J Leukoc Biol 2024; 115:958-984. [PMID: 38236200 DOI: 10.1093/jleuko/qiae013] [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: 09/14/2023] [Revised: 12/06/2023] [Accepted: 01/04/2024] [Indexed: 01/19/2024] Open
Abstract
Myeloid-derived suppressor cells are heterogenous immature myeloid lineage cells that can differentiate into neutrophils, monocytes, and dendritic cells as well. These cells have been characterized to have potent immunosuppressive capacity in neoplasia and a neoplastic chronic inflammatory microenvironment. Increased accumulation of myeloid-derived suppressor cells was reported with poor clinical outcomes in patients. They support neoplastic progression by abrogating antitumor immunity through inhibition of lymphocyte functions and directly by facilitating tumor development. Yet the shifting genetic signatures of this myeloid lineage cell toward immunosuppressive functionality in progressive tumor development remain elusive. We have attempted to identify the gene expression profile using lineage-specific markers of these unique myeloid lineage cells in a tumor microenvironment and bone marrow using a liquid transplantable mice tumor model to trace the changing influence of the tumor microenvironment on myeloid-derived suppressor cells. We analyzed the phenotype, functional shift, suppressive activity, differentiation status, and microarray-based gene expression profile of CD11b+Gr1+ lineage-specific cells isolated from the tumor microenvironment and bone marrow of 4 stages of tumor-bearing mice and compared them with control counterparts. Our analysis of differentially expressed genes of myeloid-derived suppressor cells isolated from bone marrow and the tumor microenvironment reveals unique gene expression patterns in the bone marrow and tumor microenvironment-derived myeloid-derived suppressor cells. It also suggests T-cell suppressive activity of myeloid-derived suppressor cells progressively increases toward the mid-to-late phase of the tumor and a significant differentiation bias of tumor site myeloid-derived suppressor cells toward macrophages, even in the presence of differentiating agents, indicating potential molecular characteristics of myeloid-derived suppressor cells in different stages of the tumor that can emerge as an intervention target.
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Affiliation(s)
- Krishna Mahanti
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Ranchi Road, Saink School, Purulia, West Bengal 723104, India
| | - Jayasree Saha
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Ranchi Road, Saink School, Purulia, West Bengal 723104, India
- Currently, DST-SERB NPDF, School of Bioscience, IIT Kharagpur, Paschim Medinipur, West Bengal 721302, India
| | - Debanjan Sarkar
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Ranchi Road, Saink School, Purulia, West Bengal 723104, India
| | - Anik Pramanik
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Ranchi Road, Saink School, Purulia, West Bengal 723104, India
| | - Nabanita Roy Chattopadhyay
- Department of Biotechnology, Siksha Bhaban, Visva Bharati, Shantiniketan, Birbhum, West Bengal 731235, India
- Currently, Department of Biotechnology, Haldia Institute of Technology, ICARE Complex, Haldia, West Bengal 721657, India
| | - Sankar Bhattacharyya
- Immunobiology and Translational Medicine Laboratory, Department of Zoology, Sidho Kanho Birsha University, Ranchi Road, Saink School, Purulia, West Bengal 723104, India
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Zannikou M, Fish EN, Platanias LC. Signaling by Type I Interferons in Immune Cells: Disease Consequences. Cancers (Basel) 2024; 16:1600. [PMID: 38672681 PMCID: PMC11049350 DOI: 10.3390/cancers16081600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/08/2024] [Accepted: 04/18/2024] [Indexed: 04/28/2024] Open
Abstract
This review addresses interferon (IFN) signaling in immune cells and the tumor microenvironment (TME) and examines how this affects cancer progression. The data reveal that IFNs exert dual roles in cancers, dependent on the TME, exhibiting both anti-tumor activity and promoting cancer progression. We discuss the abnormal IFN signaling induced by cancerous cells that alters immune responses to permit their survival and proliferation.
