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Krawczyk A, Sladowska GE, Strzalka-Mrozik B. The Role of the Gut Microbiota in Modulating Signaling Pathways and Oxidative Stress in Glioma Therapies. Cancers (Basel) 2025; 17:719. [PMID: 40075568 PMCID: PMC11899293 DOI: 10.3390/cancers17050719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2025] [Revised: 02/16/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
Tumors of the central nervous system (CNS), especially gliomas, pose a significant clinical challenge due to their aggressive nature and limited therapeutic options. Emerging research highlights the critical role of the gut microbiota in regulating CNS health and disease. The composition of the gut microbiota is essential for maintaining CNS homeostasis, as it modulates immune responses, oxidative status, and neuroinflammation. The microbiota-gut-brain axis, a bidirectional communication network, plays a pivotal role in cancer and CNS disease treatment, exerting its influence through neural, endocrine, immunological, and metabolic pathways. Recent studies suggest that the gut microbiota influences the solidification of the tumor microenvironment and that dysbiosis may promote glioma development by modulating systemic inflammation and oxidative stress, which contributes to tumorigenesis and CNS tumor progression. This review interrogates the impact of the gut microbiota on glioma, focusing on critical pathways such as NF-κB, MAPK, PI3K/Akt/mTOR, and Kynurenine/AhR that drive tumor proliferation, immune evasion, and therapy resistance. Furthermore, we explore emerging therapeutic strategies, including probiotics and microbiota-based interventions, which show potential in modulating these pathways and enhancing immunotherapies such as checkpoint inhibitors. By focusing on the multifaceted interactions between the gut microbiota, oxidative stress, and CNS tumors, this review highlights the potential of microbiota-targeted therapies and their manipulation to complement and enhance current treatments.
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Affiliation(s)
| | | | - Barbara Strzalka-Mrozik
- Department of Molecular Biology, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, 40-055 Katowice, Poland; (A.K.); (G.E.S.)
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Conte M, Tomaciello M, De Feo MS, Frantellizzi V, Marampon F, De Cristofaro F, De Vincentis G, Filippi L. The Tight Relationship Between the Tumoral Microenvironment and Radium-223. Biomedicines 2025; 13:456. [PMID: 40002869 PMCID: PMC11853176 DOI: 10.3390/biomedicines13020456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2025] [Revised: 02/04/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Radium-223 (223Ra) was the first radioactive isotope approved for treating castration-resistant prostate cancer (CRPC) with symptomatic bone metastases without visceral metastatic disease. To better understand the action of 223Ra, its role in the tumor microenvironment represents a crucial aspect. A literature search was conducted using the PubMed/MEDLINE database and studies regarding the relationship between 223Ra and the tumoral microenvironment were considered. The tumoral microenvironment is a complex setting in which complex interactions between cells and molecules occur. Radium-223, as an alpha-emitter, induces double-stranded DNA breaks; to potentiate this effect, it could be used in patients with genetic instability but also in combination with therapies which inhibit DNA repair, modulate the immune response, or control tumor growth. In conclusion, a few studies have taken into consideration the tumoral microenvironment in association with 223Ra. However, its understanding is a priority to better comprehend how to effectively exploit 223Ra and its action mechanism.
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Affiliation(s)
- Miriam Conte
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Miriam Tomaciello
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Maria Silvia De Feo
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Viviana Frantellizzi
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Francesco Marampon
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Flaminia De Cristofaro
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Giuseppe De Vincentis
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Luca Filippi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
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Cho E, Na SW, Jeong MK. Therapeutic and immunomodulatory effects of Bojungikki-tang on cancer: a scoping review. BMC Cancer 2024; 24:1169. [PMID: 39300400 PMCID: PMC11414168 DOI: 10.1186/s12885-024-12924-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Cancer remains a major global health concern, with conventional treatments often limited by side effects and resistance. Bojungikki-tang (BJIKT), a traditional herbal formula, has shown promise in alleviating cancer-related symptoms and enhancing anti-cancer effects when combined with conventional treatments. As immune checkpoint inhibitors (ICIs) have become the standard for cancer treatment, a combination of BJIKT and ICIs may exhibit immune-mediated anti-cancer effects. This review aims to summarize the recent evidence on BJIKT use in cancer treatment, investigate its immunomodulatory effects, and identify research gaps. METHODS This review was conducted and reported following the Arksey and O'Malley framework and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Scoping Review. A comprehensive search of six electronic databases was conducted, and studies published between 2013 and 2022 were identified. Reports on oral administration of BJIKT to patients with cancer were included and analyzed by two reviewers. The extracted data were synthesized using descriptive reporting and meta-analysis. RESULTS Overall, 56 studies met the inclusion criteria: 36 human studies, 14 experimental studies, and 6 reviews on clinical and preclinical investigations. The use of BJIKT in restoring immune function and improving fatigue, cancer-related fever, and quality of life after chemotherapy has been reported in clinical studies. The different medication forms of BJIKT included decoction, extract granules, pills, and water extract. The meta-analysis revealed a significantly higher Karnofsky Performance Scale score in the BJIKT plus chemotherapy group than in the chemotherapy alone group. Preclinical studies have demonstrated that BJIKT has anti-cancer effects, enhances gastrointestinal function and immunomodulatory effects, and supports favorable chemotherapy outcomes. CONCLUSION In recent clinical research on BJIKT, its impact on fatigue, quality of life, and alleviating cancer-related fever has mostly been examined. The direct anti-cancer activities and immunomodulatory mechanisms of BJIKT have been reported in preclinical studies; however, clinical research on BJIKT-induced enhancement of immune function is lacking. Further research on the efficacy and safety of ICI combined with BJIKT and the association of immunomarker changes with clinical outcomes is required to precisely identify the effect of BJIKT on immune system modulation.
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Affiliation(s)
- Eunbyul Cho
- KM Science Research Division, Korea Institute of Oriental Medicine, 1672, Yuseong-Daero, Yuseong-Gu, Daejeon, 34054, Republic of Korea
| | - Se Won Na
- KM Convergence Research Division, Korea Institute of Oriental Medicine, 1672, Yuseong-Daero, Yuseong-Gu, Daejeon, 34054, Republic of Korea
| | - Mi-Kyung Jeong
- KM Convergence Research Division, Korea Institute of Oriental Medicine, 1672, Yuseong-Daero, Yuseong-Gu, Daejeon, 34054, Republic of Korea.
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Feng Y, He C, Liu C, Shao B, Wang D, Wu P. Exploring the Complexity and Promise of Tumor Immunotherapy in Drug Development. Int J Mol Sci 2024; 25:6444. [PMID: 38928150 PMCID: PMC11204037 DOI: 10.3390/ijms25126444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/06/2024] [Accepted: 06/07/2024] [Indexed: 06/28/2024] Open
Abstract
Cancer represents a significant threat to human health, and traditional chemotherapy or cytotoxic therapy is no longer the sole or preferred approach for managing malignant tumors. With advanced research into the immunogenicity of tumor cells and the growing elderly population, tumor immunotherapy has emerged as a prominent therapeutic option. Its significance in treating elderly cancer patients is increasingly recognized. In this study, we review the conceptual classifications and benefits of immunotherapy, and discuss recent developments in new drugs and clinical progress in cancer treatment through various immunotherapeutic modalities with different mechanisms. Additionally, we explore the impact of immunosenescence on the effectiveness of cancer immunotherapy and propose innovative and effective strategies to rejuvenate senescent T cells.
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Affiliation(s)
| | | | | | | | - Dong Wang
- School of Basic Medical Sciences and State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.F.); (C.H.); (C.L.); (B.S.)
| | - Peijie Wu
- School of Basic Medical Sciences and State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; (Y.F.); (C.H.); (C.L.); (B.S.)
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Wang N, Lin Y, Shen L, Song H, Huang W, Huang J, Chen F, Liu F, Wang J, Qiu Y, Shi B, Lin L, He B. Prognostic value of pretreatment lymphocyte percentage in oral cancer: A prospective cohort study. Oral Dis 2024; 30:2176-2187. [PMID: 37357359 DOI: 10.1111/odi.14658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 06/08/2023] [Accepted: 06/11/2023] [Indexed: 06/27/2023]
Abstract
OBJECTIVE To assess the prognostic role of pretreatment lymphocyte percentage (LY%) for patients with oral squamous cell carcinoma (OSCC). METHODS A large-scale prospective cohort study between July 2002 and March 2021 was conducted. Propensity score-matched (PSM) analysis and inverse probability of treatment weighting (IPTW) analysis were performed to adjust for potential confounders. Using random survival forest (RSF), the relative importance of pretreatment LY% in prognosis prediction was also assessed. RESULTS A total of 743 patients were enrolled and followed up (median: 2.75 years, interquartile range: 1.25-4.42 years). A high pretreatment LY% was significantly associated with better disease-specific survival of patients with OSCC (Hazard ratio [HR] = 0.60, 95% confidence interval [CI]: 0.42, 0.84). The same tendency was observed in PSM (HR = 0.57, 95% CI: 0.38, 0.85) and IPTW analysis (HR = 0.57, 95% CI: 0.40, 0.82). RSF showed that LY% ranked the fifth among importance ranking of all prognostic factors. CONCLUSION Pretreatment LY% showed a moderate predictive ability, suggesting it might be a valuable tool to predict prognosis for patients with OSCC.
