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1
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Peter A, Berneman ZN, Cools N. Cellular respiration in dendritic cells: Exploring oxygen-dependent pathways for potential therapeutic interventions. Free Radic Biol Med 2025; 227:536-556. [PMID: 39643130 DOI: 10.1016/j.freeradbiomed.2024.12.014] [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: 08/06/2024] [Revised: 12/01/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
Dendritic cells (DCs) are specialized antigen-presenting cells crucial for initiating and regulating adaptive immune responses, making them promising candidates for therapeutic interventions in various immune-mediated diseases. Increasing evidence suggests that the microenvironment in which cells are cultured, as well as the milieu in which they perform their functions, significantly impact their immunomodulatory properties. Among these environmental factors, the role of oxygen in DC biology and its significance for both their in vitro generation and in vivo therapeutic application require investigation. Unlike the atmospheric oxygen level of 21 % commonly used in in vitro assays, physiological oxygen levels are much lower (3-9 %), and hypoxia (<1.3 %) is a prevalent condition of both healthy tissues and disease states. This mismatch between laboratory and physiological conditions underscores the critical need to culture and evaluate therapeutic cells under physiologically relevant oxygen levels to improve their translational relevance and clinical outcomes. This review explores the characteristic hallmarks of human DCs that are influenced by oxygen-dependent pathways, including metabolism, phenotype, cytokine secretion, and migration. Furthermore, we discuss the potential of manipulating oxygen levels to refine the generation and functionality of DCs for therapeutic purposes.
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Affiliation(s)
- Antonia Peter
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium.
| | - Zwi N Berneman
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium; Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, 2650 Edegem, Belgium
| | - Nathalie Cools
- Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute (VAXINFECTIO), Faculty of Medicine and Health Sciences, University of Antwerp, 2610 Antwerp, Belgium; Center for Cell Therapy and Regenerative Medicine, Antwerp University Hospital, 2650 Edegem, Belgium
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2
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Chen J, Duan Y, Che J, Zhu J. Dysfunction of dendritic cells in tumor microenvironment and immunotherapy. Cancer Commun (Lond) 2024; 44:1047-1070. [PMID: 39051512 PMCID: PMC11492303 DOI: 10.1002/cac2.12596] [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: 01/31/2024] [Revised: 06/10/2024] [Accepted: 07/13/2024] [Indexed: 07/27/2024] Open
Abstract
Dendritic cells (DCs) comprise diverse cell populations that play critical roles in antigen presentation and triggering immune responses in the body. However, several factors impair the immune function of DCs and may promote immune evasion in cancer. Understanding the mechanism of DC dysfunction and the diverse functions of heterogeneous DCs in the tumor microenvironment (TME) is critical for designing effective strategies for cancer immunotherapy. Clinical applications targeting DCs summarized in this report aim to improve immune infiltration and enhance the biological function of DCs to modulate the TME to prevent cancer cells from evading the immune system. Herein, factors in the TME that induce DC dysfunction, such as cytokines, hypoxic environment, tumor exosomes and metabolites, and co-inhibitory molecules, have been described. Furthermore, several key signaling pathways involved in DC dysfunction and signal-relevant drugs evaluated in clinical trials were identified. Finally, this review provides an overview of current clinical immunotherapies targeting DCs, especially therapies with proven clinical outcomes, and explores future developments in DC immunotherapies.
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Affiliation(s)
- Jie Chen
- Jecho Institute Co., LtdShanghaiP. R. China
| | - Yuhang Duan
- Engineering Research Center of Cell & Therapeutic AntibodyMinistry of EducationBeijingP. R. China
- Shanghai Jiao Tong University, School of PharmacyShanghaiP. R. China
| | - Junye Che
- Jecho Institute Co., LtdShanghaiP. R. China
| | - Jianwei Zhu
- Jecho Institute Co., LtdShanghaiP. R. China
- Engineering Research Center of Cell & Therapeutic AntibodyMinistry of EducationBeijingP. R. China
- Shanghai Jiao Tong University, School of PharmacyShanghaiP. R. China
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3
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Mickael C, Sanders LA, Lee MH, Kumar R, Fonseca-Balladares D, Gandjeva A, Cautivo-Reyes K, Kassa B, Kumar S, Irwin D, Swindle D, Phang T, Stearman RS, Molofsky AB, McKee AS, Stenmark KR, Graham BB, Tuder RM. Classical dendritic cells contribute to hypoxia-induced pulmonary hypertension. FASEB J 2024; 38:e70015. [PMID: 39212294 PMCID: PMC11462638 DOI: 10.1096/fj.202400338rr] [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: 02/13/2024] [Revised: 08/06/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024]
Abstract
Pulmonary hypertension (PH) is a chronic and progressive disease with significant morbidity and mortality. It is characterized by remodeled pulmonary vessels associated with perivascular and intravascular accumulation of inflammatory cells. Although there is compelling evidence that bone marrow-derived cells, such as macrophages and T cells, cluster in the vicinity of pulmonary vascular lesions in humans and contribute to PH development in different animal models, the role of dendritic cells in PH is less clear. Dendritic cells' involvement in PH is likely since they are responsible for coordinating innate and adaptive immune responses. We hypothesized that dendritic cells drive hypoxic PH. We demonstrate that a classical dendritic cell (cDC) subset (cDC2) is increased and activated in wild-type mouse lungs after hypoxia exposure. We observe significant protection after the depletion of cDCs in ZBTB46 DTR chimera mice before hypoxia exposure and after established hypoxic PH. In addition, we find that cDC depletion is associated with a reduced number of two macrophage subsets in the lung (FolR2+ MHCII+ CCR2+ and FolR2+ MHCII+ CCR2-). We found that depleting cDC2s, but not cDC1s, was protective against hypoxic PH. Finally, proof-of-concept studies in human lungs show increased perivascular cDC2s in patients with Idiopathic Pulmonary Arterial Hypertension (IPAH). Our data points to an essential role of cDCs, particularly cDC2s, in the pathophysiology of experimental PH.
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Grants
- R01 HL142701 NHLBI NIH HHS
- R01 HL161004 NHLBI NIH HHS
- R01 AI162806 NIAID NIH HHS
- R01HL142701 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- R01AI162806 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- American Thoracic Society (ATS)
- K01 HL161024 NHLBI NIH HHS
- K08HL168310 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- K01HL161024 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- R01 HL135872 NHLBI NIH HHS
- W81XWH2210457 U.S. Department of Defense (DOD)
- Cardiovascular Medical Research and Education Fund (CMREF)
- Actelion Pharmaceuticals (Actelion Pharmaceuticals Ltd)
- R25HL146166 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- R25 HL146166 NHLBI NIH HHS
- R01NS126765 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- K08 HL168310 NHLBI NIH HHS
- United Therapeutics Corporation (Uni Ther)
- R01 NS126765 NINDS NIH HHS
- 19CDA34730030 American Heart Association (AHA)
- R01HL135872 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- PO1HL152961 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- R01 HL158076 NHLBI NIH HHS
- R01 H161004 HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)
- P01 HL152961 NHLBI NIH HHS
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Affiliation(s)
- Claudia Mickael
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA
- Cardiovascular Research Laboratories, University of Colorado, Aurora, Colorado, USA
| | - Linda A. Sanders
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA
- Cardiovascular Research Laboratories, University of Colorado, Aurora, Colorado, USA
| | - Michael H. Lee
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
- Lung Biology Center, Zuckerberg San Francisco General Hospital, San Francisco, California, USA
| | - Rahul Kumar
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
- Lung Biology Center, Zuckerberg San Francisco General Hospital, San Francisco, California, USA
| | - Dara Fonseca-Balladares
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
- Lung Biology Center, Zuckerberg San Francisco General Hospital, San Francisco, California, USA
| | - Aneta Gandjeva
- Cardiovascular Research Laboratories, University of Colorado, Aurora, Colorado, USA
| | - Kelly Cautivo-Reyes
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA
- Gilead Sciences, Foster City, California, USA
| | - Biruk Kassa
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
- Lung Biology Center, Zuckerberg San Francisco General Hospital, San Francisco, California, USA
| | - Sushil Kumar
- Cardiovascular Research Laboratories, University of Colorado, Aurora, Colorado, USA
| | - David Irwin
- Cardiovascular Research Laboratories, University of Colorado, Aurora, Colorado, USA
| | - Delaney Swindle
- Cardiovascular Research Laboratories, University of Colorado, Aurora, Colorado, USA
| | - Tzu Phang
- Section of Hematology, Oncology, and Bone Marrow Transplantation-Cellular Therapeutics (BMT-CT), Department of Pediatrics, School of Medicine, University of Colorado, Aurora, Colorado, USA
| | - Robert S. Stearman
- Department of Medicine, Division of Pulmonary, Critical Care, Sleep, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ari B. Molofsky
- Department of Laboratory Medicine, University of California San Francisco, San Francisco, California, USA
| | - Amy S. McKee
- Department of Medicine, Division of Clinical Immunology, University of Colorado, Aurora, Colorado, USA
- Department of Microbiology and Immunology and ClinImmune Cell and Gene Therapy, University of Colorado, Aurora, Colorado, USA
| | - Kurt R. Stenmark
- Cardiovascular Research Laboratories, University of Colorado, Aurora, Colorado, USA
| | - Brian B. Graham
- Department of Medicine, University of California San Francisco, San Francisco, California, USA
- Lung Biology Center, Zuckerberg San Francisco General Hospital, San Francisco, California, USA
| | - Rubin M. Tuder
- Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, Colorado, USA
- Cardiovascular Research Laboratories, University of Colorado, Aurora, Colorado, USA
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Luo J, Wang H, Chen J, Wei X, Feng J, Zhang Y, Zhou Y. The Application of Drugs and Nano-Therapies Targeting Immune Cells in Hypoxic Inflammation. Int J Nanomedicine 2024; 19:3441-3459. [PMID: 38617798 PMCID: PMC11015843 DOI: 10.2147/ijn.s456533] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Accepted: 03/29/2024] [Indexed: 04/16/2024] Open
Abstract
Immune cells are pivotal in the dynamic interplay between hypoxia and inflammation. During hypoxic conditions, HIF-1α, a crucial transcription factor, facilitates the adaptation of immune cells to the hypoxic micro-environment. This adaptation includes regulating immune cell metabolism, significantly impacting inflammation development. Strategies for anti-inflammatory and hypoxic relief have been proposed, aiming to disrupt the hypoxia-inflammation nexus. Research extensively focuses on anti-inflammatory agents and materials that target immune cells. These primarily mitigate hypoxic inflammation by encouraging M2-macrophage polarization, restraining neutrophil proliferation and infiltration, and maintaining Treg/TH17 balance. Additionally, oxygen-releasing nano-materials play a significant role. By alleviating hypoxia and clearing reactive oxygen species (ROS), these nano-materials indirectly influence immune cell functions. This paper delves into the response of immune cells under hypoxic conditions and the resultant effects on inflammation. It provides a comprehensive overview of various therapies targeting specific immune cells for anti-inflammatory purposes and explores nano-materials that either carry or generate oxygen to alleviate anoxic micro-environments.