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Affiliation(s)
- Markella Zannikou
- Robert H. Lurie Comprehensive Cancer Center, Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, 303 East Superior Ave., Chicago, IL 60611, USA
| | - Eleanor N. Fish
- Toronto General Hospital Research Institute, University Health Network, 67 College Street, Toronto, ON M5G 2M1, Canada;
- Department of Immunology, University of Toronto, 1 King’s College Circle, Toronto, ON M5S 1A8, Canada
| | - Leonidas C. Platanias
- Robert H. Lurie Comprehensive Cancer Center, Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, 303 East Superior Ave., Chicago, IL 60611, USA
- Department of Medicine, Jesse Brown Veterans Affairs Medical Center, 820 S. Damen Ave., Chicago, IL 60612, USA
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Nie J, Ai J, Hong W, Bai Z, Wang B, Yang J, Zhang Z, Mo F, Yang J, Sun Q, Wei X. Cisplatin-induced oxPAPC release enhances MDSCs infiltration into LL2 tumour tissues through MCP-1/CCL2 and LTB4/LTB4R pathways. Cell Prolif 2024; 57:e13570. [PMID: 37905494 PMCID: PMC10984104 DOI: 10.1111/cpr.13570] [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: 05/25/2023] [Revised: 10/09/2023] [Accepted: 10/15/2023] [Indexed: 11/02/2023] Open
Abstract
Lung cancer is the leading global cause of cancer-related death, however, resistance to chemotherapy drugs remains a huge barrier to effective treatment. The elevated recruitment of myeloid derived suppressor cells (MDSCs) to tumour after chemotherapy has been linked to resistance of chemotherapy drugs. Nevertheless, the specific mechanism remains unclear. oxPAPC is a bioactive principal component of minimally modified low-density lipoproteins and regulates inflammatory response. In this work, we found that cisplatin, oxaliplatin and ADM all increased oxPAPC release in tumour. Treating macrophages with oxPAPC in vitro stimulated the secretion of MCP-1 and LTB4, which strongly induced monocytes and neutrophils chemotaxis, respectively. Injection of oxPAPC in vivo significantly upregulated the percentage of MDSCs in tumour microenvironment (TME) of wild-type LL2 tumour-bearing mice, but not CCL2-/- mice and LTB4R-/- mice. Critically, oxPAPC acted as a pro-tumor factor in LL2 tumour model. Indeed, cisplatin increased oxPAPC level in tumour tissues of WT mice, CCL2-/- and LTB4R-/- mice, but caused increased infiltration of Ly6Chigh monocytes and neutrophils only in WT LL2-bearing mice. Collectively, our work demonstrates cisplatin treatment induces an overproduction of oxPAPC and thus recruits MDSCs infiltration to promote the tumour growth through the MCP-1/CCL2 and LTB4/LTB4R pathways, which may restrict the effect of multiple chemotherapy. This provides evidence for a potential strategy to enhance the efficacy of multiple chemotherapeutic drugs in the treatment of lung cancer by targeting oxPAPC.
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Affiliation(s)
- Ji Nie
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
- Department of Pulmonary and Critical Care Medicine, The First People's Hospital of Yunnan ProvinceThe Affiliated Hospital of Kunming University of Science and TechnologyKunmingYunnanChina
| | - Jiayuan Ai
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Weiqi Hong
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Ziyi Bai
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Binhan Wang
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Jingyun Yang
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Ziqi Zhang
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Fei Mo
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Jing Yang
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
| | - Qiu Sun
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
- West China Medical Publishers, West China Hospital, Sichuan UniversityChengduSichuanChina
| | - Xiawei Wei
- Department of Biotherapy, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy, National Clinical Research Center for GeriatricsWest China Hospital, Sichuan UniversityChengduSichuanChina
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Costa TFR, Catta-Preta CMC, Goundry A, Carvalho DB, Rodrigues NS, Vivarini AC, de Abreu MF, Reis FCG, Lima APCA. The ecotin-like peptidase inhibitor of Trypanosoma cruzi prevents TMPRSS2-PAR2-TLR4 crosstalk downmodulating infection and inflammation. FASEB J 2024; 38:e23566. [PMID: 38526868 DOI: 10.1096/fj.202302091rr] [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: 10/15/2023] [Revised: 02/24/2024] [Accepted: 03/06/2024] [Indexed: 03/27/2024]
Abstract
Trypanosoma cruzi is the causative agent of Chagas disease, a chronic pathology that affects the heart and/or digestive system. This parasite invades and multiplies in virtually all nucleated cells, using a variety of host cell receptors for infection. T. cruzi has a gene that encodes an ecotin-like inhibitor of serine peptidases, ISP2. We generated ISP2-null mutants (Δisp2) in T. cruzi Dm28c using CRISPR/Cas9. Epimastigotes of Δisp2 grew normally in vitro but were more susceptible to lysis by human serum compared to parental and ISP2 add-back lines. Tissue culture trypomastigotes of Δisp2 were more infective to human muscle cells in vitro, which was reverted by the serine peptidase inhibitors aprotinin and camostat, suggesting that host cell epitheliasin/TMPRSS2 is the target of ISP2. Pretreatment of host cells with an antagonist to the protease-activated receptor 2 (PAR2) or an inhibitor of Toll-like receptor 4 (TLR4) selectively counteracted the increased cell invasion by Δisp2, but did not affect invasion by parental and add-back lines. The same was observed following targeted gene silencing of PAR2, TLR4 or TMPRSS2 in host cells by siRNA. Furthermore, Δisp2 caused increased tissue edema in a BALB/c mouse footpad infection model after 3 h differently to that observed following infection with parental and add-back lines. We propose that ISP2 contributes to protect T. cruzi from the anti-microbial effects of human serum and to prevent triggering of PAR2 and TLR4 in host cells, resulting in the modulation of host cell invasion and contributing to decrease inflammation during acute infection.