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Affiliation(s)
- Na Wang
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fujian, China
| | - Yulan Lin
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fujian, China
| | - Liling Shen
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fujian, China
| | - Haoyuan Song
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fujian, China
| | - Weihai Huang
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fujian, China
| | - Jingyao Huang
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fujian, China
| | - Fa Chen
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fujian, China
| | - Fengqiong Liu
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fujian, China
| | - Jing Wang
- Laboratory Center, The Major Subject of Environment and Health of Fujian Key Universities, School of Public Health, Fujian Medical University, Fujian, China
| | - Yu Qiu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Bin Shi
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Lisong Lin
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Baochang He
- Department of Epidemiology and Health Statistics, Fujian Provincial Key Laboratory of Environment Factors and Cancer, School of Public Health, Fujian Medical University, Fujian, China
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fujian, China
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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Aljarrah D, Chalour N, Zorgani A, Nissan T, Pranjol MZI. Exploring the gut microbiota and its potential as a biomarker in gliomas. Biomed Pharmacother 2024; 173:116420. [PMID: 38471271 DOI: 10.1016/j.biopha.2024.116420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 02/24/2024] [Accepted: 03/07/2024] [Indexed: 03/14/2024] Open
Abstract
Gut microbiome alterations are associated with various cancers including brain tumours such as glioma and glioblastoma. The gut communicates with the brain via a bidirectional pathway known as the gut-brain axis (GBA) which is essential for maintaining homeostasis. The gut microbiota produces many metabolites including short chain fatty acids (SCFAs) and essential amino acids such as glutamate, glutamine, arginine and tryptophan. Through the modulation of these metabolites the gut microbiome is able to regulate several functions of brain cells, immune cells and tumour cells including DNA methylation, mitochondrial function, the aryl hydrocarbon receptor (AhR), T-cell proliferation, autophagy and even apoptosis. Here, we summarise current findings on gut microbiome with respect to brain cancers, an area of research that is widely overlooked. Several studies investigated the relationship between gut microbiota and brain tumours. However, it remains unclear whether the gut microbiome variation is a cause or product of cancer. Subsequently, a biomarker panel was constructed for use as a predictive, prognostic and diagnostic tool with respect to multiple cancers including glioma and glioblastoma multiforme (GBM). This review further presents the intratumoural microbiome, a fascinating microenvironment within the tumour as a possible treatment target that can be manipulated to maximise effectiveness of treatment via personalised therapy. Studies utilising the microbiome as a biomarker and therapeutic strategy are necessary to accurately assess the effectiveness of the gut microbiome as a clinical tool with respect to brain cancers.
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Affiliation(s)
- Dana Aljarrah
- Department of Chemistry, School of Life Sciences, University of Sussex, Brighton, UK.
| | - Naima Chalour
- Cognitive and Behavioural Neuroscience laboratory, Houari Boumediene University of Science and Technology, Bab Ezzouar, Algiers, Algeria; Faculty of Biological Sciences, Houari Boumediene University of Science and Technology, Bab Ezzouar, Algiers, Algeria.
| | - Amine Zorgani
- The Microbiome Mavericks, 60 rue Christian Lacouture, Bron 69500, France.
| | - Tracy Nissan
- Department of Molecular Biosciences, the Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
| | - Md Zahidul I Pranjol
- Department of Chemistry, School of Life Sciences, University of Sussex, Brighton, UK.
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Tsunedomi R, Shindo Y, Nakajima M, Yoshimura K, Nagano H. The tumor immune microenvironment in pancreatic cancer and its potential in the identification of immunotherapy biomarkers. Expert Rev Mol Diagn 2023; 23:1121-1134. [PMID: 37947389 DOI: 10.1080/14737159.2023.2281482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 11/06/2023] [Indexed: 11/12/2023]
Abstract
INTRODUCTION Pancreatic cancer (PC) has an extremely poor prognosis, even with surgical resection and triplet chemotherapy treatment. Cancer immunotherapy has been recently approved for tumor-agnostic treatment with genome analysis, including in PC. However, it has limited efficacy. AREAS COVERED In addition to the low tumor mutation burden, one of the difficulties of immunotherapy in PC is the presence of abundant stromal cells in its microenvironment. Among stromal cells, cancer-associated fibroblasts (CAFs) play a major role in immunotherapy resistance, and CAF-targeted therapies are currently under development, including those in combination with immunotherapies. Meanwhile, microbiomes and tumor-derived exosomes (TDEs) have been shown to alter the behavior of distant receptor cells in PC. This review discusses the role of CAFs, microbiomes, and TDEs in PC tumor immunity. EXPERT OPINION Elucidating the mechanisms by which CAFs, microbiomes, and TDEs are involved in the tumorigenesis of PC will be helpful for developing novel immunotherapeutic strategies and identifying companion biomarkers for immunotherapy. Spatial single-cell analysis of the tumor microenvironment will be useful for identifying biomarkers of PC immunity. Furthermore, given the complexity of immune mechanisms, artificial intelligence models will be beneficial for predicting the efficacy of immunotherapy.
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Affiliation(s)
- Ryouichi Tsunedomi
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Yoshitaro Shindo
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Masao Nakajima
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
| | - Kiyoshi Yoshimura
- Division of Medical Oncology, Department of Medicine, Showa University School of Medicine, Shinagawa, Tokyo, Japan
- Department of Clinical Immuno-Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Setagaya, Tokyo, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan
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Liu S, Sun Q, Ren X. Novel strategies for cancer immunotherapy: counter-immunoediting therapy. J Hematol Oncol 2023; 16:38. [PMID: 37055849 PMCID: PMC10099030 DOI: 10.1186/s13045-023-01430-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/21/2023] [Indexed: 04/15/2023] Open
Abstract
The advent of immunotherapy has made an indelible mark on the field of cancer therapy, especially the application of immune checkpoint inhibitors in clinical practice. Although immunotherapy has proven its efficacy and safety in some tumors, many patients still have innate or acquired resistance to immunotherapy. The emergence of this phenomenon is closely related to the highly heterogeneous immune microenvironment formed by tumor cells after undergoing cancer immunoediting. The process of cancer immunoediting refers to the cooperative interaction between tumor cells and the immune system that involves three phases: elimination, equilibrium, and escape. During these phases, conflicting interactions between the immune system and tumor cells result in the formation of a complex immune microenvironment, which contributes to the acquisition of different levels of immunotherapy resistance in tumor cells. In this review, we summarize the characteristics of different phases of cancer immunoediting and the corresponding therapeutic tools, and we propose normalized therapeutic strategies based on immunophenotyping. The process of cancer immunoediting is retrograded through targeted interventions in different phases of cancer immunoediting, making immunotherapy in the context of precision therapy the most promising therapy to cure cancer.
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Affiliation(s)
- Shaochuan Liu
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
- Key Laboratory of Cancer Immunology and Biotherapy, 300060, Tianjin, China
- Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China
- Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China
| | - Qian Sun
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, 300060, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
- Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
- Key Laboratory of Cancer Immunology and Biotherapy, 300060, Tianjin, China.
- Key Laboratory of Cancer Prevention and Therapy, 300060, Tianjin, China.
- Tianjin's Clinical Research Center for Cancer, 300060, Tianjin, China.
- Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, 300060, Tianjin, China.
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Alshaebi F, Safi M, Algabri YA, Al-Azab M, Aldanakh A, Alradhi M, Reem A, Zhang C. Interleukin-34 and immune checkpoint inhibitors: Unified weapons against cancer. Front Oncol 2023; 13:1099696. [PMID: 36798830 PMCID: PMC9927403 DOI: 10.3389/fonc.2023.1099696] [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: 11/24/2022] [Accepted: 01/09/2023] [Indexed: 02/03/2023] Open
Abstract
Interleukin-34 (IL-34) is a cytokine that is involved in the regulation of immune cells, including macrophages, in the tumor microenvironment (TME). Macrophages are a type of immune cell that can be found in large numbers within the TME and have been shown to have a role in the suppression of immune responses in cancer. This mmune suppression can contribute to cancer development and tumors' ability to evade the immune system. Immune checkpoint inhibitors (ICIs) are a type of cancer treatment that target proteins on immune cells that act as "checkpoints," regulating the activity of the immune system. Examples of these proteins include programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). ICIs work by blocking the activity of these proteins, allowing the immune system to mount a stronger response against cancer cells. The combination of IL-34 inhibition with ICIs has been proposed as a potential treatment option for cancer due to the role of IL-34 in the TME and its potential involvement in resistance to ICIs. Inhibiting the activity of IL-34 or targeting its signaling pathways may help to overcome resistance to ICIs and improve the effectiveness of these therapies. This review summarizes the current state of knowledge concerning the involvement of IL-34-mediated regulation of TME and the promotion of ICI resistance. Besides, this work may shed light on whether targeting IL-34 might be exploited as a potential treatment option for cancer patients in the future. However, further research is needed to fully understand the mechanisms underlying the role of IL-34 in TME and to determine the safety and efficacy of this approach in cancer patients.