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Affiliation(s)
- Jiaxin Luo
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Hanchi Wang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jingxia Chen
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Xuyan Wei
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Jian Feng
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Yidi Zhang
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
| | - Yanmin Zhou
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
- Department of Oral Implantology, Hospital of Stomatology, Jilin University, Changchun, 130021, People’s Republic of China
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5
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Guo S, Wang Z. Unveiling the immunosuppressive landscape of pancreatic ductal adenocarcinoma: implications for innovative immunotherapy strategies. Front Oncol 2024; 14:1349308. [PMID: 38590651 PMCID: PMC10999533 DOI: 10.3389/fonc.2024.1349308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/12/2024] [Indexed: 04/10/2024] Open
Abstract
Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), stands as the fourth leading cause of cancer-related deaths in the United States, marked by challenging treatment and dismal prognoses. As immunotherapy emerges as a promising avenue for mitigating PDAC's malignant progression, a comprehensive understanding of the tumor's immunosuppressive characteristics becomes imperative. This paper systematically delves into the intricate immunosuppressive network within PDAC, spotlighting the significant crosstalk between immunosuppressive cells and factors in the hypoxic acidic pancreatic tumor microenvironment. By elucidating these mechanisms, we aim to provide insights into potential immunotherapy strategies and treatment targets, laying the groundwork for future studies on PDAC immunosuppression. Recognizing the profound impact of immunosuppression on PDAC invasion and metastasis, this discussion aims to catalyze the development of more effective and targeted immunotherapies for PDAC patients.
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Affiliation(s)
- Songyu Guo
- First Clinical Medical College, Inner Mongolia Medical University, Hohhot, China
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
| | - Zhenxia Wang
- Department of Hepatic-Biliary-Pancreatic Surgery, The Affiliated Hospital of Inner Mongolia Medical University, Hohhot, China
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6
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Liang J, Qiao X, Qiu L, Xu H, Xiang H, Ding H, Chen Y. Engineering Versatile Nanomedicines for Ultrasonic Tumor Immunotherapy. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2305392. [PMID: 38041509 PMCID: PMC10797440 DOI: 10.1002/advs.202305392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 10/15/2023] [Indexed: 12/03/2023]
Abstract
Due to the specific advantages of ultrasound (US) in therapeutic disease treatments, the unique therapeutic US technology has emerged. In addition to featuring a low-invasive targeted cancer-cell killing effect, the therapeutic US technology has been demonstrated to modulate the tumor immune landscape, amplify the therapeutic effect of other antitumor therapies, and induce immunosensitization of tumors to immunotherapy, shedding new light on the cancer treatment. Tremendous advances in nanotechnology are also expected to bring unprecedented benefits to enhancing the antitumor efficiency and immunological effects of therapeutic US, as well as therapeutic US-derived bimodal and multimodal synergistic therapies. This comprehensive review summarizes the immunological effects induced by different therapeutic US technologies, including ultrasound-mediated micro-/nanobubble destruction (UTMD/UTND), sonodynamic therapy (SDT), and focused ultrasound (FUS), as well as the main underlying mechanisms involved. It is also discussed that the recent research progress of engineering intelligent nanoplatform in improving the antitumor efficiency of therapeutic US technologies. Finally, focusing on clinical translation, the key issues and challenges currently faced are summarized, and the prospects for promoting the clinical translation of these emerging nanomaterials and ultrasonic immunotherapy in the future are proposed.
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Affiliation(s)
- Jing Liang
- Department of UltrasoundHuashan HospitalFudan UniversityShanghai200040China
| | - Xiaohui Qiao
- Department of UltrasoundHuashan HospitalFudan UniversityShanghai200040China
| | - Luping Qiu
- Department of UltrasoundHuashan HospitalFudan UniversityShanghai200040China
| | - Huning Xu
- Department of UltrasoundHuashan HospitalFudan UniversityShanghai200040China
| | - Huijing Xiang
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai2000444China
| | - Hong Ding
- Department of UltrasoundHuashan HospitalFudan UniversityShanghai200040China
| | - Yu Chen
- Materdicine LabSchool of Life SciencesShanghai UniversityShanghai2000444China
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7
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Bhatt K, Nukovic A, Colombani T, Bencherif SA. Biomaterial-assisted local oxygenation safeguards the prostimulatory phenotype and functions of human dendritic cells in hypoxia. Front Immunol 2023; 14:1278397. [PMID: 38169677 PMCID: PMC10758617 DOI: 10.3389/fimmu.2023.1278397] [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: 08/16/2023] [Accepted: 11/08/2023] [Indexed: 01/05/2024] Open
Abstract
Dendritic cells (DCs), professional antigen-presenting cells, function as sentinels of the immune system. DCs initiate and fine-tune adaptive immune responses by presenting antigenic peptides to B and T lymphocytes to mount an effective immune response against cancer and pathogens. However, hypoxia, a condition characterized by low oxygen (O2) tension in different tissues, significantly impacts DC functions, including antigen uptake, activation and maturation, migration, as well as T-cell priming and proliferation. In this study, we employed O2-releasing biomaterials (O2-cryogels) to study the effect of localized O2 supply on human DC phenotype and functions. Our results indicate that O2-cryogels effectively mitigate DC exposure to hypoxia under hypoxic conditions. Additionally, O2-cryogels counteract hypoxia-induced inhibition of antigen uptake and migratory activity in DCs through O2 release and hyaluronic acid (HA) mediated mechanisms. Furthermore, O2-cryogels preserve and restore DC maturation and co-stimulation markers, including HLA-DR, CD86, and CD40, along with the secretion of proinflammatory cytokines in hypoxic conditions. Finally, our findings demonstrate that the supplemental O2 released from the cryogels preserves DC-mediated T-cell priming, ultimately leading to the activation and proliferation of allogeneic CD3+ T cells. This work emphasizes the potential of local oxygenation as a powerful immunomodulatory agent to improve DC activation and functions in hypoxia, offering new approaches for cancer and infectious disease treatments.
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Affiliation(s)
- Khushbu Bhatt
- Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, United States
| | - Alexandra Nukovic
- Department of Chemical Engineering, Northeastern University, Boston, MA, United States
| | - Thibault Colombani
- Department of Chemical Engineering, Northeastern University, Boston, MA, United States
| | - Sidi A. Bencherif
- Department of Chemical Engineering, Northeastern University, Boston, MA, United States
- Department of Bioengineering, Northeastern University, Boston, MA, United States
- Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, United States
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8
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Xiao Z, Wang R, Wang X, Yang H, Dong J, He X, Yang Y, Guo J, Cui J, Zhou Z. Impaired function of dendritic cells within the tumor microenvironment. Front Immunol 2023; 14:1213629. [PMID: 37441069 PMCID: PMC10333501 DOI: 10.3389/fimmu.2023.1213629] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/13/2023] [Indexed: 07/15/2023] Open
Abstract
Dendritic cells (DCs), a class of professional antigen-presenting cells, are considered key factors in the initiation and maintenance of anti-tumor immunity due to their powerful ability to present antigen and stimulate T-cell responses. The important role of DCs in controlling tumor growth and mediating potent anti-tumor immunity has been demonstrated in various cancer models. Accordingly, the infiltration of stimulatory DCs positively correlates with the prognosis and response to immunotherapy in a variety of solid tumors. However, accumulating evidence indicates that DCs exhibit a significantly dysfunctional state, ultimately leading to an impaired anti-tumor immune response due to the effects of the immunosuppressive tumor microenvironment (TME). Currently, numerous preclinical and clinical studies are exploring immunotherapeutic strategies to better control tumors by restoring or enhancing the activity of DCs in tumors, such as the popular DC-based vaccines. In this review, an overview of the role of DCs in controlling tumor progression is provided, followed by a summary of the current advances in understanding the mechanisms by which the TME affects the normal function of DCs, and concluding with a brief discussion of current strategies for DC-based tumor immunotherapy.
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Affiliation(s)
- Zhihua Xiao
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Ruiqi Wang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Xuyan Wang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Haikui Yang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Jiamei Dong
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Xin He
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Yang Yang
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
| | - Jiahao Guo
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Jiawen Cui
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
- College of Pharmacy, Jinan University, Guangzhou, China
| | - Zhiling Zhou
- Department of Pharmacy, Zhuhai People’s Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, China
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9
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Perez RC, Kim D, Maxwell AWP, Camacho JC. Functional Imaging of Hypoxia: PET and MRI. Cancers (Basel) 2023; 15:3336. [PMID: 37444446 DOI: 10.3390/cancers15133336] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/22/2023] [Accepted: 06/22/2023] [Indexed: 07/15/2023] Open
Abstract
Molecular and functional imaging have critical roles in cancer care. Existing evidence suggests that noninvasive detection of hypoxia within a particular type of cancer can provide new information regarding the relationship between hypoxia, cancer aggressiveness and altered therapeutic responses. Following the identification of hypoxia inducible factor (HIF), significant progress in understanding the regulation of hypoxia-induced genes has been made. These advances have provided the ability to therapeutically target HIF and tumor-associated hypoxia. Therefore, by utilizing the molecular basis of hypoxia, hypoxia-based theranostic strategies are in the process of being developed which will further personalize care for cancer patients. The aim of this review is to provide an overview of the significance of tumor hypoxia and its relevance in cancer management as well as to lay out the role of imaging in detecting hypoxia within the context of cancer.
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Affiliation(s)
- Ryan C Perez
- Florida State University College of Medicine, Tallahassee, FL 32306, USA
| | - DaeHee Kim
- Department of Diagnostic Imaging, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Aaron W P Maxwell
- Department of Diagnostic Imaging, The Warren Alpert Medical School, Brown University, Providence, RI 02903, USA
| | - Juan C Camacho
- Department of Clinical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
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10
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Smith V, Lee D, Reardon M, Shabbir R, Sahoo S, Hoskin P, Choudhury A, Illidge T, West CML. Hypoxia Is Associated with Increased Immune Infiltrates and Both Anti-Tumour and Immune Suppressive Signalling in Muscle-Invasive Bladder Cancer. Int J Mol Sci 2023; 24:ijms24108956. [PMID: 37240301 DOI: 10.3390/ijms24108956] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 04/25/2023] [Accepted: 05/03/2023] [Indexed: 05/28/2023] Open
Abstract
Hypoxia and a suppressive tumour microenvironment (TME) are both independent negative prognostic factors for muscle-invasive bladder cancer (MIBC) that contribute to treatment resistance. Hypoxia has been shown to induce an immune suppressive TME by recruiting myeloid cells that inhibit anti-tumour T cell responses. Recent transcriptomic analyses show hypoxia increases suppressive and anti-tumour immune signalling and infiltrates in bladder cancer. This study sought to investigate the relationship between hypoxia-inducible factor (HIF)-1 and -2, hypoxia, and immune signalling and infiltrates in MIBC. ChIP-seq was performed to identify HIF1α, HIF2α, and HIF1β binding in the genome of the MIBC cell line T24 cultured in 1% and 0.1% oxygen for 24 h. Microarray data from four MIBC cell lines (T24, J82, UMUC3, and HT1376) cultured under 1%, 0.2%, and 0.1% oxygen for 24 h were used. Differences in the immune contexture between high- and low-hypoxia tumours were investigated using in silico analyses of two bladder cancer cohorts (BCON and TCGA) filtered to only include MIBC cases. GO and GSEA were used with the R packages "limma" and "fgsea". Immune deconvolution was performed using ImSig and TIMER algorithms. RStudio was used for all analyses. Under hypoxia, HIF1α and HIF2α bound to ~11.5-13.5% and ~4.5-7.5% of immune-related genes, respectively (1-0.1% O2). HIF1α and HIF2α both bound to genes associated with T cell activation and differentiation signalling pathways. HIF1α and HIF2α had distinct roles in immune-related signalling. HIF1 was associated with interferon production specifically, whilst HIF2 was associated with generic cytokine signalling as well as humoral and toll-like receptor immune responses. Neutrophil and myeloid cell signalling was enriched under hypoxia, alongside hallmark pathways associated with Tregs and macrophages. High-hypoxia MIBC tumours had increased expression of both suppressive and anti-tumour immune gene signatures and were associated with increased immune infiltrates. Overall, hypoxia is associated with increased inflammation for both suppressive and anti-tumour-related immune signalling and immune infiltrates, as seen in vitro and in situ using MIBC patient tumours.