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Affiliation(s)
- Tatiana F R Costa
- Laboratório de Bioquímica e Biologia Molecular de Proteases, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Carolina M C Catta-Preta
- Laboratório de Bioquímica e Biologia Molecular de Proteases, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Amy Goundry
- Laboratório de Bioquímica e Biologia Molecular de Proteases, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Danielle B Carvalho
- Laboratório de Bioquímica e Biologia Molecular de Proteases, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Nathalia S Rodrigues
- Laboratório de Bioquímica e Biologia Molecular de Proteases, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Aislan C Vivarini
- Departamento de Biologia Celular e Molecular, Insituto de Biologia, Universidade Federal Fluminense, Niteroi, Brazil
| | - Mayra Fonseca de Abreu
- Laboratório de Bioquímica e Biologia Molecular de Proteases, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Flavia C G Reis
- Laboratório de Bioquímica e Biologia Molecular de Proteases, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ana Paula C A Lima
- Laboratório de Bioquímica e Biologia Molecular de Proteases, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Arshad J, Rao A, Repp ML, Rao R, Wu C, Merchant JL. Myeloid-Derived Suppressor Cells: Therapeutic Target for Gastrointestinal Cancers. Int J Mol Sci 2024; 25:2985. [PMID: 38474232 PMCID: PMC10931832 DOI: 10.3390/ijms25052985] [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: 01/02/2024] [Revised: 02/26/2024] [Accepted: 02/29/2024] [Indexed: 03/14/2024] Open
Abstract
Gastrointestinal cancers represent one of the more challenging cancers to treat. Current strategies to cure and control gastrointestinal (GI) cancers like surgery, radiation, chemotherapy, and immunotherapy have met with limited success, and research has turned towards further characterizing the tumor microenvironment to develop novel therapeutics. Myeloid-derived suppressor cells (MDSCs) have emerged as crucial drivers of pathogenesis and progression within the tumor microenvironment in GI malignancies. Many MDSCs clinical targets have been defined in preclinical models, that potentially play an integral role in blocking recruitment and expansion, promoting MDSC differentiation into mature myeloid cells, depleting existing MDSCs, altering MDSC metabolic pathways, and directly inhibiting MDSC function. This review article analyzes the role of MDSCs in GI cancers as viable therapeutic targets for gastrointestinal malignancies and reviews the existing clinical trial landscape of recently completed and ongoing clinical studies testing novel therapeutics in GI cancers.
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Affiliation(s)
- Junaid Arshad
- University of Arizona Cancer Center, GI Medical Oncology, Tucson, AZ 85724, USA;
| | - Amith Rao
- Banner University Medical Center—University of Arizona, Tucson, AZ 85719, USA; (A.R.)
| | - Matthew L. Repp
- College of Medicine, University of Arizona, Tucson, AZ 85719, USA;
| | - Rohit Rao
- University Hospitals Cleveland Medical Center, Case Western Reserve School of Medicine, Cleveland, OH 44106, USA;
| | - Clinton Wu
- Banner University Medical Center—University of Arizona, Tucson, AZ 85719, USA; (A.R.)
| | - Juanita L. Merchant
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine, Tucson, AZ 85724, USA
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Tsutsumi C, Ohuchida K, Katayama N, Yamada Y, Nakamura S, Okuda S, Otsubo Y, Iwamoto C, Torata N, Horioka K, Shindo K, Mizuuchi Y, Ikenaga N, Nakata K, Nagai E, Morisaki T, Oda Y, Nakamura M. Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer. Gastric Cancer 2024; 27:248-262. [PMID: 38217732 DOI: 10.1007/s10120-023-01456-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 12/07/2023] [Indexed: 01/15/2024]
Abstract
BACKGROUND Gastric cancer (GC) is characterized by an immunosuppressive and treatment-resistant tumor immune microenvironment (TIME). Here, we investigated the roles of different immunosuppressive cell types in the development of the GC TIME. METHODS Single-cell RNA sequencing (scRNA-seq) and multiplex immunostaining of samples from untreated or immune checkpoint inhibitor (ICI)-resistant GC patients were used to examine the correlation between certain immunosuppressive cells and the prognosis of GC patients. RESULTS The results of the scRNA-seq analysis revealed that tumor-infiltrating monocytic myeloid-derived suppressor cells (TI-M-MDSCs) expressed higher levels of genes with immunosuppressive functions than other immunosuppressive cell types. Additionally, M-MDSCs in GC tissues expressed significantly higher levels of these markers than adjacent normal tissues. The M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues. Among the immunosuppressive cell types assessed, the M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues; moreover, their presence was most strongly associated with a poor prognosis. Immediate early response 3 (IER3), which we identified as a differentially expressed gene between M-MDSCs of GC and adjacent normal tissues, was an independent poor prognostic factor in GC patients (P = 0.0003). IER3+ M-MDSCs expressed higher levels of genes with immunosuppressive functions than IER3- M-MDSCs and were abundant in treatment-resistant GC patients. CONCLUSIONS The present study suggests that TI-M-MDSCs, especially IER3+ ones, may play a predominant role in the development of the immunosuppressive and ICI-resistant GC TIME.