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Affiliation(s)
- Fadhl Alshaebi
- Department of Respiratory, Shandong Second Provincial General Hospital, Shandong University, Jinan, Shandong, China
| | - Mohammed Safi
- Department of Respiratory, Shandong Second Provincial General Hospital, Shandong University, Jinan, Shandong, China,*Correspondence: Mohammed Safi, ; Caiqing Zhang,
| | - Yousif A. Algabri
- Department of Biomedical Engineering, School of Control Science and Engineering, Shandong University, Jinan, Shandong, China
| | - Mahmoud Al-Azab
- Department of Immunology, Guangzhou Institute of Pediatrics, Guangzhou Women and Children’s Medical Center, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou Medical University, Guangzhou, China
| | - Abdullah Aldanakh
- Department of Urology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Mohammed Alradhi
- Department of Urology, The Affiliated Hospital of Qingdao Binhai University, Qingdao, Shandong, China
| | - Alariqi Reem
- Faculty of Medicine and Health Sciences, Amran University, Amran, Yemen
| | - Caiqing Zhang
- Department of Respiratory, Shandong Second Provincial General Hospital, Shandong University, Jinan, Shandong, China,*Correspondence: Mohammed Safi, ; Caiqing Zhang,
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10
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Di Girolamo D, Tajbakhsh S. Pathological features of tissues and cell populations during cancer cachexia. CELL REGENERATION 2022; 11:15. [PMID: 35441960 PMCID: PMC9021355 DOI: 10.1186/s13619-022-00108-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 12/28/2021] [Indexed: 11/10/2022]
Abstract
Cancers remain among the most devastating diseases in the human population in spite of considerable advances in limiting their impact on lifespan and healthspan. The multifactorial nature of cancers, as well as the number of tissues and organs that are affected, have exposed a considerable diversity in mechanistic features that are reflected in the wide array of therapeutic strategies that have been adopted. Cachexia is manifested in a number of diseases ranging from cancers to diabetes and ageing. In the context of cancers, a majority of patients experience cachexia and succumb to death due to the indirect effects of tumorigenesis that drain the energy reserves of different organs. Considerable information is available on the pathophysiological features of cancer cachexia, however limited knowledge has been acquired on the resident stem cell populations, and their function in the context of these diseases. Here we review current knowledge on cancer cachexia and focus on how tissues and their resident stem and progenitor cell populations are individually affected.
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Hsieh CC, Chang CC, Hsu YC, Lin CL. Immune Modulation by Myeloid-Derived Suppressor Cells in Diabetic Kidney Disease. Int J Mol Sci 2022; 23:13263. [PMID: 36362050 PMCID: PMC9655277 DOI: 10.3390/ijms232113263] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 10/29/2022] [Accepted: 10/30/2022] [Indexed: 09/22/2023] Open
Abstract
Diabetic kidney disease (DKD) frequently leads to end-stage renal disease and other life-threatening illnesses. The dysregulation of glomerular cell types, including mesangial cells, endothelial cells, and podocytes, appears to play a vital role in the development of DKD. Myeloid-derived suppressor cells (MDSCs) exhibit immunoregulatory and anti-inflammatory properties through the depletion of L-arginine that is required by T cells, through generation of oxidative stress, interference with T-cell recruitment and viability, proliferation of regulatory T cells, and through the promotion of pro-tumorigenic functions. Under hyperglycemic conditions, mouse mesangial cells reportedly produce higher levels of fibronectin and pro-inflammatory cytokines. Moreover, the number of MDSCs is noticeably decreased, weakening inhibitory immune activities, and creating an inflammatory environment. In diabetic mice, immunotherapy with MDSCs that were induced by a combination of granulocyte-macrophage colony-stimulating factor, interleukin (IL)-1β, and IL-6, reduced kidney to body weight ratio, fibronectin expression, and fibronectin accumulation in renal glomeruli, thus ameliorating DKD. In conclusion, MDSCs exhibit anti-inflammatory activities that help improve renal fibrosis in diabetic mice. The therapeutic targeting of the proliferative or immunomodulatory pathways of MDSCs may represent an alternative immunotherapeutic strategy for DKD.
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Affiliation(s)
- Ching-Chuan Hsieh
- Division of General Surgery, Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
| | - Cheng-Chih Chang
- Division of General Surgery, Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
| | - Yung-Chien Hsu
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
- Division of Nephrology, Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
| | - Chun-Liang Lin
- Kidney and Diabetic Complications Research Team (KDCRT), Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
- Division of Nephrology, Chang Gung Memorial Hospital, Chiayi 261363, Taiwan
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12
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The distinct roles of exosomes in innate immune responses and therapeutic applications in cancer. Eur J Pharmacol 2022; 933:175292. [PMID: 36150532 DOI: 10.1016/j.ejphar.2022.175292] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 09/13/2022] [Accepted: 09/15/2022] [Indexed: 11/21/2022]
Abstract
The innate immune system is one of the major constituents of the host's defense against invading pathogens and extracellular vesicles (EVs) are involved in regulating its responses. Exosomes, a subclass of EVs, released from eukaryotic cells, contribute to intracellular communication and drive various biological processes by transferring nuclei acids, proteins, lipids, and carbohydrates between cells, protecting cargo from enzymatic degradation and immune recognition and consequent elimination by the immune system. A growing body of evidence has revealed that exosomes produced from host cells, infected cells, tumor cells, and immune cells regulate innate immune signaling and responses and thus play a significant role in the propagation of pathogens. Immune cells can recognize exosomes-bearing components including DNA strands, viral RNAs, and even proteins by various mechanisms such as through Toll-like receptor/NF-κB signaling, inducing cytokine production and reprogramming the innate immune responses, immunosuppression or immunesupportive. There is persuasive preclinical and clinical evidence that exosomes are therapeutic strategies for immunotherapy, cancer vaccine, drug-delivery system, and diagnostic biomarker. However, further scrutiny is essential to validate these findings. In this review, we describe the current facts on the regulation of innate immune responses by exosomes. We also describe the translational application of exosomes as cancer-therapy agents and immunotherapy.
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13
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Liang J, Li T, Zhao J, Wang C, Sun H. Current understanding of the human microbiome in glioma. Front Oncol 2022; 12:781741. [PMID: 36003766 PMCID: PMC9393498 DOI: 10.3389/fonc.2022.781741] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Accepted: 07/11/2022] [Indexed: 11/17/2022] Open
Abstract
There is mounting evidence that the human microbiome is highly associated with a wide variety of central nervous system diseases. However, the link between the human microbiome and glioma is rarely noticed. The exact mechanism of microbiota to affect glioma remains unclear. Recent studies have demonstrated that the microbiome may affect the development, progress, and therapy of gliomas, including the direct impacts of the intratumoral microbiome and its metabolites, and the indirect effects of the gut microbiome and its metabolites. Glioma-related microbiome (gut microbiome and intratumoral microbiome) is associated with both tumor microenvironment and tumor immune microenvironment, which ultimately influence tumorigenesis, progression, and responses to treatment. In this review, we briefly summarize current knowledge regarding the role of the glioma-related microbiome, focusing on its gut microbiome fraction and a brief description of the intratumoral microbiome, and put forward the prospects in which microbiome can be applied in the future and some challenges still need to be solved.
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Affiliation(s)
- Jianhao Liang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Ting Li
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Jiajia Zhao
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Cheng Wang
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Sun
- Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Department of Laboratory Medicine, Clinical Biobank Center, Microbiome Medicine Center, Zhujiang Hospital, Southern Medical University, Guangzhou, China
- Key Laboratory of Mental Health of the Ministry of Education, Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Southern Medical University, Guangzhou, China
- *Correspondence: Haitao Sun,
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14
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Guo J, Shen Y, Hu S, Rui T, Liu J, Yuan Y. Neobavaisoflavone inhibits antitumor immunosuppression via myeloid-derived suppressor cells. Int Immunopharmacol 2022; 111:109103. [PMID: 35944461 DOI: 10.1016/j.intimp.2022.109103] [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: 05/20/2022] [Revised: 07/16/2022] [Accepted: 07/25/2022] [Indexed: 12/12/2022]
Abstract
Neobavaisoflavone (Neo), as a traditional Chinese medicine, is the active ingredient in the herb Psoralea corylifolial and has antitumor activity. Myeloid-derived suppressor cells (MDSCs), which are a heterogeneous population of haematopoietic cells of the myeloid lineage, have been reported to be closely related to the pathogenesis of tumour progression, but whether Neo can regulate MDSC expansion and function remains unclear. Here, we found that Neo could inhibit the expansion and suppressive function of MDSCs by targeting STAT3. Importantly, Neo inhibited the growth of 4T1 and LLC tumours in vivo, as well as lung metastasis of 4T1 tumours in vivo. Furthermore, we identified MDSCs as the direct targets by which Neo attenuated tumour progression. In addition, Neo notably enhanced anti-PD-1 efficacy in anti-PD-1-insensitive 4T1 tumours. Therefore, our study sheds light on the development of Neobased therapeutic strategies against cancer.
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Affiliation(s)
- Jufeng Guo
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Yingying Shen
- Laboratory of Cancer Biology, The Key Lab of Biotherapy in Zhejiang Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310020, China; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Shufang Hu
- Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Tao Rui
- Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
| | - Jian Liu
- Department of Breast Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China; Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China.