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Affiliation(s)
- Vicky Smith
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
| | - Dave Lee
- Computational Biology Support, CRUK Manchester Institute, Alderley Park SK10 4TG, UK
| | - Mark Reardon
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
| | - Rekaya Shabbir
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
| | - Sudhakar Sahoo
- Computational Biology Support, CRUK Manchester Institute, Alderley Park SK10 4TG, UK
| | - Peter Hoskin
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
- The Christie Hospital NHS Foundation Trust, Manchester M20 4BX, UK
- Mount Vernon Cancer Centre, Northwood HA6 2RN, UK
| | - Ananya Choudhury
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
- The Christie Hospital NHS Foundation Trust, Manchester M20 4BX, UK
- Manchester Academic Health Science Centre, Manchester M13 9NQ, UK
| | - Timothy Illidge
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
- The Christie Hospital NHS Foundation Trust, Manchester M20 4BX, UK
- Manchester Academic Health Science Centre, Manchester M13 9NQ, UK
| | - Catharine M L West
- Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK
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11
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Velasco RM, García AG, Sánchez PJ, Sellart IM, Sánchez-Arévalo Lobo VJ. Tumour microenvironment and heterotypic interactions in pancreatic cancer. J Physiol Biochem 2023; 79:179-192. [PMID: 35102531 DOI: 10.1007/s13105-022-00875-8] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 01/18/2022] [Indexed: 12/27/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a disease with a survival rate of 9%; this is due to its chemoresistance and the large tumour stroma that occupies most of the tumour mass. It is composed of a large number of cells of the immune system, such as Treg cells, tumour-associated macrophages (TAMs), myeloid suppressor cells (MDCs) and tumour-associated neutrophiles (TANs) that generate an immunosuppressive environment by the release of inflammatory cytokines. Moreover, cancer-associated fibroblast (CAFs) provide a protective coverage that would difficult the access of chemotherapy to the tumour. According to this, new therapies that could remodel this heterogeneous tumour microenvironment, such as adoptive T cell therapies (ACT), immune checkpoint inhibitors (ICI), and CD40 agonists, should be developed for targeting PDA. This review organizes the different cell populations found in the tumour stroma involved in tumour progression in addition to the different therapies that are being studied to counteract the tumour.
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Affiliation(s)
- Raúl Muñoz Velasco
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain
| | - Ana García García
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain
| | - Paula Jiménez Sánchez
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain
| | - Inmaculada Montanuy Sellart
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain
| | - Víctor Javier Sánchez-Arévalo Lobo
- Molecular Oncology Group, Faculty of Experimental Sciences, Biosanitary Research Institute, Francisco de Vitoria University, 28223, Pozuelo de Alarcón, Madrid, UFV, Spain.
- Instituto de Investigación Hospital 12 de Octubre, Pathology Department, Av. Córdoba, s/n, 28041, Madrid, Spain.
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12
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Liao C, Liu X, Zhang C, Zhang Q. Tumor hypoxia: From basic knowledge to therapeutic implications. Semin Cancer Biol 2023; 88:172-186. [PMID: 36603793 PMCID: PMC9929926 DOI: 10.1016/j.semcancer.2022.12.011] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 12/07/2022] [Accepted: 12/31/2022] [Indexed: 01/04/2023]
Abstract
Diminished oxygen availability, termed hypoxia, within solid tumors is one of the most common characteristics of cancer. Hypoxia shapes the landscape of the tumor microenvironment (TME) into a pro-tumorigenic and pro-metastatic niche through arrays of pathological alterations such as abnormal vasculature, altered metabolism, immune-suppressive phenotype, etc. In addition, emerging evidence suggests that limited efficacy or the development of resistance towards antitumor therapy may be largely due to the hypoxic TME. This review will focus on summarizing the knowledge about the molecular machinery that mediates the hypoxic cellular responses and adaptations, as well as highlighting the effects and consequences of hypoxia, especially for angiogenesis regulation, cellular metabolism alteration, and immunosuppressive response within the TME. We also outline the current advances in novel therapeutic implications through targeting hypoxia in TME. A deep understanding of the basics and the role of hypoxia in the tumor will help develop better therapeutic avenues in cancer treatment.
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Affiliation(s)
- Chengheng Liao
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Xijuan Liu
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC 27599, USA
| | - Cheng Zhang
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Qing Zhang
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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13
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Winning S, Fandrey J. Oxygen Sensing in Innate Immune Cells: How Inflammation Broadens Classical Hypoxia-Inducible Factor Regulation in Myeloid Cells. Antioxid Redox Signal 2022; 37:956-971. [PMID: 35088604 DOI: 10.1089/ars.2022.0004] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Significance: Oxygen deprivation (hypoxia) is a common feature at sites of inflammation. Immune cells and all other cells present at the inflamed site have to adapt to these conditions. They do so by stabilization and activation of hypoxia-inducible factor subunit α (HIF-1α and HIF-2α, respectively), enabling constant generation of adenosine triphosphate (ATP) under these austere conditions by the induction of, for example, glycolytic pathways. Recent Advances: During recent years, it has become evident that HIFs play a far more important role than initially believed because they shape the inflammatory phenotype of immune cells. They are indispensable for migration, phagocytosis, and the induction of inflammatory cytokines by innate immune cells and thereby enable a crosstalk between innate and adaptive immunity. In short, they ensure the survival and function of immune cells under critical conditions. Critical Issues: Up to now, there are still open questions regarding the individual roles of HIF-1 and HIF-2 for the different cell types. In particular, the loss of both HIF-1 and HIF-2 in myeloid cells led to unexpected and contradictory results in the mouse models analyzed so far. Similarly, the role of HIF-1 in dendritic cell maturation is unclear due to inconsistent results from in vitro experiments. Future Directions: The HIFs are indispensable for immune cell survival and action under inflammatory conditions, but they might also trigger over-activation of immune cells. Therefore, they might be excellent setscrews to adjust the inflammatory response by pharmaceuticals. China and Japan and very recently (August 2021) Europe have approved prolyl hydroxylase inhibitors (PHIs) to stabilize HIF such as roxadustat for clinical use to treat anemia by increasing the production of erythropoietin, the classical HIF target gene. Nonetheless, we need further work regarding the use of PHIs under inflammatory conditions, because HIFs show specific activation and distinct expression patterns in innate immune cells. The extent to which HIF-1 or HIF-2 as a transcription factor regulates the adaptation of immune cells to inflammatory hypoxia differs not only by the cell type but also with the inflammatory challenge and the surrounding tissue. Therefore, we urgently need isoform- and cell type-specific modulators of the HIF pathway. Antioxid. Redox Signal. 37, 956-971.
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Affiliation(s)
- Sandra Winning
- Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | - Joachim Fandrey
- Institut für Physiologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
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14
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Hu J, Li X, Yang L, Li H. Hypoxia, a key factor in the immune microenvironment. Biomed Pharmacother 2022; 151:113068. [PMID: 35676780 DOI: 10.1016/j.biopha.2022.113068] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 04/15/2022] [Accepted: 04/28/2022] [Indexed: 11/29/2022] Open
Abstract
The physical and chemical pressures in the tumor microenvironment (TME) play an important role in tumor development by regulating stromal elements, including immune cells. Hypoxia can induce a cascade of events in tumor initiation and development via immune regulation. As a dangerous factor, hypoxia activates multiple signaling pathways to reshape the immune microenvironment, leading to immunosuppression. Consequently, targeting hypoxia in the TME is a potential strategy to prevent immune escape and inhibit malignant tumor progression. In this review, we summarized the role of hypoxia-induced factors in the tumor immune escape process and provide a novel pathway to restrain tumor progression and development.
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Affiliation(s)
- Jingyao Hu
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
| | - Xinyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
| | - Liang Yang
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
| | - Hangyu Li
- Department of General Surgery, The Fourth Affiliated Hospital, China Medical University, Shenyang 110032, China.
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15
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DFO treatment protects against depression-like behaviors and cognitive impairment in CUMS mice. Brain Res Bull 2022; 187:75-84. [PMID: 35779818 DOI: 10.1016/j.brainresbull.2022.06.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 06/18/2022] [Accepted: 06/26/2022] [Indexed: 11/24/2022]
Abstract
Depression has several negative effects on emotion as well as learning and memory abilities. Previous studies showed that depression could exacerbate inflammation, which in turn further aggravated depression. Deferoxamine (DFO) is a chelating agent binding iron and aluminium, and is clinically applied to treat acute ion poisoning and hemochromatosis. Researches showed that it could reduce inflammation via increasing the expression of hypoxia-inducible factor-1alpha (HIF-1α). Here, we established a chronic unpredictable mild stress (CUMS) model to investigate whether DFO exerted a neuroprotective function in depression. The results demonstrated that CUMS (4 weeks) effectively induced depression-like behaviors in mice based on sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), open field test (OFT), and elevated plus-maze test (EPT). It also brought cognitive deficits based on Morris water maze (MWM) test and the impairment of synaptic plasticity based on in vivo electrophysiological recordings. Additionally, CUMS exposure significantly decreased the expression of hippocampal synapse related proteins and the spine density of neurons in the DG region, accompanied by increasing the expression of hippocampal inflammatory cytokines, and promoted the activation of microglia in the hippocampus. The expression of HIF-1α was down-regulated as expected. However, DFO distinctly reversed the CUMS-induced impairments. The mechanism is associated with the DFO inhibition of inflammation by upregulating HIF-1 expression, thereby alleviating a series of pathology changes. Together, these findings suggest that DFO likely plays a protective role in cognitive impairments and synaptic plasticity deficits resulting from depression.