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Affiliation(s)
- Chikanori Tsutsumi
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kenoki Ohuchida
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
- Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Naoki Katayama
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yutaka Yamada
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shoichi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Sho Okuda
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yoshiki Otsubo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Chika Iwamoto
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Nobuhiro Torata
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kohei Horioka
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Koji Shindo
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Yusuke Mizuuchi
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Naoki Ikenaga
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Kohei Nakata
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Eishi Nagai
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
| | - Takashi Morisaki
- Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masafumi Nakamura
- Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
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Gherman A, Bolundut D, Ecea R, Balacescu L, Curcean S, Dina C, Balacescu O, Cainap C. Molecular Subtypes, microRNAs and Immunotherapy Response in Metastatic Colorectal Cancer. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:397. [PMID: 38541123 PMCID: PMC10972200 DOI: 10.3390/medicina60030397] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 02/10/2024] [Accepted: 02/18/2024] [Indexed: 11/12/2024]
Abstract
Currently, only a limited set of molecular traits are utilized to direct treatment for metastatic CRC (mCRC). The molecular classification of CRC depicts tumor heterogeneity based on gene expression patterns and aids in comprehending the biological characteristics of tumor formation, growth and prognosis. Additionally, it assists physicians in tailoring the therapeutic approach. Microsatellite instability (MSI-H)/deficient mismatch repair proteins (MMRd) status has become a ubiquitous biomarker in solid tumors, caused by mutations or methylation of genes and, in turn, the accumulation of mutations and antigens that subsequently induce an immune response. Immune checkpoint inhibitors (ICI) have recently received approval for the treatment of mCRC with MSI-H/MMRd status. However, certain individuals experience either initial or acquired resistance. The tumor-programmed cell death ligand 1 (PD-L1) has been linked to the ability of CRC to evade the immune system and promote its growth. Through comprehensive research conducted via the PUBMED database, the objectives of this paper were to review the molecular characteristics linked to tumor response in metastatic CRC in light of improved patients' outcomes following ICI therapies as seen in clinical trials and to identify particular microRNAs that can modulate the expression of specific oncoproteins, such as PD-L1, and disrupt the mechanisms that allow the immune system to be evaded.
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Affiliation(s)
- Alexandra Gherman
- 10th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (A.G.); (C.C.)
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (D.B.); (R.E.)
| | - Dinu Bolundut
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (D.B.); (R.E.)
| | - Radu Ecea
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (D.B.); (R.E.)
| | - Loredana Balacescu
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania;
| | - Sebastian Curcean
- 10th Department of Radiation Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania;
- Department of Radiation Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania
| | - Constantin Dina
- Department of Anatomy, Faculty of Medicine, Ovidius University, 124 Mamaia Boulevard, 900527 Constanta, Romania
| | - Ovidiu Balacescu
- Department of Genetics, Genomics and Experimental Pathology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 400015 Cluj-Napoca, Romania;
| | - Calin Cainap
- 10th Department of Medical Oncology, University of Medicine and Pharmacy “Iuliu Hatieganu”, 8 Victor Babes Street, 400012 Cluj-Napoca, Romania; (A.G.); (C.C.)
- Department of Medical Oncology, The Oncology Institute “Prof. Dr. Ion Chiricuta”, 34-36 Republicii Street, 400015 Cluj-Napoca, Romania; (D.B.); (R.E.)
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Borgna E, Gamba JC, Prochetto E, Marcipar I, Cabrera G. Simple protocol for measuring CD11b+ GR-1+ (Ly6C+/Ly6G+) myeloid cells from a minimum volume of mouse peripheral blood. Methods Cell Biol 2024; 184:59-68. [PMID: 38555158 DOI: 10.1016/bs.mcb.2024.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
Myeloid-derived suppressor cells (MDSCs) comprise a heterogeneous population of myeloid origin and immature state, whose hallmark is the capacity to suppress T cells and other immune populations. In mice, the first approach to identify MDSCs relies in the measurement of their phenotypical markers: CD11b and GR-1. In addition, two main subtypes of MDSCs have been defined based on the expression of the following markers: CD11b+ Ly6G- Ly6C+ (monocytic-MDSCs, M-MDSCs) and CD11b+ Ly6G+ Ly6C+/low (polymorphonuclear-MDSCs, PMN-MDSCs). Since CD11b+ GR-1+ (Ly6C+/Ly6G+) MDSCs can increase significantly in peripheral blood during numerous acute or chronic processes, measuring alterations in the phenotypic markers CD11b and GR-1 could be important as a first step before assessing the suppressive function of the cells. In many cases it could be necessary to measure CD11b+ Gr-1+ cells from a minimum volume of peripheral blood cells without greatly affecting animal viability, since this approach would allow for further studies to be conducted on subsequent days, such as measuring parameters of the immune response or even survival in the context of the pathology under study. The following protocol describes a simple and optimized protocol for measuring the presence of CD11b+ GR-1+ (Ly6C+/Ly6G+) myeloid cells using 2+ channel flow cytometry, from a minimum volume of mouse peripheral blood obtained by facial vein puncture.