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15
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Wang G, Wang J, Niu C, Zhao Y, Wu P. Neutrophils: New Critical Regulators of Glioma. Front Immunol 2022; 13:927233. [PMID: 35860278 PMCID: PMC9289230 DOI: 10.3389/fimmu.2022.927233] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/06/2022] [Indexed: 11/22/2022] Open
Abstract
In cancer, neutrophils are an important part of the tumour microenvironment (TME). Previous studies have shown that circulating and infiltrating neutrophils are associated with malignant progression and immunosuppression in gliomas. However, recent studies have shown that neutrophils have an antitumour effect. In this review, we focus on the functional roles of neutrophils in the circulation and tumour sites in patients with glioma. The mechanisms of neutrophil recruitment, immunosuppression and the differentiation of neutrophils are discussed. Finally, the potential of neutrophils as clinical biomarkers and therapeutic targets is highlighted. This review can help us gain a deeper and systematic understanding of the role of neutrophils, and provide new insights for treatment in gliomas.
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Affiliation(s)
- Guanyu Wang
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jinpeng Wang
- Department of Urology, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Chaoshi Niu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Stereotactic Neurosurgical Institute, Hefei, China
- Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, China
- Anhui Provincial Clinical Research Center for Neurosurgical Disease, Hefei, China
| | - Yan Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Pengfei Wu
- Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
- Anhui Provincial Stereotactic Neurosurgical Institute, Hefei, China
- Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, China
- Anhui Provincial Clinical Research Center for Neurosurgical Disease, Hefei, China
- Anhui Province Key Laboratory of Translational Cancer Research, Bengbu Medical College, Bengbu, China
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16
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Joshi S, Sharabi A. Targeting myeloid-derived suppressor cells to enhance natural killer cell-based immunotherapy. Pharmacol Ther 2022; 235:108114. [DOI: 10.1016/j.pharmthera.2022.108114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 01/06/2022] [Accepted: 01/11/2022] [Indexed: 12/09/2022]
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17
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Dong P, Chen L, Wu H, Huo J, Jiang Z, Shao Y, Ren X, Huang J, Li X, Wang M, Nie N, Zhang J, Jin P, Zheng Y, Ge M. Impaired immunosuppressive role of myeloid-derived suppressor cells in acquired aplastic anemia. Haematologica 2022; 107:2834-2845. [PMID: 35734923 PMCID: PMC9713570 DOI: 10.3324/haematol.2021.280292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Indexed: 12/14/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSC) are a group of heterogeneous immature myeloid cells and display immunosuppressive function. In this study, MDSC populations were evaluated in acquired aplastic anemia (AA) (n=65) in which aberrant immune mechanisms contributed to bone marrow destruction. Our data demonstrate that both the proportion and immunosuppressive function of MDSC are impaired in AA patients. Decreased percentage of MDSC, especially monocytic MDSC, in the blood of AA patients (n=15) is positively correlated with the frequency of T-regulatory cells, bone marrow level of WT1 and decreased plasma level of arginase-1. RNA sequencing analyses reveal that multiple pathways including DNA damage, interleukin 4, apoptosis, and Jak kinase singnal transducer and activator of transcription are upregulated, whereas transcription, IL-6, IL-18, glycolysis, transforming growth factor and reactive oxygen species are downregulated in MDSC of AA (n=4), compared with that of healthy donors (n=3). These data suggest that AA MDSC are defective. Administration of rapamycin significantly increases the absolute number of MDSC and levels of intracellular enzymes, including arginase-1 and inducible nitric-oxide synthase. Moreover, rapamycin inhibits MDSC from differentiating into mature myeloid cells. These findings reveal that impaired MDSC are involved in the immunopathogenesis of AA. Pharmacologically targeting of MDSC by rapamycin might provide a promising therapeutic strategy for AA.
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Affiliation(s)
- Peiyuan Dong
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin,Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China,*PD and LC contributed equally as co-first authors
| | - Lingyun Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin,*PD and LC contributed equally as co-first authors
| | - Hongfei Wu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Jiali Huo
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Zhongxing Jiang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingqi Shao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Xiang Ren
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Jinbo Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Xingxin Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Min Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Neng Nie
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Jing Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Peng Jin
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Yizhou Zheng
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin
| | - Meili Ge
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin,M.Ge
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18
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Li B, Luo Y, Zhou Y, Wu J, Fang Z, Li Y. Role of sanguinarine in regulating immunosuppression in a Lewis lung cancer mouse model. Int Immunopharmacol 2022; 110:108964. [PMID: 35728305 DOI: 10.1016/j.intimp.2022.108964] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2022] [Revised: 06/11/2022] [Accepted: 06/12/2022] [Indexed: 12/24/2022]
Abstract
Myeloid-derived suppressor cells (MDSCs) play an important role in the tumor-induced immunosuppressive microenvironment and have been linked with tumor development, proliferation, and resistance to treatment. Therefore, therapies that target MDSCs, such as sanguinarine (SNG), are now being considered potential treatments for lung cancer. However, the role of SNG in regulating the immune response in lung cancer is still not clear. In view of this, we evaluated the mechanism involved in the antitumor and immunoregulatory response to SNG therapy in a Lewis lung cancer (LLC) mouse model. The tumor mass and volume in the SNG treated LLC mouse model were significantly lower when compared with the control group (p < 0.05), indicating a good response to SNG. SNG also reduced the damage to the spleen, decreased the proportion of MDSCs, and increased the production of T helper 1 (Th1), T helper 2 (Th2), cytotoxic T-lymphocyte (CTL), macrophages, dendritic cells (DC) within the spleen. However, it did not affect the proportion of T helper 17 (Th17) and regulatory T cells (Treg). SNG also down-regulated the proportion of MDSCs in vitro and promoted their apoptosis, differentiation, and maturation. SNG was found to induce the differentiation of MDSCs into macrophages and DC through the nuclear factor kappa-B (NF-κB) pathway in vitro, while it also decreased the expression of arginase-1 (Arg-1) anti-inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS) in MDSCs.SNG also reduced the inhibitory effect on the proliferation of CD8+T cells. SNG may reduce the immunosuppressive state induced by lung cancer by promoting cell differentiation and by inhibiting the immunosuppressive activity of MDSCs.
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Affiliation(s)
- Bei Li
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Jing'an, Shanghai 200071, China
| | - Yingbin Luo
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Jing'an, Shanghai 200071, China
| | - Yixi Zhou
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Jing'an, Shanghai 200071, China
| | - Jianchun Wu
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Jing'an, Shanghai 200071, China
| | - Zhihong Fang
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Jing'an, Shanghai 200071, China
| | - Yan Li
- Department of Oncology, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Jing'an, Shanghai 200071, China.
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19
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Li CX, Liu Y, Zhang YZ, Li JC, Lai J. Astragalus polysaccharide: a review of its immunomodulatory effect. Arch Pharm Res 2022; 45:367-389. [PMID: 35713852 DOI: 10.1007/s12272-022-01393-3] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 06/12/2022] [Indexed: 12/27/2022]
Abstract
The Astragalus polysaccharide is an important bioactive component derived from the dry root of Astragalus membranaceus. This review aims to provide a comprehensive overview of the research progress on the immunomodulatory effect of Astragalus polysaccharide and provide valuable reference information. We review the immunomodulatory effect of Astragalus polysaccharide on central and peripheral immune organs, including bone marrow, thymus, lymph nodes, spleen, and mucosal tissues. Furthermore, the immunomodulatory effect of Astragalus polysaccharide on a variety of immune cells is summarized. Studies have shown that Astragalus polysaccharide can promote the activities of macrophages, natural killer cells, dendritic cells, T lymphocytes, B lymphocytes and microglia and induce the expression of a variety of cytokines and chemokines. The immunomodulatory effect of Astragalus polysaccharide makes it promising for the treatment of many diseases, including cancer, infection, type 1 diabetes, asthma, and autoimmune disease. Among them, the anticancer effect is the most prominent. In short, Astragalus polysaccharide is a valuable immunomodulatory medicine, but further high-quality studies are warranted to corroborate its clinical efficacy.
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Affiliation(s)
- Chun-Xiao Li
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ying Liu
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu-Zhen Zhang
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jing-Chun Li
- Department of Dermatology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Jiang Lai
- Department of Anorectal Surgery, Third People's Hospital of Chengdu, Chengdu, China.
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20
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Farshidpour M, Hutson W. Immune Checkpoint Inhibitors Induced Hepatotoxicity; Gastroenterologists' Perspectives. Middle East J Dig Dis 2022; 14:244-253. [PMID: 36619143 PMCID: PMC9489307 DOI: 10.34172/mejdd.2022.279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 01/10/2022] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND: Immune checkpoint inhibitors (ICIs) have promising clinical activity and are essential medications for patients with several malignancies. However, by deranging the immune system, these novel agents could lead to immune-related adverse events (IRAEs). Hepatotoxicity with checkpoint inhibitors usually results in acute hepatitis or drug-induced liver injury. METHODS: This review article discusses the recent clinical evidence available regarding checkpoint inhibitor-induced hepatitis and reviews an approach to their diagnosis and management. CONCLUSION: ICIs have improved patients' outcomes with different forms of malignancy; however, ICIs-related liver damage is a clinically significant entity in these patients. All patients should be monitored carefully for IRAEs while undergoing treatment with ICIs.