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16
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Onishi H, Nakamura K, Yanai K, Nagai S, Nakayama K, Oyama Y, Fujimura A, Ozono K, Yamasaki A. Cancer therapy that targets the Hedgehog signaling pathway considering the cancer microenvironment (Review). Oncol Rep 2022; 47:93. [DOI: 10.3892/or.2022.8304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 02/25/2022] [Indexed: 11/05/2022] Open
Affiliation(s)
- Hideya Onishi
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Katsuya Nakamura
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kosuke Yanai
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Shuntaro Nagai
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Kazunori Nakayama
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Yasuhiro Oyama
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Akiko Fujimura
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Keigo Ozono
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
| | - Akio Yamasaki
- Department of Cancer Therapy and Research, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812‑8582, Japan
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17
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He X, Ding J, Cheng X, Xiong M. Hypoxia-Related Gene-Based Signature Can Evaluate the Tumor Immune Microenvironment and Predict the Prognosis of Colon Adenocarcinoma Patients. Int J Gen Med 2021; 14:9853-9862. [PMID: 34938106 PMCID: PMC8687688 DOI: 10.2147/ijgm.s343216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/01/2021] [Indexed: 12/31/2022] Open
Abstract
Background Colon adenocarcinoma (COAD) is a common gastrointestinal tumor and often occurs in the left colon with a poor prognosis. The progression of COAD is closely related to the tumor microenvironment, especially the hypoxia. Currently, few studies have reported the correlation between hypoxia-related genes and the prognosis of COAD patients. Furthermore, we constructed a prognostic model using four hypoxia-related genes to predict the prognosis of COAD patients. Methods The mRNA expression profiles and corresponding clinicopathological data were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). The string online analysis tool was used to construct a protein–protein interaction network (PPI) of hypoxia-related genes. Kaplan–Meier curve was used to analyze the relationship of hypoxia risk score and the overall survival of COAD patients, and the receiver operating characteristic (ROC) curve was used to assess the reliability. Results We screened out four hypoxia genes, including TKTL1 (transketolase like 1), SLC2A3 (solute carrier family 2 member 3), ALDOB (aldolase, fructose-bisphosphate B) and ENO3 (enolase 3), which were used to construct a hypoxia risk model to predict the overall survival of COAD patients. Besides, we also found that the hypoxia risk score was correlated with the immunosuppression of tumor microenvironment. Conclusion The model we constructed with four survival-related hypoxia genes, including TKTL1, SLC2A3, ALDOB and ENO3, could be used to predict the overall survival of COAD patients with high stability.
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Affiliation(s)
- Xiaobo He
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Jianfeng Ding
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
| | - Xiao Cheng
- Ningbo Diagnostic Pathology Center Department of Pathology, Ningbo, Zhejiang, 315021, People’s Republic of China
| | - Maoming Xiong
- Department of General Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, People’s Republic of China
- Correspondence: Maoming Xiong Email
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18
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Blocking HIF to Enhance NK Cells: Hints for New Anti-Tumor Therapeutic Strategies? Vaccines (Basel) 2021; 9:vaccines9101144. [PMID: 34696251 PMCID: PMC8539190 DOI: 10.3390/vaccines9101144] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/30/2021] [Accepted: 10/01/2021] [Indexed: 12/18/2022] Open
Abstract
Natural Killer (NK) cells are becoming an ever more promising tool to design new anti-tumor strategies. However, two major issues are still a challenge to obtain versatile and effective NK-based therapies: the way to maximize the persistency of powerful NK effectors in the patient, and the way to overcome the multiple escape mechanisms that keep away or suppress NK cells at the tumor site. In this regard, targeting the hypoxia-inducible factors (HIFs), which is important for both tumor progression and immune suppression, may be an opportunity. Especially, in the context of the ongoing studies focused on more effective NK-based therapeutic products.
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19
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Son SW, Yun BD, Song MG, Lee JK, Choi SY, Kuh HJ, Park JK. The Hypoxia-Long Noncoding RNA Interaction in Solid Cancers. Int J Mol Sci 2021; 22:ijms22147261. [PMID: 34298879 PMCID: PMC8307739 DOI: 10.3390/ijms22147261] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 02/07/2023] Open
Abstract
Hypoxia is one of the representative microenvironment features in cancer and is considered to be associated with the dismal prognosis of patients. Hypoxia-driven cellular pathways are largely regulated by hypoxia-inducible factors (HIFs) and notably exert influence on the hallmarks of cancer, such as stemness, angiogenesis, invasion, metastasis, and the resistance towards apoptotic cell death and therapeutic resistance; therefore, hypoxia has been considered as a potential hurdle for cancer therapy. Growing evidence has demonstrated that long noncoding RNAs (lncRNAs) are dysregulated in cancer and take part in gene regulatory networks owing to their various modes of action through interacting with proteins and microRNAs. In this review, we focus attention on the relationship between hypoxia/HIFs and lncRNAs, in company with the possibility of lncRNAs as candidate molecules for controlling cancer.
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Affiliation(s)
- Seung Wan Son
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Ba Da Yun
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Mun Gyu Song
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Jin Kyeong Lee
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Soo Young Choi
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
| | - Hyo Jeong Kuh
- Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Jong Kook Park
- Department of Biomedical Science, Research Institute for Bioscience & Biotechnology, Hallym University, Chunchon 24252, Korea; (S.W.S.); (B.D.Y.); (M.G.S.); (J.K.L.); (S.Y.C.)
- Correspondence: ; Tel.: +82-33-248-2114
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20
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King R, Hayes C, Donohoe CL, Dunne MR, Davern M, Donlon NE. Hypoxia and its impact on the tumour microenvironment of gastroesophageal cancers. World J Gastrointest Oncol 2021; 13:312-331. [PMID: 34040696 PMCID: PMC8131902 DOI: 10.4251/wjgo.v13.i5.312] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Revised: 02/24/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
The malfeasant role of the hypoxic tumour microenvironment (TME) in cancer progression was recognized decades ago but the exact mechanisms that augment the hallmarks of cancer and promote treatment resistance continue to be elucidated. Gastroesophageal cancers (GOCs) represent a major burden of worldwide disease, responsible for the deaths of over 1 million people annually. Disentangling the impact of hypoxia in GOCs enables a better overall understanding of the disease pathogenesis while shining a light on novel therapeutic strategies and facilitating precision treatment approaches with the ultimate goal of improving outcomes for patients with these diseases. This review discusses the underlying principles and processes of the hypoxic response and the effect of hypoxia in promoting the hallmarks of cancer in the context of GOCs. We focus on its bidirectional influence on inflammation and how it drives angiogenesis, innate and adaptive immune evasion, metastasis, and the reprogramming of cellular bioenergetics. The contribution of the hypoxic GOC TME to treatment resistance is examined and a brief overview of the pharmacodynamics of hypoxia-targeted therapeutics is given. The principal methods that are used in measuring hypoxia and how they may enhance prognostication or provide rationale for individually tailored management in the case of tumours with significant hypoxic regions are also discussed.
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Affiliation(s)
- Ross King
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Conall Hayes
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Claire L Donohoe
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Margaret R Dunne
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Maria Davern
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
| | - Noel E Donlon
- Department of Surgery, St. James’s Hospital Campus, Trinity Translational Medicine Institute, Dublin D8, Ireland
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21
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Jiang M, Ren L, Chen Y, Wang H, Wu H, Cheng S, Li G, Yu S. Identification of a Hypoxia-Related Signature for Predicting Prognosis and the Immune Microenvironment in Bladder Cancer. Front Mol Biosci 2021; 8:613359. [PMID: 34026819 PMCID: PMC8138130 DOI: 10.3389/fmolb.2021.613359] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 04/22/2021] [Indexed: 01/19/2023] Open
Abstract
Accumulating evidence indicates that hypoxia is highly associated with bladder cancer genesis, progression, and immune microenvironment. Nevertheless, few studies have identified the role of hypoxia-related genes as a prognostic signature in bladder cancer. This study aimed to establish a hypoxia-related signature with high accuracy for prognosis and immune microenvironment prediction in bladder cancer. We obtained expression profiles and clinical information from Gene Expression Omnibus and The Cancer Genome Atlas. Then the univariate Cox regression, random survival forest algorithm, and multivariate Cox regression analysis were conducted to identify the core genes and four hypoxia-related genes (ANXA2, GALK1, COL5A1, and HS3ST1) were selected to construct the signature. Kaplan-Meier survival analysis demonstrated that patients with a low-risk score had a higher disease-specific survival rate (p < 0.0001). The areas under the curve of the signature were 0.829 at 1 year, 0.869 at 3 years, and 0.848 at 5 years, respectively. Additionally, we found this hypoxia-related signature was highly correlated with tumor immune microenvironment and had the potential to predict the efficacy of immunotherapy. In summary, our study developed a hypoxia-related signature, which had high accuracy for prognosis prediction and the potential to guide the immunotherapy for bladder cancer patients.
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Affiliation(s)
- Minxiao Jiang
- Department of Urology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Liangliang Ren
- Department of Urology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yuanlei Chen
- Department of Urology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Huan Wang
- Department of Urology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haiyang Wu
- Department of Urology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Sheng Cheng
- Department of Urology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Gonghui Li
- Department of Urology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Shicheng Yu
- Department of Urology, Sir Run-Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
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22
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Weng CY, Kao CX, Chang TS, Huang YH. Immuno-Metabolism: The Role of Cancer Niche in Immune Checkpoint Inhibitor Resistance. Int J Mol Sci 2021; 22:1258. [PMID: 33514004 PMCID: PMC7865434 DOI: 10.3390/ijms22031258] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 01/24/2021] [Accepted: 01/25/2021] [Indexed: 12/12/2022] Open
Abstract
The use of immune checkpoint inhibitors (ICI) in treating cancer has revolutionized the approach to eradicate cancer cells by reactivating immune responses. However, only a subset of patients benefits from this treatment; the majority remains unresponsive or develops resistance to ICI therapy. Increasing evidence suggests that metabolic machinery in the tumor microenvironment (TME) plays a role in the development of ICI resistance. Within the TME, nutrients and oxygen are scarce, forcing immune cells to undergo metabolic reprogramming to adapt to harsh conditions. Cancer-induced metabolic deregulation in immune cells can attenuate their anti-cancer properties, but can also increase their immunosuppressive properties. Therefore, targeting metabolic pathways of immune cells in the TME may strengthen the efficacy of ICIs and prevent ICI resistance. In this review, we discuss the interactions of immune cells and metabolic alterations in the TME. We also discuss current therapies targeting cellular metabolism in combination with ICIs for the treatment of cancer, and provide possible mechanisms behind the cellular metabolic rewiring that may improve clinical outcomes.
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Affiliation(s)
- Chao-Yuan Weng
- School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan;
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
| | - Cheng-Xiang Kao
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Te-Sheng Chang
- School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan 33382, Taiwan
- Division of Internal Medicine, Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chiayi 61363, Taiwan
| | - Yen-Hua Huang
- Department of Biochemistry and Molecular Cell Biology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cell Therapy and Regeneration Medicine, Taipei Medical University, Taipei 11031, Taiwan
- International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Center for Reproductive Medicine, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
- Comprehensive Cancer Center of Taipei Medical University, Taipei 11031, Taiwan
- PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
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23
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The Role of HIF in Immunity and Inflammation. Cell Metab 2020; 32:524-536. [PMID: 32853548 DOI: 10.1016/j.cmet.2020.08.002] [Citation(s) in RCA: 372] [Impact Index Per Article: 74.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/07/2020] [Accepted: 08/05/2020] [Indexed: 12/19/2022]
Abstract
HIF is a transcription factor that plays an essential role in the cellular response to low oxygen, orchestrating a metabolic switch that allows cells to survive in this environment. In immunity, infected and inflamed tissues are often hypoxic, and HIF helps immune cells adapt. HIF-α stabilization can also occur under normoxia during immunity and inflammation, where it regulates metabolism but in addition can directly regulate expression of immune genes. Here we review the role of HIF in immunity, including its role in macrophages, dendritic cells, neutrophils, T cells, and B cells. Its role in immunity is as essential for cellular responses as it is in its original role in hypoxia, with HIF being implicated in multiple inflammatory diseases and in immunosuppression in tumors.