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Affiliation(s)
- Eliana Borgna
- Laboratorio de Tecnología Inmunológica, Facultad de Bioquímica y Ciencias Biológicas (FBCB), Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Juan Cruz Gamba
- Laboratorio de Tecnología Inmunológica, Facultad de Bioquímica y Ciencias Biológicas (FBCB), Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Estefanía Prochetto
- Laboratorio de Tecnología Inmunológica, Facultad de Bioquímica y Ciencias Biológicas (FBCB), Universidad Nacional del Litoral, Santa Fe, Argentina; Facultad de Ciencias Médicas, Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Iván Marcipar
- Laboratorio de Tecnología Inmunológica, Facultad de Bioquímica y Ciencias Biológicas (FBCB), Universidad Nacional del Litoral, Santa Fe, Argentina
| | - Gabriel Cabrera
- Laboratorio de Tecnología Inmunológica, Facultad de Bioquímica y Ciencias Biológicas (FBCB), Universidad Nacional del Litoral, Santa Fe, Argentina.
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Del Pilar C, Garrido-Matilla L, Del Pozo-Filíu L, Lebrón-Galán R, Arias RF, Clemente D, Alonso JR, Weruaga E, Díaz D. Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration. J Neuroinflammation 2024; 21:49. [PMID: 38355633 PMCID: PMC10867997 DOI: 10.1186/s12974-023-03000-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 12/18/2023] [Indexed: 02/16/2024] Open
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) constitute a recently discovered bone-marrow-derived cell type useful for dealing with neuroinflammatory disorders. However, these cells are only formed during inflammatory conditions from immature myeloid cells (IMCs) that acquire immunosuppressive activity, thus being commonly gathered from diseased animals. Then, to obtain a more clinically feasible source, we characterized IMCs directly derived from healthy bone marrow and proved their potential immunosuppressive activity under pathological conditions in vitro. We then explored their neuroprotective potential in a model of human cerebellar ataxia, the Purkinje Cell Degeneration (PCD) mouse, as it displays a well-defined neurodegenerative and neuroinflammatory process that can be also aggravated by invasive surgeries. METHODS IMCs were obtained from healthy bone marrow and co-cultured with activated T cells. The proliferation and apoptotic rate of the later were analyzed with Tag-it Violet. For in vivo studies, IMCs were transplanted by stereotactic surgery into the cerebellum of PCD mice. We also used sham-operated animals as controls of the surgical effects, as well as their untreated counterparts. Motor behavior of mice was assessed by rotarod test. The Purkinje cell density was measured by immunohistochemistry and cell death assessed with the TUNEL technique. We also analyzed the microglial phenotype by immunofluorescence and the expression pattern of inflammation-related genes by qPCR. Parametric tests were applied depending on the specific experiment: one or two way ANOVA and Student's T test. RESULTS IMCs were proven to effectively acquire immunosuppressive activity under pathological conditions in vitro, thus acting as MDSCs. Concerning in vivo studios, sham-operated PCD mice suffered detrimental effects in motor coordination, Purkinje cell survival and microglial activation. After intracranial administration of IMCs into the cerebellum of PCD mice, no special benefits were detected in the transplanted animals when compared to untreated mice. Nonetheless, this transplant almost completely prevented the impairments caused by the surgery in PCD mice, probably by the modulation of the inflammatory patterns. CONCLUSIONS Our work comprise two main translational findings: (1) IMCs can be directly used as they behave as MDSCs under pathological conditions, thus avoiding their gathering from diseased subjects; (2) IMCs are promising adjuvants when performing neurosurgery.
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Affiliation(s)
- Carlos Del Pilar
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain
| | - Lucía Garrido-Matilla
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Departamento de Psicobiología, Facultad de Psicología, Universidad Nacional de Educación a Distancia (UNED), Madrid, Spain
| | - Lucía Del Pozo-Filíu
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Translational Stroke Laboratory (TREAT), Clinical Neurosciences Research Laboratory (LINC), Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, Spain
| | - Rafael Lebrón-Galán
- Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45004, Toledo, Spain
- Hospital Universitario de Toledo, Avd. Río Guadiana, s/n, 45007, Toledo, Spain
| | - Raúl F Arias
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain
| | - Diego Clemente
- Neuroimmuno-Repair Group, Hospital Nacional de Parapléjicos-SESCAM, Finca La Peraleda s/n, 45004, Toledo, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Carlos III Health Institute, Av. Monforte de Lemos, 3-5, 28029, Madrid, Spain
| | - José Ramón Alonso
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain
| | - Eduardo Weruaga
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain.