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Affiliation(s)
- Maham Farshidpour
- Loma Linda University Transplantation Institute,Corresponding Author: Maham Farshidpour, MD Loma Linda University Transplant Institute 197 E Caroline St, Suite 1400, San Bernardino, CA 92408 Tel: + 909 558 3636 Fax: + 909 337 2222
| | - William Hutson
- West Virginia University - Department of Medicine Section of Gastroenterology & Hepatology
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21
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Zhang Y, Luo X, Yu J, Qian K, Zhu H. An Immune Feature-Based, Three-Gene Scoring System for Prognostic Prediction of Head-and-Neck Squamous Cell Carcinoma. Front Oncol 2022; 11:739182. [PMID: 35087741 PMCID: PMC8786713 DOI: 10.3389/fonc.2021.739182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2021] [Accepted: 12/14/2021] [Indexed: 12/13/2022] Open
Abstract
Head-and-neck squamous cell carcinoma (HNSCC) is characterized by a high frequency of neck lymph node metastasis (LNM), a key prognostic factor. Therefore, identifying the biological processes during LNM of HNSCC has significant clinical implications for risk stratification. This study performed Gene Ontology enrichment analysis of differentially expressed genes between tumors with LNM and those without LNM and identified the involvement of immune response in the lymphatic metastasis of HNSCC. We further identified greater infiltrations of CD8+ T cells in tumors than in adjacent normal tissues through immunochemistry in the patient cohort (n = 62), indicating the involvement of CD8+ T cells in the antitumor immunity. Hierarchical clustering analysis was conducted to initially identify the candidate genes relevant to lymphocyte-mediated antitumor response. The candidate genes were applied to construct a LASSO Cox regression analysis model. Three genes were eventually screened out as progression-related differentially expressed candidates in HNSCC and a risk scoring system was established based on LASSO Cox regression model to predict the outcome in patients with HNSCC. The score was calculated using the formula: 0.0636 × CXCL11 - 0.4619 × CXCR3 + 0.2398 × CCR5. Patients with high scores had significantly worse overall survival than those with low scores (p < 0.001). The risk score showed good performance in characterizing tumor-infiltrating lymphocytes and provided a theoretical basis for stratifying patients receiving immune therapies. Additionally, a nomogram including the risk score, age, and TNM stage was constructed. The prediction model displayed marginally better discrimination ability and higher agreement in predicting the survival of patients with HNSCC compared with the TNM stage.
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Affiliation(s)
- Yamin Zhang
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.,School of Stomatology, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Hangzhou, China
| | - Xiayan Luo
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Jing Yu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Kejia Qian
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Huiyong Zhu
- Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
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22
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Morales E, Olson M, Iglesias F, Luetkens T, Atanackovic D. Targeting the tumor microenvironment of Ewing sarcoma. Immunotherapy 2021; 13:1439-1451. [PMID: 34670399 DOI: 10.2217/imt-2020-0341] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Ewing sarcoma is an aggressive tumor type with an age peak in adolescence. Despite the use of dose-intensified chemotherapy as well as radiation and surgery for local control, patients with upfront metastatic disease or relapsed disease have a dismal prognosis, highlighting the need for additional therapeutic options. Different types of immunotherapies have been investigated with only very limited clinical success, which may be due to the presence of immunosuppressive factors in the tumor microenvironment. Here we provide an overview on different factors contributing to Ewing sarcoma immune escape. We demonstrate ways to target these factors in order to make current and future immunotherapies more effective and achieve deeper and more durable responses in patients with Ewing sarcoma.
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Affiliation(s)
- Erin Morales
- Pediatric Hematology/Oncology Department, University of Utah, Salt Lake City, UT 84132, USA
| | - Michael Olson
- Department of Pathology, University of Utah, Salt Lake City, UT 84112, USA.,Hematology & Hematologic Malignancies, University of Utah/Huntsman Cancer Institute, Salt Lake City, UT 84112, USA
| | - Fiorella Iglesias
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Tim Luetkens
- Department of Microbiology & Immunology, School of Medicine, University of Maryland Baltimore, MD 21201, USA.,Department of Medicine, University of Maryland School of Medicine & Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
| | - Djordje Atanackovic
- Department of Microbiology & Immunology, School of Medicine, University of Maryland Baltimore, MD 21201, USA.,Department of Medicine, University of Maryland School of Medicine & Marlene & Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD 21201, USA
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23
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de Paula Silva E, Marti LC, Andreghetto FM, de Sales RO, Hoberman M, Dos Santos Dias B, Diniz LFA, Dos Santos AM, Moyses RA, Curioni OA, Lopez RVM, Nunes FD, Tajara EH, Severino P. Extracellular vesicles cargo from head and neck cancer cell lines disrupt dendritic cells function and match plasma microRNAs. Sci Rep 2021; 11:18534. [PMID: 34535708 PMCID: PMC8448882 DOI: 10.1038/s41598-021-97753-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 08/26/2021] [Indexed: 12/25/2022] Open
Abstract
Extracellular vesicles (EVs) are mediators of the immune system response. Encapsulated in EVs, microRNAs can be transferred between cancer and immune cells. To define the potential effects of EVs originated from squamous cell carcinoma cells on immune system response, we performed microRNA profiling of EVs released from two distinct cell lines and treated dendritic cells derived from circulating monocytes (mono-DCs) with these EVs. We confirmed the internalization of EVs by mono-DCs and the down-regulation of microRNA mRNA targets in treated mono-DCs. Differences in surface markers of dendritic cells cultivated in the presence of EVs indicated that their content disrupts the maturation process. Additionally, microRNAs known to interfere with dendritic cell function, and detected in EVs, matched microRNAs from squamous cell carcinoma patients' plasma: miR-17-5p in oropharyngeal squamous cell carcinoma, miR-21 in oral squamous cell carcinoma, miR-16, miR-24, and miR-181a circulating in both oral and oropharyngeal squamous cell carcinoma, and miR-23b, which has not been previously described in plasma of head and neck squamous cell carcinoma, was found in plasma from patients with these cancer subtypes. This study contributes with insights on EVs in signaling between cancer and immune cells in squamous cell carcinoma of the head and neck.
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Affiliation(s)
- Elisangela de Paula Silva
- Centro de Pesquisa Experimental, Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Luciana Cavalheiro Marti
- Centro de Pesquisa Experimental, Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Flávia Maziero Andreghetto
- Centro de Pesquisa Experimental, Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Romário Oliveira de Sales
- Centro de Pesquisa Experimental, Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Martin Hoberman
- Centro de Pesquisa Experimental, Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Bárbara Dos Santos Dias
- Centro de Pesquisa Experimental, Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Larissa Figueiredo Alves Diniz
- Centro de Pesquisa Experimental, Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Alessandro Marins Dos Santos
- Centro de Pesquisa Experimental, Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo, Brazil
| | - Raquel Ajub Moyses
- Head and Neck Surgery Department, Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, Sao Paulo, Brazil
| | - Otávio Alberto Curioni
- Departamento de Cirurgia de Cabeça e Pescoço e Otorrinolaringologia, Hospital Heliópolis, Sao Paulo, Brazil
| | | | - Fabio Daumas Nunes
- Department of Oral Pathology, School of Dentistry, Universidade de São Paulo, Sao Paulo, Brazil
| | - Eloiza Helena Tajara
- Department of Molecular Biology, Faculdade de Medicina de São José Do Rio Preto, Sao Paulo, Brazil
| | - Patricia Severino
- Centro de Pesquisa Experimental, Albert Einstein Research and Education Institute, Hospital Israelita Albert Einstein, Sao Paulo, Brazil.
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24
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de Lange MJ, Nell RJ, van der Velden PA. Scientific and clinical implications of genetic and cellular heterogeneity in uveal melanoma. MOLECULAR BIOMEDICINE 2021; 2:25. [PMID: 35006486 PMCID: PMC8607395 DOI: 10.1186/s43556-021-00048-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Accepted: 07/16/2021] [Indexed: 10/27/2022] Open
Abstract
Here, we discuss the presence and roles of heterogeneity in the development of uveal melanoma. Both genetic and cellular heterogeneity are considered, as their presence became undeniable due to single cell approaches that have recently been used in uveal melanoma analysis. However, the presence of precursor clones and immune infiltrate in uveal melanoma have been described as being part of the tumour already decades ago. Since uveal melanoma grow in the corpus vitreous, they present a unique tumour model because every cell present in the tumour tissue is actually part of the tumour and possibly plays a role. For an effective treatment of uveal melanoma metastasis, it should be clear whether precursor clones and normal cells play an active role in progression and metastasis. We propagate analysis of bulk tissue that allows analysis of tumour heterogeneity in a clinical setting.
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Affiliation(s)
- Mark J de Lange
- Department of Ophthalmology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | - Rogier J Nell
- Department of Ophthalmology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands
| | - Pieter A van der Velden
- Department of Ophthalmology, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands.