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24
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Iberg CA, Hawiger D. Natural and Induced Tolerogenic Dendritic Cells. THE JOURNAL OF IMMUNOLOGY 2020; 204:733-744. [PMID: 32015076 DOI: 10.4049/jimmunol.1901121] [Citation(s) in RCA: 167] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 10/04/2019] [Indexed: 11/19/2022]
Abstract
Dendritic cells (DCs) are highly susceptible to extrinsic signals that modify the functions of these crucial APCs. Maturation of DCs induced by diverse proinflammatory conditions promotes immune responses, but certain signals also induce tolerogenic functions in DCs. These "induced tolerogenic DCs" help to moderate immune responses such as those to commensals present at specific anatomical locations. However, also under steady-state conditions, some DCs are characterized by inherent tolerogenic properties. The immunomodulatory mechanisms constitutively present in such "natural tolerogenic DCs" help to promote tolerance to peripheral Ags. By extending tolerance initially established in the thymus, these functions of DCs help to regulate autoimmune and other immune responses. In this review we will discuss the mechanisms and functions of natural and induced tolerogenic DCs and offer further insight into how their possible manipulations may ultimately lead to more precise treatments for various immune-mediated conditions and diseases.
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Affiliation(s)
- Courtney A Iberg
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104
| | - Daniel Hawiger
- Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, MO 63104
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25
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Korbecki J, Kojder K, Barczak K, Simińska D, Gutowska I, Chlubek D, Baranowska-Bosiacka I. Hypoxia Alters the Expression of CC Chemokines and CC Chemokine Receptors in a Tumor-A Literature Review. Int J Mol Sci 2020; 21:ijms21165647. [PMID: 32781743 PMCID: PMC7460668 DOI: 10.3390/ijms21165647] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 02/06/2023] Open
Abstract
Hypoxia, i.e., oxygen deficiency condition, is one of the most important factors promoting the growth of tumors. Since its effect on the chemokine system is crucial in understanding the changes in the recruitment of cells to a tumor niche, in this review we have gathered all the available data about the impact of hypoxia on β chemokines. In the introduction, we present the chronic (continuous, non-interrupted) and cycling (intermittent, transient) hypoxia together with the mechanisms of activation of hypoxia inducible factors (HIF-1 and HIF-2) and NF-κB. Then we describe the effect of hypoxia on the expression of chemokines with the CC motif: CCL1, CCL2, CCL3, CCL4, CCL5, CCL7, CCL8, CCL11, CCL13, CCL15, CCL16, CCL17, CCL18, CCL19, CCL20, CCL21, CCL22, CCL24, CCL25, CCL26, CCL27, CCL28 together with CC chemokine receptors: CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, and CCR10. To better understand the effect of hypoxia on neoplastic processes and changes in the expression of the described proteins, we summarize the available data in a table which shows the effect of individual chemokines on angiogenesis, lymphangiogenesis, and recruitment of eosinophils, myeloid-derived suppressor cells (MDSC), regulatory T cells (Treg), and tumor-associated macrophages (TAM) to a tumor niche.
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Affiliation(s)
- Jan Korbecki
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
| | - Klaudyna Kojder
- Department of Anaesthesiology and Intensive Care, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-281 Szczecin, Poland;
| | - Katarzyna Barczak
- Department of Conservative Dentistry and Endodontics, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Donata Simińska
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
| | - Izabela Gutowska
- Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wlkp. 72, 70-111 Szczecin, Poland;
| | - Dariusz Chlubek
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
| | - Irena Baranowska-Bosiacka
- Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powstańców Wielkopolskich 72, 70-111 Szczecin, Poland; (J.K.); (D.S.); (D.C.)
- Correspondence: ; Tel.: +48-914661515; Fax: +48-914661516
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Miranda-Galvis M, Teng Y. Targeting Hypoxia-Driven Metabolic Reprogramming to Constrain Tumor Progression and Metastasis. Int J Mol Sci 2020; 21:ijms21155487. [PMID: 32751958 PMCID: PMC7432774 DOI: 10.3390/ijms21155487] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 07/24/2020] [Accepted: 07/30/2020] [Indexed: 02/07/2023] Open
Abstract
Hypoxia in locally advanced solid tumors develops due to uncontrollable cell proliferation, altered metabolism, and the severe structural and functional abnormality of the tumor vasculature, leading to an imbalance between oxygen supply and consumption in the fast-growing tumors and negative impact on the therapeutic outcome. Several hypoxia-responsive molecular determinants, such as hypoxia-inducible factors, guide the cellular adaptation to hypoxia by gene activation, which is critical for promoting malignant progression in the hostile tumor microenvironment. Over time, a large body of evidence exists to suggest that tumor hypoxia also influences the tumor metabolic reprogramming, resulting in neoangiogenesis, metastasis, and immune evasion. In this respect, our review aims to understand the biological processes, key events, and consequences regarding the hypoxia-driven metabolic adaptation of tumor cells. We also assess the potential therapeutic impact of hypoxia and highlight our review by discussing possible therapeutic strategies targeting hypoxia, which would advance the current understanding of hypoxia-associated tumor propagation and malignant progression and improve the management of tumor hypoxia.
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Affiliation(s)
- Marisol Miranda-Galvis
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA;
| | - Yong Teng
- Department of Oral Biology and Diagnostic Sciences, Dental College of Georgia, Augusta University, Augusta, GA 30912, USA;
- Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
- Department of Medical Laboratory, Imaging and Radiologic Sciences, College of Allied Health, Augusta University, Augusta, GA 30912, USA
- Correspondence: ; Tel.: +1-70-6446-5611; Fax: +1-70-6721-9415
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27
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Chang WH, Lai AG. The hypoxic tumour microenvironment: A safe haven for immunosuppressive cells and a therapeutic barrier to overcome. Cancer Lett 2020; 487:34-44. [PMID: 32470490 DOI: 10.1016/j.canlet.2020.05.011] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Revised: 04/28/2020] [Accepted: 05/12/2020] [Indexed: 12/14/2022]
Abstract
Dating back to the seminal work of Paul Ehrlich, the idea of harnessing our immune system to eliminate cancerous cells is now over a century old. In the presence of a functional immune system that so efficiently guards the host against developing neoplasms, tumour cells must evolve sophisticated strategies to escape immune destruction in order to give rise to clinically detectable cancers. A new way of treating cancer would thus be to target the immune system itself rather than the tumour, and extensive studies in randomised trials have cemented the possibility of using immunotherapy for treating advanced-stage cancers. Immunotherapy, however, is only tolerated in a minority of patients and in many cases, patients suffer from adverse immune-related reactions when the immune system goes into overdrive. A primary barrier thwarting the development of effective immunotherapy seems to coalesce into the peculiarities of the tumour microenvironment for which hypoxia is a key feature. Here, we review emerging themes on how hypoxia contributes to immune suppression and obstructs anti-tumour effector cell functions. We discuss the challenges and opportunities relating to the potential for dually targeting hypoxia and the immune system to promote durable and favourable responses in cancer patients.
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Affiliation(s)
- Wai Hoong Chang
- Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, United Kingdom
| | - Alvina G Lai
- Institute of Health Informatics, University College London, 222 Euston Road, London, NW1 2DA, United Kingdom.
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28
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Abstract
Recent years have witnessed an emergence of interest in understanding metabolic changes associated with immune responses, termed immunometabolism. As oxygen is central to all aerobic metabolism, hypoxia is now recognized to contribute fundamentally to inflammatory and immune responses. Studies from a number of groups have implicated a prominent role for oxygen metabolism and hypoxia in innate immunity of healthy tissue (physiologic hypoxia) and during active inflammation (inflammatory hypoxia). This inflammatory hypoxia emanates from a combination of recruited inflammatory cells (e.g., neutrophils, eosinophils, and monocytes), high rates of oxidative metabolism, and the activation of multiple oxygen-consuming enzymes during inflammation. These localized shifts toward hypoxia have identified a prominent role for the transcription factor hypoxia-inducible factor (HIF) in the regulation of innate immunity. Such studies have provided new and enlightening insight into our basic understanding of immune mechanisms, and extensions of these findings have identified potential therapeutic targets. In this review, we summarize recent literature around the topic of innate immunity and mucosal hypoxia with a focus on transcriptional responses mediated by HIF.
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Affiliation(s)
- Sean P Colgan
- Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado 80045, USA;
- Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Glenn T Furuta
- Mucosal Inflammation Program, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
- Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado 80045, USA
| | - Cormac T Taylor
- UCD Conway Institute, Systems Biology Ireland and School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland
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29
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Vito A, El-Sayes N, Mossman K. Hypoxia-Driven Immune Escape in the Tumor Microenvironment. Cells 2020; 9:E992. [PMID: 32316260 PMCID: PMC7227025 DOI: 10.3390/cells9040992] [Citation(s) in RCA: 142] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 04/05/2020] [Accepted: 04/13/2020] [Indexed: 12/11/2022] Open
Abstract
The tumor microenvironment is a complex ecosystem comprised of many different cell types, abnormal vasculature and immunosuppressive cytokines. The irregular growth kinetics with which tumors grow leads to increased oxygen consumption and, in turn, hypoxic conditions. Hypoxia has been associated with poor clinical outcome, increased tumor heterogeneity, emergence of resistant clones and evasion of immune detection. Additionally, hypoxia-driven cell death pathways have traditionally been thought of as tolerogenic processes. However, as researchers working in the field of immunotherapy continue to investigate and unveil new types of immunogenic cell death (ICD), it has become clear that, in some instances, hypoxia may actually induce ICD within a tumor. In this review, we will discuss hypoxia-driven immune escape that drives poor prognostic outcomes, the ability of hypoxia to induce ICD and potential therapeutic targets amongst hypoxia pathways.
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Affiliation(s)
- Alyssa Vito
- Department of Biochemistry and Biomedical Sciences, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada; (A.V.); (N.E.-S.)
| | - Nader El-Sayes
- Department of Biochemistry and Biomedical Sciences, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada; (A.V.); (N.E.-S.)
| | - Karen Mossman
- Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre, McMaster University, Hamilton, ON L8S 4K1, Canada
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30
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Brombacher EC, Everts B. Shaping of Dendritic Cell Function by the Metabolic Micro-Environment. Front Endocrinol (Lausanne) 2020; 11:555. [PMID: 33013685 PMCID: PMC7493661 DOI: 10.3389/fendo.2020.00555] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 07/07/2020] [Indexed: 12/13/2022] Open
Abstract
Nutrients are required for growth and survival of all cells, but are also crucially involved in cell fate determination of many cell types, including immune cells. There is a growing appreciation that the metabolic micro-environment also plays a major role in shaping the functional properties of dendritic cells (DCs). Under pathological conditions nutrient availability can range from a very restricted supply, such as seen in a tumor micro-environment, to an overabundance of nutrients found in for example obese adipose tissue. In this review we will discuss what is currently known about the metabolic requirements for DC differentiation and immunogenicity and compare that to how function and fate of DCs under pathological conditions can be affected by alterations in environmental levels of carbohydrates, lipids and amino acids as well as by other metabolic cues, including availability of oxygen, redox homeostasis and lactate levels. Many of these insights have been generated using in vitro model systems, which have revealed highly diverse effects of different metabolic cues on DC function. However, they also stress the importance of shifting toward more physiologically relevant experimental settings to be able to fully delineate the role of the metabolic surroundings in its full complexity in shaping the functional properties of DCs in health and disease.