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain.
| | - David Díaz
- Institute for Neuroscience of Castile and Leon, INCyL, Universidad de Salamanca, C/Pintor Fernando Gallego 1, 37007, Salamanca, Spain.
- Institute of Biomedical Research of Salamanca, IBSAL, Salamanca, Spain.
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Lasser SA, Ozbay Kurt FG, Arkhypov I, Utikal J, Umansky V. Myeloid-derived suppressor cells in cancer and cancer therapy. Nat Rev Clin Oncol 2024; 21:147-164. [PMID: 38191922 DOI: 10.1038/s41571-023-00846-y] [Citation(s) in RCA: 58] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2023] [Indexed: 01/10/2024]
Abstract
Anticancer agents continue to dominate the list of newly approved drugs, approximately half of which are immunotherapies. This trend illustrates the considerable promise of cancer treatments that modulate the immune system. However, the immune system is complex and dynamic, and can have both tumour-suppressive and tumour-promoting effects. Understanding the full range of immune modulation in cancer is crucial to identifying more effective treatment strategies. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of myeloid cells that develop in association with chronic inflammation, which is a hallmark of cancer. Indeed, MDSCs accumulate in the tumour microenvironment, where they strongly inhibit anticancer functions of T cells and natural killer cells and exert a variety of other tumour-promoting effects. Emerging evidence indicates that MDSCs also contribute to resistance to cancer treatments, particularly immunotherapies. Conversely, treatment approaches designed to eliminate cancer cells can have important additional effects on MDSC function, which can be either positive or negative. In this Review, we discuss the interplay between MDSCs and various other cell types found in tumours as well as the mechanisms by which MDSCs promote tumour progression. We also discuss the relevance and implications of MDSCs for cancer therapy.
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Affiliation(s)
- Samantha A Lasser
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
- Skin Cancer Unit, German Cancer Research Center (Deutsches Krebsforschungszentrum (DKFZ)), Heidelberg, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
| | - Feyza G Ozbay Kurt
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
- Skin Cancer Unit, German Cancer Research Center (Deutsches Krebsforschungszentrum (DKFZ)), Heidelberg, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
| | - Ihor Arkhypov
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
- Skin Cancer Unit, German Cancer Research Center (Deutsches Krebsforschungszentrum (DKFZ)), Heidelberg, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
| | - Jochen Utikal
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany
- Skin Cancer Unit, German Cancer Research Center (Deutsches Krebsforschungszentrum (DKFZ)), Heidelberg, Germany
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
| | - Viktor Umansky
- Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany.
- Skin Cancer Unit, German Cancer Research Center (Deutsches Krebsforschungszentrum (DKFZ)), Heidelberg, Germany.
- DKFZ-Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany.
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Ito N, Tsujimoto H, Miyazaki H, Takahata R, Ueno H. Pivotal role of myeloid-derived suppressor cells in infection-related tumor growth. Cancer Med 2024; 13:e6917. [PMID: 38457241 PMCID: PMC10923041 DOI: 10.1002/cam4.6917] [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: 10/11/2023] [Revised: 12/18/2023] [Accepted: 12/25/2023] [Indexed: 03/10/2024] Open
Abstract
BACKGROUND In this study, we investigated infection-related tumor growth, focusing on myeloid-derived suppressor cells (MDSCs) in clinical and experimental settings. PATIENTS AND METHODS In the clinical study, a total 109 patients who underwent gastrectomy or esophagectomy were included. Blood samples were collected from a preoperative time point through 3 months after surgery, and MDSCs were analyzed using flow cytometry. In animal experiments, peritonitis model mice were created by CLP method. We investigated the number of splenic MDSCs in these mice using flow cytometry. Malignant melanoma cells (B16F10) were inoculated on the back of the mice, and tumor growth was monitored. We compared the level of MDSC infiltration around the tumor and the migration ability between CLP and sham-operated mice-derived MDSCs. Finally, we focused on PD-L1+ MDSCs to examine the effectiveness of anti-PD-L1 antibodies on tumor growth in CLP mice. RESULTS In patients with postoperative infectious complication, MDSC number was found to remain elevated 3 months after surgery, when the inflammatory responses were normalized. CLP mice showed increased numbers of MDSCs, and following inoculation with B16F10 cells, this higher number of MDSCs was associated with significant tumor growth. CLP-mice-derived MDSCs had higher levels of accumulation around the tumor and had more enhanced migration ability. Finally, CLP mice had increased numbers of PD-L1+ MDSCs and showed more effective inhibition of tumor growth by anti-PD-L1 antibodies compared to sham-operated mice. CONCLUSION Long-lasting enhanced MDSCs associated with infection may contribute to infection-related tumor progression.