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25
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MicroRNA-150 inhibits myeloid-derived suppressor cells proliferation and function through negative regulation of ARG-1 in sepsis. Life Sci 2021; 278:119626. [PMID: 34004247 DOI: 10.1016/j.lfs.2021.119626] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 05/06/2021] [Accepted: 05/10/2021] [Indexed: 01/01/2023]
Abstract
AIMS Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The majority of sepsis-related deaths occur during late sepsis, which presents as a state of immunosuppression. Myeloid-derived suppressor cells (MDSCs) have been reported to promote immunosuppression during sepsis. Here we aim to understand the role of microRNAs in regulating MDSCs proliferation and immunosuppression function during sepsis. MAIN METHODS Murine sepsis model was established using cecal ligation and puncture (CLP). A microarray was used to identify microRNAs with differential expression in murine sepsis. The effect of microRNA-150 on MDSCs proliferation and function was then evaluated. 140 multiple trauma patients from Tongji Hospital and 10 healthy controls were recruited. Peripheral blood samples were taken and the serum level of miR-150 was measured. KEY FINDINGS In the murine model of sepsis, MDSCs expansion was noted in the spleen and bone marrow, while expression of miR-150 in MDSCs decreased. Replenishing miR-150 inhibited the expansion of MDSCs in both monocytic and polymorphonuclear subpopulations, as well as decreasing the immunosuppressive function of MDSCs, through down-regulation of ARG1. Both pro-inflammatory cytokine IL-6 and anti-inflammatory cytokines TGF-β and IL-10 were reduced by miR-150. In human, the serum level of miR-150 was down-regulated in septic patients and elevated in non-septic trauma patients compared to healthy controls. SIGNIFICANCE Our study showed that MiR-150 is down-regulated during sepsis. Replenishing miR-150 reduces the immunosuppression function of MDSCs by down-regulating ARG1 in late sepsis. MiR-150 might serve as a potential therapeutic option for sepsis.
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26
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Kho VM, Mekers VE, Span PN, Bussink J, Adema GJ. Radiotherapy and cGAS/STING signaling: Impact on MDSCs in the tumor microenvironment. Cell Immunol 2021; 362:104298. [PMID: 33592541 DOI: 10.1016/j.cellimm.2021.104298] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/14/2021] [Accepted: 01/17/2021] [Indexed: 12/20/2022]
Abstract
Myeloid derived suppressor cells (MDSCs) are a highly heterogeneous population of immature immune cells with immunosuppressive functions that are recruited to the tumor microenvironment (TME). MDSCs promote tumor growth and progression by inhibiting immune effector cell proliferation and function. MDSCs are affected by both novel anti-cancer therapies targeting the immune system to promote anti-tumor immunity, as well as by conventional treatments such as radiotherapy. Following radiotherapy, cytoplasmic double stranded DNA stimulates the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, resulting in type I interferon production. Effectiveness of radiotherapy and cGAS/STING signaling are closely intertwined: activation of cGAS and STING is key to generate systemic anti-tumor immunity after irradiation. This review focuses on how radiotherapy and cGAS/STING signaling in MDSCs and/or tumor cells impact MDSC recruitment, expansion and function. The influence of conventional and ablative radiotherapy treatment schedules, inflammatory response following radiotherapy, and hypoxia are discussed as MDSC modulators.
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Affiliation(s)
- Vera M Kho
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands
| | - Vera E Mekers
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands
| | - Paul N Span
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands
| | - Johan Bussink
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands
| | - Gosse J Adema
- Radiotherapy and OncoImmunology Laboratory, Department of Radiation Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 32, 6525 GA Nijmegen, The Netherlands.
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27
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Armitage JD, Newnes HV, McDonnell A, Bosco A, Waithman J. Fine-Tuning the Tumour Microenvironment: Current Perspectives on the Mechanisms of Tumour Immunosuppression. Cells 2021; 10:E56. [PMID: 33401460 PMCID: PMC7823446 DOI: 10.3390/cells10010056] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 12/28/2020] [Accepted: 12/30/2020] [Indexed: 02/07/2023] Open
Abstract
Immunotherapy has revolutionised the treatment of cancers by harnessing the power of the immune system to eradicate malignant tissue. However, it is well recognised that some cancers are highly resistant to these therapies, which is in part attributed to the immunosuppressive landscape of the tumour microenvironment (TME). The contexture of the TME is highly heterogeneous and contains a complex architecture of immune, stromal, vascular and tumour cells in addition to acellular components such as the extracellular matrix. While understanding the dynamics of the TME has been instrumental in predicting durable responses to immunotherapy and developing new treatment strategies, recent evidence challenges the fundamental paradigms of how tumours can effectively subvert immunosurveillance. Here, we discuss the various immunosuppressive features of the TME and how fine-tuning these mechanisms, rather than ablating them completely, may result in a more comprehensive and balanced anti-tumour response.
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Affiliation(s)
- Jesse D. Armitage
- Telethon Kids Institute, The University of Western Australia, Nedlands, WA 6009, Australia; (J.D.A.); (H.V.N.); (A.M.)
| | - Hannah V. Newnes
- Telethon Kids Institute, The University of Western Australia, Nedlands, WA 6009, Australia; (J.D.A.); (H.V.N.); (A.M.)
| | - Alison McDonnell
- Telethon Kids Institute, The University of Western Australia, Nedlands, WA 6009, Australia; (J.D.A.); (H.V.N.); (A.M.)
- National Centre for Asbestos Related Diseases, QEII Medical Centre, The University of Western Australia, Nedlands, WA 6009, Australia
| | - Anthony Bosco
- Telethon Kids Institute, The University of Western Australia, Nedlands, WA 6009, Australia; (J.D.A.); (H.V.N.); (A.M.)
| | - Jason Waithman
- Telethon Kids Institute, The University of Western Australia, Nedlands, WA 6009, Australia; (J.D.A.); (H.V.N.); (A.M.)
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28
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Martínez-Rodríguez M, Monteagudo C. CCL27 Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1302:113-132. [PMID: 34286445 DOI: 10.1007/978-3-030-62658-7_9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Chemokines are a group of small proteins which play an important role in leukocyte migration and invasion. They are also involved in the cellular proliferation and migration of tumor cells.Chemokine CCL27 (cutaneous T cell-attracting chemokine, CTACK) is mainly expressed by keratinocytes of the normal epidermis. It is well known that this chemokine plays an important role in several inflammatory diseases of the skin, such as atopic dermatitis, contact dermatitis, and psoriasis. Moreover, several studies have shown an association between CCL27 expression and a variety of neoplasms including skin cancer.In this chapter, we address the role of chemokine CCL27 in the tumor microenvironment in the most relevant cancers of the skin and other anatomical locations. We also make a brief comment on future perspectives and the potential relation of CCL27 with different immunotherapeutic modalities.
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Affiliation(s)
| | - Carlos Monteagudo
- Department of Pathology, University Clinic Hospital-INCLIVA, University of Valencia, Valencia, Spain.
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29
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Elsaied DG, Noreldin NM, Saad MA, Elkhatteb MA, Esheba NE. Myeloid-derived suppressor cells anticipate sustained treatment response in newly-diagnosed and persistent primary immune thrombocytopenia. Blood Cells Mol Dis 2020; 87:102529. [PMID: 33338696 DOI: 10.1016/j.bcmd.2020.102529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 10/13/2020] [Accepted: 11/26/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND Myeloid-Derived Suppressor Cells (MDSCs) are used as markers for short-term immune thrombocytopenia (ITP) course. This study aimed to assess their reliability to predict the sustained treatment response within 6 months. METHODS We tested the sensitivity and specificity of MDSCs and proposed cut-off MDSCs values to predict the prognosis in newly diagnosed ITP. We enrolled 80 adults with primary ITP; 50 newly diagnosed (group I), 30 chronic (group II), and 20 controls (group III). Flow cytometry was used for peripheral blood MDSCs estimation with correlation, sensitivity, and specificity of MDSCs to predict sustained treatment response. RESULTS After 6 days and 6 months of treatment, MDSCs were significantly higher than pre-treatment in group I, (P < 0.001, P < 0.001). MDSCs were significantly higher in group I compared to groups II and III, (P < 0.001 for both). Cut-off values were 15.75% and >5.9% at 6 days and 6 months respectively. MDSCs sensitivity was 85.7% and 100% and specificity was 94.44% and 100% at 6 days and 6 months. CONCLUSIONS MDSCs may constitute a reliable predictor for ITP initial and prolonged treatment response with good sensitivity and specificity. This may guide the use of a specific therapeutic agent as maintenance therapy or its replacement in practice.
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Affiliation(s)
- Dina G Elsaied
- Department of Internal Medicine, Hematology Unit, Tanta University, Faculty of Medicine, Tanta, Gharbiah, P.O 31527, Egypt
| | - Nashwa M Noreldin
- Department of Internal Medicine, Hematology Unit, Tanta University, Faculty of Medicine, Tanta, Gharbiah, P.O 31527, Egypt
| | - Mohamed A Saad
- Clinical Pathology Department, Tanta University, Faculty of Medicine, Tanta, Gharbiah, P.O 31527, Egypt
| | - Mervat A Elkhatteb
- Department of Internal Medicine, Hematology Unit, Tanta University, Faculty of Medicine, Tanta, Gharbiah, P.O 31527, Egypt
| | - Noha E Esheba
- Department of Internal Medicine, Hematology Unit, Tanta University, Faculty of Medicine, Tanta, Gharbiah, P.O 31527, Egypt.