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31
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Dai H, Thomson AW, Rogers NM. Dendritic Cells as Sensors, Mediators, and Regulators of Ischemic Injury. Front Immunol 2019; 10:2418. [PMID: 31681306 PMCID: PMC6803430 DOI: 10.3389/fimmu.2019.02418] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 09/27/2019] [Indexed: 12/18/2022] Open
Abstract
Dendritic cells (DCs) are highly specialized, bone marrow (BM)-derived antigen-processing and -presenting cells crucial to the induction, integration and regulation of innate, and adaptive immunity. They are stimulated by damage-associated molecular patterns (DAMPS) via pattern recognition receptors to promote inflammation and initiate immune responses. In addition to residing within the parenchyma of all organs as part of the heterogeneous mononuclear phagocyte system, DCs are an abundant component of the inflammatory cell infiltrate that appears in response to ischemia reperfusion injury (IRI). They can play disparate roles in the pathogenesis of IRI since their selective depletion has been found to be protective, deleterious, or of no benefit in mouse models of IRI. In addition, administration of DC generated and manipulated ex vivo can protect organs from IRI by suppressing inflammatory cytokine production, limiting the capacity of DCs to activate NKT cells, or enhancing regulatory T cell function. Few studies however have investigated specific signal transduction mechanisms underlying DC function and how these affect IRI. Here, we address current knowledge of the role of DCs in regulation of IRI, current gaps in understanding and prospects for innovative therapeutic intervention at the biological and pharmacological levels.
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Affiliation(s)
- Helong Dai
- Department of Urological Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, China
- Clinical Research Center for Organ Transplantation of Hunan Province, Changsha, China
| | - Angus W. Thomson
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
| | - Natasha M. Rogers
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
- Center for Transplant and Renal Research, Westmead Institute for Medical Research, Westmead, NSW, Australia
- Renal Division, Westmead Hospital, Westmead, NSW, Australia
- Westmead Clinical School, University of Sydney, Camperdown, NSW, Australia
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32
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Ki KK, Faddy HM, Flower RL, Dean MM. Packed Red Blood Cell Transfusion Modulates Myeloid Dendritic Cell Activation and Inflammatory Response In Vitro. J Interferon Cytokine Res 2019; 38:111-121. [PMID: 29565746 DOI: 10.1089/jir.2017.0099] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Transfusion of packed red blood cells (PRBCs) modulates patients' immune responses and clinical outcomes; however, the underpinning mechanism(s) remain unknown. The potential for PRBC to modulate myeloid dendritic cells (mDC) and blood DC antigen 3 was assessed using an in vitro transfusion model. In parallel, to model processes activated by viral or bacterial infection, toll-like receptor agonists polyinosinic:polycytidylic acid or lipopolysaccharide were added. Exposure to PRBC upregulated expression of CD83 and downregulated CD40 and CD80 on both DC subsets, and it suppressed production of interleukin (IL)-6, IL-8, IL-12, tumor necrosis factor-α, and interferon-gamma-inducible protein-10 by these cells. Similar effects were observed when modeling processes activated by concurrent infection. Furthermore, exposure to PRBC at date of expiry was associated with more pronounced effects in all assays. Our study suggests PRBC have an impact on recipient DC function, which may result in failure to establish an appropriate immune response, particularly in patients with underlying infection.
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Affiliation(s)
- Katrina K Ki
- 1 Research and Development Laboratory, The Australian Red Cross Blood Service , Kelvin Grove, Queensland, Australia .,2 School of Medicine, The University of Queensland , Brisbane, St. Lucia, Queensland, Australia
| | - Helen M Faddy
- 1 Research and Development Laboratory, The Australian Red Cross Blood Service , Kelvin Grove, Queensland, Australia .,2 School of Medicine, The University of Queensland , Brisbane, St. Lucia, Queensland, Australia
| | - Robert L Flower
- 1 Research and Development Laboratory, The Australian Red Cross Blood Service , Kelvin Grove, Queensland, Australia
| | - Melinda M Dean
- 1 Research and Development Laboratory, The Australian Red Cross Blood Service , Kelvin Grove, Queensland, Australia
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33
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Riera-Domingo C, Audigé A, Granja S, Cheng WC, Ho PC, Baltazar F, Stockmann C, Mazzone M. Immunity, Hypoxia, and Metabolism-the Ménage à Trois of Cancer: Implications for Immunotherapy. Physiol Rev 2019; 100:1-102. [PMID: 31414610 DOI: 10.1152/physrev.00018.2019] [Citation(s) in RCA: 205] [Impact Index Per Article: 34.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
It is generally accepted that metabolism is able to shape the immune response. Only recently we are gaining awareness that the metabolic crosstalk between different tumor compartments strongly contributes to the harsh tumor microenvironment (TME) and ultimately impairs immune cell fitness and effector functions. The major aims of this review are to provide an overview on the immune system in cancer; to position oxygen shortage and metabolic competition as the ground of a restrictive TME and as important players in the anti-tumor immune response; to define how immunotherapies affect hypoxia/oxygen delivery and the metabolic landscape of the tumor; and vice versa, how oxygen and metabolites within the TME impinge on the success of immunotherapies. By analyzing preclinical and clinical endeavors, we will discuss how a metabolic characterization of the TME can identify novel targets and signatures that could be exploited in combination with standard immunotherapies and can help to predict the benefit of new and traditional immunotherapeutic drugs.
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Affiliation(s)
- Carla Riera-Domingo
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium; Institute of Anatomy, University of Zurich, Zurich, Switzerland; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; and Ludwig Cancer Research Institute, Epalinges, Switzerland
| | - Annette Audigé
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium; Institute of Anatomy, University of Zurich, Zurich, Switzerland; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; and Ludwig Cancer Research Institute, Epalinges, Switzerland
| | - Sara Granja
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium; Institute of Anatomy, University of Zurich, Zurich, Switzerland; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; and Ludwig Cancer Research Institute, Epalinges, Switzerland
| | - Wan-Chen Cheng
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium; Institute of Anatomy, University of Zurich, Zurich, Switzerland; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; and Ludwig Cancer Research Institute, Epalinges, Switzerland
| | - Ping-Chih Ho
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium; Institute of Anatomy, University of Zurich, Zurich, Switzerland; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; and Ludwig Cancer Research Institute, Epalinges, Switzerland
| | - Fátima Baltazar
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium; Institute of Anatomy, University of Zurich, Zurich, Switzerland; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; and Ludwig Cancer Research Institute, Epalinges, Switzerland
| | - Christian Stockmann
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium; Institute of Anatomy, University of Zurich, Zurich, Switzerland; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; and Ludwig Cancer Research Institute, Epalinges, Switzerland
| | - Massimiliano Mazzone
- Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, VIB, Leuven, Belgium; Laboratory of Tumor Inflammation and Angiogenesis, Center for Cancer Biology, Department of Oncology, KU Leuven, Leuven, Belgium; Institute of Anatomy, University of Zurich, Zurich, Switzerland; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland; and Ludwig Cancer Research Institute, Epalinges, Switzerland
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Shimizu K, Iyoda T, Okada M, Yamasaki S, Fujii SI. Immune suppression and reversal of the suppressive tumor microenvironment. Int Immunol 2019; 30:445-454. [PMID: 29939325 DOI: 10.1093/intimm/dxy042] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 06/22/2018] [Indexed: 12/18/2022] Open
Abstract
Most tumors employ multiple strategies to attenuate T-cell-mediated immune responses. In particular, immune suppression surrounding the tumor is achieved by interfering with antigen-presenting cells and effector T cells. Controlling both the tumor and the tumor microenvironment (TME) is critical for cancer treatment. Checkpoint blockade therapy can overcome tumor-induced immune suppression, but more than half of the patients fail to respond to this treatment; therefore, more effective cancer immunotherapies are needed. Generation of an anti-tumor immune response is a multi-step process of immune activation against the tumor that requires effector T cells to recognize and exert toxic effects against tumor cells, for which two strategies are employed-inhibition of various types of immune suppressor cells, such as myeloid cells and regulatory T cells, and establishment of anti-tumor immune surveillance including, activation of natural killer cells and cytotoxic T cells. It was recently shown that anti-cancer drugs not only directly kill tumor cells, but also influence the immune response to cancer by promoting immunogenic cell death, enhancing antigen presentation or depleting immunosuppressive cells. Herein, we review the mechanisms by which tumors exert immune suppression as well as their regulation. We then discuss how the complex reciprocal interactions between immunosuppressive and immunostimulatory cells influence immune cell dynamics in the TME. Finally, we highlight the new therapies that can reverse immune suppression in the TME and promote anti-tumor immunity.
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Affiliation(s)
- Kanako Shimizu
- Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa, Japan
| | - Tomonori Iyoda
- Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa, Japan
| | - Masahiro Okada
- Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa, Japan
| | - Satoru Yamasaki
- Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa, Japan
| | - Shin-Ichiro Fujii
- Laboratory for Immunotherapy, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa, Japan
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35
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Abstract
Data from observational studies indicate that both physical activity as well as exercise (ie, structured physical activity) is associated with reductions in the risk of recurrence and cancer mortality after a diagnosis of certain forms of cancer. Emerging evidence from preclinical studies indicates that physical activity/exercise paradigms regulate intratumoral vascular maturity and perfusion, hypoxia, and metabolism and augments the antitumor immune response. Such responses may, in turn, enhance response to standard anticancer treatments. For instance, exercise improves efficacy of chemotherapeutic agents, and there is rationale to believe that it will also improve radiotherapy response. This review overviews the current preclinical as well as clinical evidence supporting exercise modulation of therapeutic response and postulated biological mechanisms underpinning such effects. We also examine the implications for tumor response to radiation, chemotherapy, and immunotherapy.
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Affiliation(s)
- Kathleen A Ashcraft
- Departments of Radiation Oncology, Duke University School of Medicine, Durham, NC
| | | | - Lee W Jones
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.; Weill Cornell Medical College, New York, NY
| | - Mark W Dewhirst
- Departments of Radiation Oncology, Duke University School of Medicine, Durham, NC..
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36
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Paardekooper LM, Vos W, van den Bogaart G. Oxygen in the tumor microenvironment: effects on dendritic cell function. Oncotarget 2019; 10:883-896. [PMID: 30783517 PMCID: PMC6368231 DOI: 10.18632/oncotarget.26608] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 01/09/2019] [Indexed: 12/13/2022] Open
Abstract
Solid tumors grow at a high speed leading to insufficient blood supply to tumor cells. This makes the tumor hypoxic, resulting in the Warburg effect and an increased generation of reactive oxygen species (ROS). Hypoxia and ROS affect immune cells in the tumor micro-environment, thereby affecting their immune function. Here, we review the known effects of hypoxia and ROS on the function and physiology of dendritic cells (DCs). DCs can (cross-)present tumor antigen to activate naive T cells, which play a pivotal role in anti-tumor immunity. ROS might enter DCs via aquaporins in the plasma membrane, diffusion across the plasma membrane or via extracellular vesicles (EVs) released by tumor cells. Hypoxia and ROS exert complex effects on DCs, and can both inhibit and activate maturation of immature DCs. Furthermore, ROS transferred by EVs and/or produced by the DC can both promote antigen (cross-)presentation through phagosomal alkalinization, which preserves antigens by inhibiting proteases, and by direct oxidative modification of proteases. Hypoxia leads to a more migratory and inflammatory DC phenotype. Lastly, hypoxia alters DCs to shift the T- cell response towards a tumor suppressive Th17 phenotype. From numerous studies, the concept is emerging that hypoxia and ROS are mutually dependent effectors on DC function in the tumor micro-environment. Understanding their precise roles and interplay is important given that an adaptive immune response is required to clear tumor cells.