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Affiliation(s)
- Nozomi Ito
- Department of SurgeryNational Defense Medical CollegeTokorozawaJapan
| | | | - Hiromi Miyazaki
- Division of Biomedical EngineeringResearch Institute, National Defense Medical CollegeTokorozawaJapan
| | - Risa Takahata
- Department of SurgeryNational Defense Medical CollegeTokorozawaJapan
| | - Hideki Ueno
- Department of SurgeryNational Defense Medical CollegeTokorozawaJapan
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Hou S, Kong F, Li X, Xu Y, Chen S, Zhang S, Zhang L, Li T, Fu Y, Li C, Wang W. Role of myeloid-derived suppressor cells in chronic brucellosis. Front Cell Infect Microbiol 2024; 14:1347883. [PMID: 38352057 PMCID: PMC10861671 DOI: 10.3389/fcimb.2024.1347883] [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: 12/01/2023] [Accepted: 01/15/2024] [Indexed: 02/16/2024] Open
Abstract
Introduction Human brucellosis, a Brucella infection caused most common zoonosis in the world, remains a serious public health burden in China. Brucella chronic infection always causes immunosuppressive status and results in severe organ or tissue damages. The aim of this work was to study the role of the myeloid-derived suppressor cells (MDSCs) in human chronic brucellosis. Methods Fifty cases of chronic brucellosis and 40 healthy individual controls were enrolled in this study. We analyzed the frequency and subsets of MDSCs in PBMC between the chronic brucellosis and healthy control groups by flow cytometry. Furthermore, we also measured the inflammatory-related cytokines in serum samples and the MDSCs inhibition ability to the proliferation of T cells in vitro. Results We found that the frequency of MDSCs in peripheral blood and the level of IL-6 and IL-10 Th2 cytokines and Arginase-1 were significantly increased in chronic brucellosis patients. In addition, we also found that the T cell function was suppressed in vitro by co-culturing with MDSCs from brucellosis patients. Conclusion Our study described an increase of immunosuppressive MDSCs in peripheral blood of chronic brucellosis patients. These results contribute to the understanding of Brucella persistent infection, which may provide an insight for effective treatment of chronic brucellosis patients in clinical practice.
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Affiliation(s)
- Shuiping Hou
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
- Department of Microbiology, Guangzhou Center for Disease Control and Prevention (CDC), Guangzhou, China
| | - Fandong Kong
- Department of Medical Administration, He Xian Memorial Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Xintong Li
- Department of Blood Components, Guangzhou Blood Center, Guangzhou, China
| | - Yanwen Xu
- Department of Obstetrics, He Xian Memorial Affiliated Hospital of Southern Medical University, Guangzhou, China
| | - Shouyi Chen
- Department of Parasitic Disease and Endemic Disease Control and Prevention, Guangzhou Center for Disease Control and Prevention (CDC), Guangzhou, China
| | - Sheng Zhang
- Administration Office, Baoan Central Blood Station, Shenzhen, China
| | - Ling Zhang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Tingting Li
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Yongshui Fu
- Clinical Transfusion Institute, Guangzhou Blood Center, Guangzhou, China
| | - Chengyao Li
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
| | - Wenjing Wang
- Department of Transfusion Medicine, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, China
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Youssef R, Maniar R, Khan J, Mesa H. Metabolic Interplay in the Tumor Microenvironment: Implications for Immune Function and Anticancer Response. Curr Issues Mol Biol 2023; 45:9753-9767. [PMID: 38132455 PMCID: PMC10742411 DOI: 10.3390/cimb45120609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 11/26/2023] [Accepted: 11/29/2023] [Indexed: 12/23/2023] Open
Abstract
Malignant tumors exhibit rapid growth and high metabolic rates, similar to embryonic stem cells, and depend on aerobic glycolysis, known as the "Warburg effect". This understanding has enabled the use of radiolabeled glucose analogs in tumor staging and therapeutic response assessment via PET scans. Traditional treatments like chemotherapy and radiotherapy target rapidly dividing cells, causing significant toxicity. Despite immunotherapy's impact on solid tumor treatment, gaps remain, leading to research on cancer cell evasion of immune response and immune tolerance induction via interactions with the tumor microenvironment (TME). The TME, consisting of immune cells, fibroblasts, vessels, and the extracellular matrix, regulates tumor progression and therapy responses. TME-targeted therapies aim to transform this environment from supporting tumor growth to impeding it and fostering an effective immune response. This review examines the metabolic disparities between immune cells and cancer cells, their impact on immune function and therapeutic targeting, the TME components, and the complex interplay between cancer cells and nontumoral cells. The success of TME-targeted therapies highlights their potential to achieve better cancer control or even a cure.