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30
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Dehhaghi M, Kazemi Shariat Panahi H, Heng B, Guillemin GJ. The Gut Microbiota, Kynurenine Pathway, and Immune System Interaction in the Development of Brain Cancer. Front Cell Dev Biol 2020; 8:562812. [PMID: 33330446 PMCID: PMC7710763 DOI: 10.3389/fcell.2020.562812] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2020] [Accepted: 10/26/2020] [Indexed: 12/20/2022] Open
Abstract
Human gut microbiota contains a large, complex, dynamic microbial community of approximately 1014 microbes from more than 1,000 microbial species, i.e., equivalent to 4 × 106 genes. Numerous evidence links gut microbiota with human health and diseases. Importantly, gut microbiota is involved in the development and function of the brain through a bidirectional pathway termed as the gut-brain axis. Interaction between gut microbiota and immune responses can modulate the development of neuroinflammation and cancer diseases in the brain. With respect of brain cancer, gut microbiota could modify the levels of antioxidants, amyloid protein and lipopolysaccharides, arginase 1, arginine, cytochrome C, granulocyte-macrophage colony-stimulating factor signaling (GM-CSF), IL-4, IL-6, IL-13, IL-17A, interferon gamma (IFN-γ), reactive oxygen species (ROS), reactive nitrogen species (e.g., nitric oxide and peroxynitrite), short-chain fatty acids (SCFAs), tryptophan, and tumor necrosis factor-β (TGF-β). Through these modifications, gut microbiota can modulate apoptosis, the aryl hydrocarbon receptor (AhR), autophagy, caspases activation, DNA integrity, microglia dysbiosis, mitochondria permeability, T-cell proliferation and functions, the signal transducer and activator of transcription (STAT) pathways, and tumor cell proliferation and metastasis. The outcome of such interventions could be either oncolytic or oncogenic. This review scrutinizes the oncogenic and oncolytic effects of gut microbiota by classifying the modification mechanisms into (i) amino acid deprivation (arginine and tryptophan); (ii) kynurenine pathway; (iii) microglia dysbiosis; and (iv) myeloid-derived suppressor cells (MDSCs). By delineating the complexity of the gut-microbiota-brain-cancer axis, this review aims to help the research on the development of novel therapeutic strategies that may aid the efficient eradication of brain cancers.
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Affiliation(s)
- Mona Dehhaghi
- Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.,Pandis Community, Sydney, NSW, Australia.,Department of Microbial Biotechnology, School of Biology and Centre of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran
| | - Hamed Kazemi Shariat Panahi
- Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.,Department of Microbial Biotechnology, School of Biology and Centre of Excellence in Phylogeny of Living Organisms, College of Science, University of Tehran, Tehran, Iran
| | - Benjamin Heng
- Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia
| | - Gilles J Guillemin
- Neuroinflammation Group, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia.,Pandis Community, Sydney, NSW, Australia
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31
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Zhang H, Houghton AM. Good cops turn bad: The contribution of neutrophils to immune-checkpoint inhibitor treatment failures in cancer. Pharmacol Ther 2020; 217:107662. [PMID: 32805297 DOI: 10.1016/j.pharmthera.2020.107662] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 08/10/2020] [Indexed: 12/29/2022]
Abstract
Immune checkpoint inhibitor therapy activates tumor-killing T-cells by releasing the brake of anti-tumor immunity. It has been approved as first- or second-line therapy in many cancer types. Unfortunately, a majority of immune checkpoint inhibitor recipients are refractory to the therapy. Recent investigations of the peripheral blood and tumor microenvironment of cancer patients indicate that high neutrophil content is associated with poor response rates, suggesting an opportunity for synergistic therapy. In the current review, we discuss the mechanisms of neutrophil-mediated immunosuppression in cancer and recent findings suggesting that neutrophil antagonism will improve the efficacy of immune checkpoint inhibitor therapy.
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Affiliation(s)
- Huajia Zhang
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - A McGarry Houghton
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America.
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32
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Yang T, Li J, Li R, Yang C, Zhang W, Qiu Y, Yang C, Rong R. Correlation between MDSC and Immune Tolerance in Transplantation: Cytokines, Pathways and Cell-cell Interaction. Curr Gene Ther 2020; 19:81-92. [PMID: 31237207 DOI: 10.2174/1566523219666190618093707] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 05/06/2019] [Accepted: 05/24/2019] [Indexed: 11/22/2022]
Abstract
MDSCs play an important role in the induction of immune tolerance. Cytokines and chemokines (GM-CSF, IL-6) contributed to the expansion, accumulation of MDSCs, and MDSCs function through iNOS, arginase and PD-L1. MDSCs are recruited and regulated through JAK/STAT, mTOR and Raf/MEK/ERK signaling pathways. MDSCs' immunosuppressive functions were realized through Tregs-mediated pathways and their direct suppression of immune cells. All of the above contribute to the MDSC-related immune tolerance in transplantation. MDSCs have huge potential in prolonging graft survival and reducing rejection through different ways and many other factors worthy to be further investigated are also introduced.
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Affiliation(s)
- Tianying Yang
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Jiawei Li
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ruimin Li
- Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.,Biomedical Research Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chunchen Yang
- Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Weitao Zhang
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Yue Qiu
- Department of Critical Care Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Cheng Yang
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China
| | - Ruiming Rong
- Department of Urology, ZhongShan Hospital, Fudan University, Shanghai, China.,Shanghai Key Laboratory of Organ Transplantation, Shanghai, China.,Department of Transfusion, Zhongshan Hospital, Fudan University, Shanghai, China
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33
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Zhang H, Dong S, Li Z, Feng X, Xu W, Tulinao CMS, Jiang Y, Ding J. Biointerface engineering nanoplatforms for cancer-targeted drug delivery. Asian J Pharm Sci 2020; 15:397-415. [PMID: 32952666 PMCID: PMC7486517 DOI: 10.1016/j.ajps.2019.11.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/22/2019] [Accepted: 11/18/2019] [Indexed: 12/30/2022] Open
Abstract
Over the past decade, nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy. Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis. Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery. Keeping in mind the biological framework of the tumor microenvironment, biomembrane-camouflaged nanoplatforms have been a research focus, reflecting their superiority in cancer targeting. In this review, we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancer-targeted drug delivery, which are classified according to the membranes from different cells. The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.
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Affiliation(s)
- Huaiyu Zhang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
| | - Shujun Dong
- VIP Integrated Department, School and Hospital of Stomatology, Jilin University, Changchun 130021, China
| | - Zhongmin Li
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
| | - Xiangru Feng
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
| | - Weiguo Xu
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
| | | | - Yang Jiang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Jianxun Ding
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China
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34
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Stokidis S, Fortis SP, Kogionou P, Anagnostou T, Perez SA, Baxevanis CN. HLA Class I Allele Expression and Clinical Outcome in De Novo Metastatic Prostate Cancer. Cancers (Basel) 2020; 12:cancers12061623. [PMID: 32570992 PMCID: PMC7352811 DOI: 10.3390/cancers12061623] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/09/2020] [Accepted: 06/11/2020] [Indexed: 12/15/2022] Open
Abstract
The prognostic value of human leukocyte antigen (HLA) class I molecules in prostate cancer (PCa) remains unclear. Herein, we investigated the prognostic relevance of the most frequently expressed HLA-A alleles in Greece (A*02:01 and HLA-A*24:02) in de novo metastatic hormone-sensitive PCa (mPCa), which is a rare and aggressive disease characterized by a rapid progression to castration-resistance (CR) and poor overall survival (OS), contributing to almost 50% of PCa-related deaths. We identified 56 patients who had either progressed to CR (these patients were retrospectively analyzed for the time to the progression of CR and prospectively for OS) or had at least three months’ follow-up postdiagnosis without CR progression and, thus, were prospectively analyzed for both CR and OS. Patients expressing HLA-A*02:01 showed poor clinical outcomes vs. HLA-A*02:01−negative patients. HLA-A*24:02−positive patients progressed slower to CR and had increased OS. Homozygous HLA-A*02:01 patients progressed severely to CR, with very short OS. Multivariate analyses ascribed to both HLA alleles significant prognostic values for the time to progression (TTP) to CR and OS. The presence of HLA-A*02:01 and HLA-A*24:02 alleles in de novo mPCa patients are significantly and independently associated with unfavorable or favorable clinical outcomes, respectively, suggesting their possible prognostic relevance for treatment decision-making in the context of precision medicine.
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Affiliation(s)
- Savvas Stokidis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras avenue, 11522 Athens, Greece; (S.S.); (S.P.F.); (P.K.); (S.A.P.)
| | - Sotirios P. Fortis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras avenue, 11522 Athens, Greece; (S.S.); (S.P.F.); (P.K.); (S.A.P.)
| | - Paraskevi Kogionou
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras avenue, 11522 Athens, Greece; (S.S.); (S.P.F.); (P.K.); (S.A.P.)
| | - Theodoros Anagnostou
- Department of Urology, Saint Savas Cancer Hospital, 171 Alexandras avenue, 11522 Athens, Greece;
| | - Sonia A. Perez
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras avenue, 11522 Athens, Greece; (S.S.); (S.P.F.); (P.K.); (S.A.P.)
| | - Constantin N. Baxevanis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras avenue, 11522 Athens, Greece; (S.S.); (S.P.F.); (P.K.); (S.A.P.)