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Affiliation(s)
- Laurent M Paardekooper
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Willemijn Vos
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Geert van den Bogaart
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.,Department of Molecular Immunology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Groningen, The Netherlands
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37
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Hypoxia potentiates monocyte-derived dendritic cells for release of tumor necrosis factor α via MAP3K8. Biosci Rep 2018; 38:BSR20182019. [PMID: 30463908 PMCID: PMC6294625 DOI: 10.1042/bsr20182019] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 11/20/2018] [Accepted: 11/20/2018] [Indexed: 01/22/2023] Open
Abstract
Dendritic cells (DCs) constantly sample peripheral tissues for antigens, which are subsequently ingested to derive peptides for presentation to T cells in lymph nodes. To do so, DCs have to traverse many different tissues with varying oxygen tensions. Additionally, DCs are often exposed to low oxygen tensions in tumors, where vascularization is lacking, as well as in inflammatory foci, where oxygen is rapidly consumed by inflammatory cells during the respiratory burst. DCs respond to oxygen levels to tailor immune responses to such low-oxygen environments. In the present study, we identified a mechanism of hypoxia-mediated potentiation of release of tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine with important roles in both anti-cancer immunity and autoimmune disease. We show in human monocyte-derived DCs (moDCs) that this potentiation is controlled exclusively via the p38/mitogen-activated protein kinase (MAPK) pathway. We identified MAPK kinase kinase 8 (MAP3K8) as a target gene of hypoxia-induced factor (HIF), a transcription factor controlled by oxygen tension, upstream of the p38/MAPK pathway. Hypoxia increased expression of MAP3K8 concomitant with the potentiation of TNF-α secretion. This potentiation was no longer observed upon siRNA silencing of MAP3K8 or with a small molecule inhibitor of this kinase, and this also decreased p38/MAPK phosphorylation. However, expression of DC maturation markers CD83, CD86, and HLA-DR were not changed by hypoxia. Since DCs play an important role in controlling T-cell activation and differentiation, our results provide novel insight in understanding T-cell responses in inflammation, cancer, autoimmune disease and other diseases where hypoxia is involved.
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38
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Valdes-Mora F, Handler K, Law AMK, Salomon R, Oakes SR, Ormandy CJ, Gallego-Ortega D. Single-Cell Transcriptomics in Cancer Immunobiology: The Future of Precision Oncology. Front Immunol 2018; 9:2582. [PMID: 30483257 PMCID: PMC6240655 DOI: 10.3389/fimmu.2018.02582] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 10/19/2018] [Indexed: 12/21/2022] Open
Abstract
Cancer is a heterogeneous and complex disease. Tumors are formed by cancer cells and a myriad of non-cancerous cell types that together with the extracellular matrix form the tumor microenvironment. These cancer-associated cells and components contribute to shape the progression of cancer and are deeply involved in patient outcome. The immune system is an essential part of the tumor microenvironment, and induction of cancer immunotolerance is a necessary step involved in tumor formation and growth. Immune mechanisms are intimately associated with cancer progression, invasion, and metastasis; as well as to tumor dormancy and modulation of sensitivity to drug therapy. Transcriptome analyses have been extensively used to understand the heterogeneity of tumors, classifying tumors into molecular subtypes and establishing signatures that predict response to therapy and patient outcomes. However, the classification of the tumor cell diversity and specially the identification of rare populations has been limited in these transcriptomic analyses of bulk tumor cell populations. Massively-parallel single-cell RNAseq analysis has emerged as a powerful method to unravel heterogeneity and to study rare cell populations in cancer, through unsupervised sampling and modeling of transcriptional states in single cells. In this context, the study of the role of the immune system in cancer would benefit from single cell approaches, as it will enable the characterization and/or discovery of the cell types and pathways involved in cancer immunotolerance otherwise missed in bulk transcriptomic information. Thus, the analysis of gene expression patterns at single cell resolution holds the potential to provide key information to develop precise and personalized cancer treatment including immunotherapy. This review is focused on the latest single-cell RNAseq methodologies able to agnostically study thousands of tumor cells as well as targeted single-cell RNAseq to study rare populations within tumors. In particular, we will discuss methods to study the immune system in cancer. We will also discuss the current challenges to the study of cancer at the single cell level and the potential solutions to the current approaches.
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Affiliation(s)
- Fatima Valdes-Mora
- Genomics and Epigenetics Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.,St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Kristina Handler
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Andrew M K Law
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Robert Salomon
- Garvan-Weizmann Centre for Cellular Genomics, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Samantha R Oakes
- St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.,The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Christopher J Ormandy
- St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.,The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - David Gallego-Ortega
- St. Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.,The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
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Parodi M, Raggi F, Cangelosi D, Manzini C, Balsamo M, Blengio F, Eva A, Varesio L, Pietra G, Moretta L, Mingari MC, Vitale M, Bosco MC. Hypoxia Modifies the Transcriptome of Human NK Cells, Modulates Their Immunoregulatory Profile, and Influences NK Cell Subset Migration. Front Immunol 2018; 9:2358. [PMID: 30459756 PMCID: PMC6232835 DOI: 10.3389/fimmu.2018.02358] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 09/24/2018] [Indexed: 12/29/2022] Open
Abstract
Hypoxia, which characterizes most tumor tissues, can alter the function of different immune cell types, favoring tumor escape mechanisms. In this study, we show that hypoxia profoundly acts on NK cells by influencing their transcriptome, affecting their immunoregulatory functions, and changing the chemotactic responses of different NK cell subsets. Exposure of human peripheral blood NK cells to hypoxia for 16 or 96 h caused significant changes in the expression of 729 or 1,100 genes, respectively. Gene Set Enrichment Analysis demonstrated that these changes followed a consensus hypoxia transcriptional profile. As assessed by Gene Ontology annotation, hypoxia-targeted genes were implicated in several biological processes: metabolism, cell cycle, differentiation, apoptosis, cell stress, and cytoskeleton organization. The hypoxic transcriptome also showed changes in genes with immunological relevance including those coding for proinflammatory cytokines, chemokines, and chemokine-receptors. Quantitative RT-PCR analysis confirmed the modulation of several immune-related genes, prompting further immunophenotypic and functional studies. Multiplex ELISA demonstrated that hypoxia could variably reduce NK cell ability to release IFNγ, TNFα, GM-CSF, CCL3, and CCL5 following PMA+Ionomycin or IL15+IL18 stimulation, while it poorly affected the response to IL12+IL18. Cytofluorimetric analysis showed that hypoxia could influence NK chemokine receptor pattern by sustaining the expression of CCR7 and CXCR4. Remarkably, this effect occurred selectively (CCR7) or preferentially (CXCR4) on CD56bright NK cells, which indeed showed higher chemotaxis to CCL19, CCL21, or CXCL12. Collectively, our data suggest that the hypoxic environment may profoundly influence the nature of the NK cell infiltrate and its effects on immune-mediated responses within tumor tissues.
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Affiliation(s)
- Monica Parodi
- UOC Immunologia, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Federica Raggi
- Laboratorio di Biologia Molecolare, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Davide Cangelosi
- Laboratorio di Biologia Molecolare, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Claudia Manzini
- Laboratorio di Immunologia Clinica e Sperimentale, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Mirna Balsamo
- Dipartimento di Medicina Sperimentale, Università di Genova, Genova, Italy
| | - Fabiola Blengio
- Laboratorio di Biologia Molecolare, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Alessandra Eva
- Laboratorio di Biologia Molecolare, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Luigi Varesio
- Laboratorio di Biologia Molecolare, IRCCS Istituto Giannina Gaslini, Genova, Italy
| | - Gabriella Pietra
- UOC Immunologia, IRCCS Ospedale Policlinico San Martino, Genova, Italy.,Dipartimento di Medicina Sperimentale, Università di Genova, Genova, Italy
| | - Lorenzo Moretta
- Immunology Area, Ospedale Pediatrico Bambin Gesù, Rome, Italy
| | - Maria Cristina Mingari
- UOC Immunologia, IRCCS Ospedale Policlinico San Martino, Genova, Italy.,Dipartimento di Medicina Sperimentale, Università di Genova, Genova, Italy.,Center of Excellence for Biomedical Research, University of Genoa, Genova, Italy
| | - Massimo Vitale
- UOC Immunologia, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| | - Maria Carla Bosco
- Laboratorio di Biologia Molecolare, IRCCS Istituto Giannina Gaslini, Genova, Italy
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40
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Awad RM, De Vlaeminck Y, Maebe J, Goyvaerts C, Breckpot K. Turn Back the TIMe: Targeting Tumor Infiltrating Myeloid Cells to Revert Cancer Progression. Front Immunol 2018; 9:1977. [PMID: 30233579 PMCID: PMC6127274 DOI: 10.3389/fimmu.2018.01977] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Accepted: 08/13/2018] [Indexed: 12/19/2022] Open
Abstract
Tumor cells frequently produce soluble factors that favor myelopoiesis and recruitment of myeloid cells to the tumor microenvironment (TME). Consequently, the TME of many cancer types is characterized by high infiltration of monocytes, macrophages, dendritic cells and granulocytes. Experimental and clinical studies show that most myeloid cells are kept in an immature state in the TME. These studies further show that tumor-derived factors mold these myeloid cells into cells that support cancer initiation and progression, amongst others by enabling immune evasion, tumor cell survival, proliferation, migration and metastasis. The key role of myeloid cells in cancer is further evidenced by the fact that they negatively impact on virtually all types of cancer therapy. Therefore, tumor-associated myeloid cells have been designated as the culprits in cancer. We review myeloid cells in the TME with a focus on the mechanisms they exploit to support cancer cells. In addition, we provide an overview of approaches that are under investigation to deplete myeloid cells or redirect their function, as these hold promise to overcome resistance to current cancer therapies.
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41
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Next Generation Cancer Vaccines-Make It Personal! Vaccines (Basel) 2018; 6:vaccines6030052. [PMID: 30096953 PMCID: PMC6161279 DOI: 10.3390/vaccines6030052] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/23/2018] [Accepted: 08/07/2018] [Indexed: 12/30/2022] Open
Abstract
Dramatic success in cancer immunotherapy has been achieved over the last decade with the introduction of checkpoint inhibitors, leading to response rates higher than with chemotherapy in certain cancer types. These responses are often restricted to cancers that have a high mutational burden and show pre-existing T-cell infiltrates. Despite extensive efforts, therapeutic vaccines have been mostly unsuccessful in the clinic. With the introduction of next generation sequencing, the identification of individual mutations is possible, enabling the production of personalized cancer vaccines. Combining immune check point inhibitors to overcome the immunosuppressive microenvironment and personalized cancer vaccines for directing the host immune system against the chosen antigens might be a promising treatment strategy.