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Affiliation(s)
- Reem Youssef
- Department of Laboratory Medicine and Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Rohan Maniar
- Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Jaffar Khan
- Department of Laboratory Medicine and Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hector Mesa
- Department of Laboratory Medicine and Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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McMahon RA, D'Souza C, Neeson PJ, Siva S. Innate immunity: Looking beyond T-cells in radiation and immunotherapy combinations. Neoplasia 2023; 46:100940. [PMID: 37913654 PMCID: PMC10637988 DOI: 10.1016/j.neo.2023.100940] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/09/2023] [Accepted: 10/10/2023] [Indexed: 11/03/2023]
Abstract
Radiation therapy is an established and effective anti-cancer treatment modality. Extensive pre-clinical experimentation has demonstrated that the pro-inflammatory properties of irradiation may be synergistic with checkpoint immunotherapy. Radiation induces double-stranded DNA breaks (dsDNA). Sensing of the dsDNA activates the cGAS/STING pathway, producing Type 1 interferons essential to recruiting antigen-presenting cells (APCs). Radiation promotes cytotoxic CD8 T-cell recruitment by releasing tumour-associated antigens captured and cross-presented by surveying antigen-presenting cells. Radiation-induced vascular normalisation may further promote T-cell trafficking and drug delivery. Radiation is also immunosuppressive. Recruitment of regulatory T cells (Tregs) and innate cells such as myeloid-derived suppressive cells (m-MDSCs) all counteract the immunostimulatory properties of radiation. Many innate immune cell types operate at the interface of the adaptive immune response. Innate immune cells, such as m-MDSCs, can exert their immunosuppressive effects by expressing immune checkpoints such as PD-L1, further highlighting the potential of combined radiation and checkpoint immunotherapy. Several early-phase clinical studies investigating the combination of radiation and immunotherapy have been disappointing. A greater appreciation of radiotherapy's impact on the innate immune system is essential to optimise radioimmunotherapy combinations. This review will summarise the impact of radiotherapy on crucial cells of the innate immune system and vital immunosuppressive cytokines.
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Affiliation(s)
- R A McMahon
- Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia.
| | - C D'Souza
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia; Cancer Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
| | - P J Neeson
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia; Cancer Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
| | - S Siva
- Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, Australia
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Yi M, Li T, Niu M, Mei Q, Zhao B, Chu Q, Dai Z, Wu K. Exploiting innate immunity for cancer immunotherapy. Mol Cancer 2023; 22:187. [PMID: 38008741 PMCID: PMC10680233 DOI: 10.1186/s12943-023-01885-w] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 10/23/2023] [Indexed: 11/28/2023] Open
Abstract
Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.
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Affiliation(s)
- Ming Yi
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Tianye Li
- Department of Gynecology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310000, People's Republic of China
| | - Mengke Niu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China
| | - Qi Mei
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China
| | - Bin Zhao
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China
| | - Qian Chu
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
| | - Zhijun Dai
- Department of Breast Surgery, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, 310000, People's Republic of China.
| | - Kongming Wu
- Cancer Center, Shanxi Bethune Hospital, Shanxi Academy of Medical Science, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, People's Republic of China.
- Department of Oncology, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, People's Republic of China.
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Neamah WH, Rutkovsky A, Abdullah O, Wilson K, Bloomquist R, Nagarkatti P, Nagarkatti M. Resveratrol Attenuates 2,3,7,8-Tetrachlorodibenzo-p-dioxin-Mediated Induction of Myeloid-Derived Suppressor Cells (MDSC) and Their Functions. Nutrients 2023; 15:4667. [PMID: 37960320 PMCID: PMC10650545 DOI: 10.3390/nu15214667] [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: 09/16/2023] [Revised: 10/06/2023] [Accepted: 10/10/2023] [Indexed: 11/15/2023] Open
Abstract
Previously, we showed that 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), an aryl hydrocarbon receptor (AhR) ligand and a potent and persistent toxicant and carcinogenic agent, induces high levels of murine myeloid-derived suppressor cell (MDSC) when injected into mice. In the current study, we demonstrate that Resveratrol (3,4,5-trihydroxy-trans-stilbene; RSV), an AhR antagonist, reduces TCDD-mediated MDSC induction. RSV decreased the number of MDSCs induced by TCDD in mice but also mitigated the immunosuppressive function of TCDD-induced MDSCs. TCDD caused a decrease in F4/80+ macrophages and an increase in CD11C+ dendritic cells, while RSV reversed these effects. TCDD caused upregulation in CXCR2, a critical molecule involved in TCDD-mediated induction of MDSCs, and Arginase-1 (ARG-1), involved in the immunosuppressive functions of MDSCs, while RSV reversed this effect. Transcriptome analysis of Gr1+ MDSCs showed an increased gene expression profile involved in the metabolic pathways in mice exposed to TCDD while RSV-treated mice showed a decrease in such pathways. The bio-energetic profile of these cells showed that RSV treatment decreased the energetic demands induced by TCDD. Overall, the data demonstrated that RSV decreased TCDD-induced MDSC induction and function by altering the dynamics of various myeloid cell populations involving their numbers, phenotype, and immunosuppressive potency. Because MDSCs play a critical role in tumor growth and metastasis, our studies also support the potential use of RSV to attenuate the immunosuppressive properties of MDSC.
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Affiliation(s)
| | | | | | | | | | | | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC 29228, USA; (W.H.N.); (A.R.); (O.A.); (K.W.); (R.B.); (P.N.)
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