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42
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Jiang H, Zhang S, Song T, Guan X, Zhang R, Chen X. Trichostatin a Protects Dendritic Cells Against Oxygen-Glucose Deprivation via the SRSF3/PKM2/Glycolytic Pathway. Front Pharmacol 2018; 9:612. [PMID: 29942258 PMCID: PMC6004525 DOI: 10.3389/fphar.2018.00612] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2017] [Accepted: 05/22/2018] [Indexed: 12/12/2022] Open
Abstract
Dendritic cells (DCs) are important to the immune system and are frequently recruited to hypoxic regions, especially during acute myocardial infarction (AMI). Emerging data indicate that histone deacetylase (HDAC) inhibitors possess immunomodulatory functions. We previously showed in a rat model of AMI that the HDAC inhibitor TSA improved tissue repair, and this was accompanied by increased DC infiltration in the infarct region, suggesting an important role of TSA in modulating DC functions. To study the potential modulatory effect of TSA on DCs, we exploited an in vitro model of hypoxia and glucose deprivation. Culturing of DCs in the presence of 200 nM TSA improved DC survival under hypoxia and glucose deprivation. However, on a phenotypic level, TSA induced the expression of the DC co-stimulatory molecules CD80 and CD86, decreased FITC-dextran uptake, and facilitated DC migration. Moreover, TSA altered cytokine secretion by reducing the pro-inflammatory cytokines IL-1β, IL-10, IL-12, and TGF-β. Furthermore, TSA treatment enhanced HIF-1α-dependent glycolytic gene expression and increased pyruvate kinase M2 by upregulating SRSF3. These results suggest that by TSA alters important DC functions under hypoxia and glucose deprivation, and that TSA is critical for DC function by modulating SRSF3-PKM2-dependent glycolytic pathways.
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Affiliation(s)
- Hongyun Jiang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Siwei Zhang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Tongtong Song
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xin Guan
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Ruojin Zhang
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Xia Chen
- Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China
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43
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Schatz V, Neubert P, Rieger F, Jantsch J. Hypoxia, Hypoxia-Inducible Factor-1α, and Innate Antileishmanial Immune Responses. Front Immunol 2018. [PMID: 29520262 PMCID: PMC5827161 DOI: 10.3389/fimmu.2018.00216] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Low oxygen environments and accumulation of hypoxia-inducible factors (HIFs) are features of infected and inflamed tissues. Here, we summarize our current knowledge on oxygen levels found in Leishmania-infected tissues and discuss which mechanisms potentially contribute to local tissue oxygenation in leishmanial lesions. Moreover, we review the role of hypoxia and HIF-1 on innate antileishmanial immune responses.
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Affiliation(s)
- Valentin Schatz
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
| | - Patrick Neubert
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
| | - Franz Rieger
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
| | - Jonathan Jantsch
- Institute of Clinical Microbiology and Hygiene, University Hospital of Regensburg, University of Regensburg, Regensburg, Germany
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44
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Sambataro M, Sambado L, Trevisiol E, Cacciatore M, Furlan A, Stefani PM, Seganfreddo E, Durante E, Conte S, Bella SD, Paccagnella A, Tos AP. Proinsulin‐expressing dendritic cells in type 2 neuropathic diabetic patients with and without foot lesions. FASEB J 2018; 32:3742-3751. [DOI: 10.1096/fj.201701279rr] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Maria Sambataro
- Endocrine, Metabolism, and Nutrition Disease UnitDepartment of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Luisa Sambado
- Endocrine, Metabolism, and Nutrition Disease UnitDepartment of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Enrica Trevisiol
- Department of Pharmaceutical and Pharmacological SciencesUniversity of PaduaPaduaItaly
| | - Matilde Cacciatore
- Department of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Anna Furlan
- Hematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Piero Maria Stefani
- Hematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Elena Seganfreddo
- Immunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Elisabetta Durante
- Immunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Stefania Conte
- Neurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Silvia Della Bella
- Department of Biomedical Technologies and Translational MedicineUniversity of MilanMilanItaly
- Laboratory of Clinical and Experimental ImmunologyHumanitas Clinical and Research CenterMilanItaly
| | - Agostino Paccagnella
- Endocrine, Metabolism, and Nutrition Disease UnitDepartment of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
| | - Angelo Paolo Tos
- Department of PathologyHematology UnitImmunohematology and Transfusional Medicine ServiceNeurology UnitSanta Maria di Ca’ Foncello HospitalTrevisoItaly
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45
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Raggi F, Pelassa S, Pierobon D, Penco F, Gattorno M, Novelli F, Eva A, Varesio L, Giovarelli M, Bosco MC. Regulation of Human Macrophage M1-M2 Polarization Balance by Hypoxia and the Triggering Receptor Expressed on Myeloid Cells-1. Front Immunol 2017; 8:1097. [PMID: 28936211 PMCID: PMC5594076 DOI: 10.3389/fimmu.2017.01097] [Citation(s) in RCA: 198] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Accepted: 08/22/2017] [Indexed: 12/18/2022] Open
Abstract
Macrophages (Mf) are a heterogeneous population of tissue-resident professional phagocytes and a major component of the leukocyte infiltrate at sites of inflammation, infection, and tumor growth. They can undergo diverse forms of activation in response to environmental factors, polarizing into specialized functional subsets. A common hallmark of the pathologic environment is represented by hypoxia. The impact of hypoxia on human Mf polarization has not been fully established. The objective of this study was to elucidate the effects of a hypoxic environment reflecting that occurring in vivo in diseased tissues on the ability of human Mf to polarize into classically activated (proinflammatory M1) and alternatively activated (anti-inflammatory M2) subsets. We present data showing that hypoxia hinders Mf polarization toward the M1 phenotype by decreasing the expression of T cell costimulatory molecules and chemokine homing receptors and the production of proinflammatory, Th1-priming cytokines typical of classical activation, while promoting their acquisition of phenotypic and secretory features of alternative activation. Furthermore, we identify the triggering receptor expressed on myeloid cells (TREM)-1, a member of the Ig-like immunoregulatory receptor family, as a hypoxia-inducible gene in Mf and demonstrate that its engagement by an agonist Ab reverses the M2-polarizing effect of hypoxia imparting a M1-skewed phenotype to Mf. Finally, we provide evidence that Mf infiltrating the inflamed hypoxic joints of children affected by oligoarticular juvenile idiopatic arthritis express high surface levels of TREM-1 associated with predominant M1 polarization and suggest the potential of this molecule in driving M1 proinflammatory reprogramming in the hypoxic synovial environment.
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Affiliation(s)
- Federica Raggi
- Laboratory of Molecular Biology, Giannina Gaslini Institute, Genoa, Italy
| | - Simone Pelassa
- Laboratory of Molecular Biology, Giannina Gaslini Institute, Genoa, Italy
| | - Daniele Pierobon
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Center for Experimental Research and Medical Studies (CERMS), AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Federica Penco
- Pediatria II, Department of Pediatrics, Giannina Gaslini Institute, University of Genoa, Genoa, Italy
| | - Marco Gattorno
- Pediatria II, Department of Pediatrics, Giannina Gaslini Institute, University of Genoa, Genoa, Italy
| | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Center for Experimental Research and Medical Studies (CERMS), AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Alessandra Eva
- Laboratory of Molecular Biology, Giannina Gaslini Institute, Genoa, Italy
| | - Luigi Varesio
- Laboratory of Molecular Biology, Giannina Gaslini Institute, Genoa, Italy
| | - Mirella Giovarelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Center for Experimental Research and Medical Studies (CERMS), AOU Città della Salute e della Scienza di Torino, Turin, Italy
| | - Maria Carla Bosco
- Laboratory of Molecular Biology, Giannina Gaslini Institute, Genoa, Italy
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46
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Ki KK, Faddy HM, Flower RL, Dean MM. Platelet concentrates modulate myeloid dendritic cell immune responses. Platelets 2017; 29:373-382. [DOI: 10.1080/09537104.2017.1306045] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Katrina K. Ki
- Research and Development, The Australian Red Cross Blood Service, Brisbane, QLD, Australia
- School of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Helen M. Faddy
- Research and Development, The Australian Red Cross Blood Service, Brisbane, QLD, Australia
- School of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Robert L. Flower
- Research and Development, The Australian Red Cross Blood Service, Brisbane, QLD, Australia
| | - Melinda M. Dean
- Research and Development, The Australian Red Cross Blood Service, Brisbane, QLD, Australia
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47
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Hu X, Wu T, Bao Y, Zhang Z. Nanotechnology based therapeutic modality to boost anti-tumor immunity and collapse tumor defense. J Control Release 2017; 256:26-45. [PMID: 28434891 DOI: 10.1016/j.jconrel.2017.04.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 04/15/2017] [Accepted: 04/18/2017] [Indexed: 12/19/2022]
Abstract
Cancer is still the leading cause of death. While traditional treatments such as surgery, chemotherapy and radiotherapy play dominating roles, recent breakthroughs in cancer immunotherapy indicate that the influence of immune system on cancer development is virtually beyond our expectation. Manipulating the immune system to fight against cancer has been thriving in recent years. Further understanding of tumor anatomy provides opportunities to put a brake on immunosuppression by overcoming tumor intrinsic resistance or modulating tumor microenvironment. Nanotechnology which provides versatile engineered approaches to enhance therapeutic effects may potentially contribute to the development of future cancer treatment modality. In this review, we will focus on the application of nanotechnology both in boosting anti-tumor immunity and collapsing tumor defense.
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Affiliation(s)
| | | | - Yuling Bao
- Tongji School of Pharmacy, PR China; Department of Pharmacy, Tongji Hospital, PR China
| | - Zhiping Zhang
- Tongji School of Pharmacy, PR China; National Engineering Research Center for Nanomedicine, PR China; Hubei Engineering Research Center for Novel Drug Delivery System, HuaZhong University of Science and Technology, Wuhan 430030, PR China.
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48
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Manoochehri Khoshinani H, Afshar S, Najafi R. Hypoxia: A Double-Edged Sword in Cancer Therapy. Cancer Invest 2016; 34:536-545. [PMID: 27824512 DOI: 10.1080/07357907.2016.1245317] [Citation(s) in RCA: 111] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hypoxia is a common feature of malignant tumors. There is an interactive connection between hypoxia and chemoresistance, radioresistance, invasiveness, and angiogenesis. Therefore, tumor hypoxia has been considered as a validated target for treating cancer. This review focuses on the role of hypoxia on chemoresistance and radioresistance. In addition, we address several approaches targeting tumor hypoxia, known as hypoxia-targeted therapy.
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Affiliation(s)
| | - Saeid Afshar
- a Research Center for Molecular Medicine, Hamadan University of Medical Sciences , Hamadan , Iran
| | - Rezvan Najafi
- a Research Center for Molecular Medicine, Hamadan University of Medical Sciences , Hamadan , Iran
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49
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Charpentier T, Hammami A, Stäger S. Hypoxia inducible factor 1α: A critical factor for the immune response to pathogens and Leishmania. Cell Immunol 2016; 309:42-49. [DOI: 10.1016/j.cellimm.2016.06.002] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 06/15/2016] [Accepted: 06/21/2016] [Indexed: 12/17/2022]
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50
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Rohm I, Aderhold N, Ratka J, Goebel B, Franz M, Pistulli R, Gecks T, Figulla HR, Yilmaz A, Jung C. Hypobaric hypoxia in 3000 m altitude leads to a significant decrease in circulating plasmacytoid dendritic cells in humans. Clin Hemorheol Microcirc 2016; 63:257-65. [DOI: 10.3233/ch-152035] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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