- Correspondence: ; Tel.: +30-210-640-9624
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Chen ZQ, Yu XS, Mao LJ, Zheng R, Xue LL, Shu J, Luo ZW, Pan JY. Prognostic value of neutrophil-lymphocyte ratio in critically ill patients with cancer: a propensity score matching study. Clin Transl Oncol 2020; 23:139-147. [PMID: 32472452 DOI: 10.1007/s12094-020-02405-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Accepted: 05/14/2020] [Indexed: 10/24/2022]
Abstract
BACKGROUND Neutrophil-lymphocyte ratio (NLR) has shown a good prognostic value in many different type of malignancies. The purpose of this study was to investigate the relationship between NLR and the outcome of critically ill patients with cancer. METHODS We performed a single-institution, retrospective study of 1317 adult critically ill patients with cancer and determined the optimal cut-off for NLR by X-tile software. Propensity score matching (PSM) and inverse probabilities of treatment weighting (IPTW) were performed to control confounders. Cox proportional hazards model was used to evaluate the relationship between NLR and 28-day, 6-month and 1-year all-cause mortality. Kaplan-Meier method, subgroup analysis, and receiver operating characteristics (ROC) analysis were applied to assess the prognostic value of NLR. RESULTS The cut-off value for NLR was 17.6. Cox proportional hazards model demonstrated that high NLR (> 17.6) was independently associated with 28-day, 6-month and 1-year all-cause mortality with hazard ratio (HR) of 1.58 (1.29, 1.94), 1.51 (1.28, 1.77) and 1.45 (1.25, 1.69), respectively. The results were consistent with survival analyses (p < 0.001, log-rank test). The ROC analyses showed that the discrimination abilities of NLR were better than other blood-based biomarkers. CONCLUSION NLR is a promising prognostic indicator of survival in unselected critical ill patients with cancer.
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Affiliation(s)
- Z-Q Chen
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - X-S Yu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - L-J Mao
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - R Zheng
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - L-L Xue
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - J Shu
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - Z-W Luo
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China
| | - J-Y Pan
- Department of Intensive Care Unit, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, Zhejiang, People's Republic of China.
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The function and clinical application of extracellular vesicles in innate immune regulation. Cell Mol Immunol 2020; 17:323-334. [PMID: 32203193 PMCID: PMC7109106 DOI: 10.1038/s41423-020-0391-1] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 02/17/2020] [Indexed: 12/21/2022] Open
Abstract
The innate immune system plays a crucial role in the host defense against viral and microbial infection. Exosomes constitute a subset of extracellular vesicles (EVs) that can be released by almost all cell types. Owing to their capacity to shield the payload from degradation and to evade recognition and subsequent removal by the immune system, exosomes efficiently transport functional components to recipient cells. Accumulating evidence has recently shown that exosomes derived from tumor cells, host cells and even bacteria and parasites mediate the communication between the invader and innate immune cells and thus play an irreplaceable function in the dissemination of pathogens and donor cell-derived molecules, modulating the innate immune responses of the host. In this review, we describe the current understanding of EVs (mainly focusing on exosomes) and summarize and discuss their crucial roles in determining innate immune responses. Additionally, we discuss the potential of using exosomes as biomarkers and cancer vaccines in diagnostic and therapeutic applications.
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Xu J, Luo Y, Yuan C, Han L, Wu Q, Xu L, Gao Y, Sun Y, Ma S, Tang G, Li S, Sun W, Gong Y, Xie C. Downregulation of Nitric Oxide Collaborated with Radiotherapy to Promote Anti-Tumor Immune Response via Inducing CD8+ T Cell Infiltration. Int J Biol Sci 2020; 16:1563-1574. [PMID: 32226302 PMCID: PMC7097922 DOI: 10.7150/ijbs.41653] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 02/15/2020] [Indexed: 12/15/2022] Open
Abstract
The production of nitric oxide (NO) is a key feature of immunosuppressive myeloid cells, which impair T cell activation and proliferation via reversibly blocking interleukin-2 receptor signaling. NO is mainly produced from L-arginine by inducible NO synthase (iNOS). Moreover, L-arginine is an essential element for T cell proliferation and behaviors. Impaired T cell function further inhibits anti-tumor immunity and promotes tumor progression. Previous studies indicated that radiotherapy activated anti-tumor immune responses in multiple tumors. However, myeloid-derived cells in the tumor microenvironment may neutralize these responses. We hypothesized that iNOS, as an important regulator of the immunosuppressive effects in myeloid-derived cells, mediated radiation resistance of cancer cells. In this study, we used 1400W dihydrochloride, a potent small-molecule inhibitor of iNOS, to explore the regulatory roles of NO in anti-tumor immunity. Radiotherapy and iNOS inhibition by 1400W collaboratively suppressed tumor growth and increased survival time, as well as increased tumor-infiltrating CD8+ T cells and specific inflammatory cytokine levels, in both lung and breast cancer cells in vivo. Our results also suggested that myeloid cell-mediated inhibition of T cell proliferation was effectively counteracted by radiation and 1400W-mediated NO blockade in vitro. Thus, these results demonstrated that iNOS was an important regulator of radiotherapy-induced antitumor immune responses. The combination of radiotherapy with iNOS blockade might be an effective therapy to improve the response of tumors to clinical radiation.
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Affiliation(s)
- Jieyu Xu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yuan Luo
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Cheng Yuan
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Linzhi Han
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Qiuji Wu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Liexi Xu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yuke Gao
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yingming Sun
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shijing Ma
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Guiliang Tang
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Shuying Li
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Wenjie Sun
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yan Gong
- Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Conghua Xie
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Key Laboratory of Tumour Biological Behaviors, Zhongnan Hospital of Wuhan University, Wuhan, China
- Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China
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Law AMK, Valdes-Mora F, Gallego-Ortega D. Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer. Cells 2020; 9:cells9030561. [PMID: 32121014 PMCID: PMC7140518 DOI: 10.3390/cells9030561] [Citation(s) in RCA: 309] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 02/22/2020] [Accepted: 02/24/2020] [Indexed: 12/15/2022] Open
Abstract
The emergence of immunotherapy has been an astounding breakthrough in cancer treatments. In particular, immune checkpoint inhibitors, targeting PD-1 and CTLA-4, have shown remarkable therapeutic outcomes. However, response rates from immunotherapy have been reported to be varied, with some having pronounced success and others with minimal to no clinical benefit. An important aspect associated with this discrepancy in patient response is the immune-suppressive effects elicited by the tumour microenvironment (TME). Immune suppression plays a pivotal role in regulating cancer progression, metastasis, and reducing immunotherapy success. Most notably, myeloid-derived suppressor cells (MDSC), a heterogeneous population of immature myeloid cells, have potent mechanisms to inhibit T-cell and NK-cell activity to promote tumour growth, development of the pre-metastatic niche, and contribute to resistance to immunotherapy. Accumulating research indicates that MDSC can be a therapeutic target to alleviate their pro-tumourigenic functions and immunosuppressive activities to bolster the efficacy of checkpoint inhibitors. In this review, we provide an overview of the general immunotherapeutic approaches and discuss the characterisation, expansion, and activities of MDSCs with the current treatments used to target them either as a single therapeutic target or synergistically in combination with immunotherapy.
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Affiliation(s)
- Andrew M. K. Law
- Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- Correspondence: (A.M.K.L.); (F.V.-M.); (D.G.-O.); Tel.: +61-(0)2-9355-5894 (A.M.K.L); +61-(0)2-9385-0143 (F.V.-M); +61-(0)2-9355-5776 (D.G.-O)
| | - Fatima Valdes-Mora
- Histone Variants Group, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW 2052, Australia
- Correspondence: (A.M.K.L.); (F.V.-M.); (D.G.-O.); Tel.: +61-(0)2-9355-5894 (A.M.K.L); +61-(0)2-9385-0143 (F.V.-M); +61-(0)2-9355-5776 (D.G.-O)
| | - David Gallego-Ortega
- Tumour Development Group, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
- St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales Sydney, Sydney, NSW 2052, Australia
- Correspondence: (A.M.K.L.); (F.V.-M.); (D.G.-O.); Tel.: +61-(0)2-9355-5894 (A.M.K.L); +61-(0)2-9385-0143 (F.V.-M); +61-(0)2-9355-5776 (D.G.-O)
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Xu P, Sun Y, Song Y, Jiao J, Shen B, Li W, Jiang C, Li Y, Zhang X, Yu J, Fu L, Guo X. ATM kinase regulates tumor immunoreactions in lymphocyte-predominant breast cancer through modulation of NKG2D ligand and TNF cytokines on tumor cells. Med Mol Morphol 2020; 53:210-220. [PMID: 32067111 DOI: 10.1007/s00795-020-00247-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 02/03/2020] [Indexed: 11/26/2022]
Abstract
To explore impact of Ataxia telangiectasia mutated (ATM) kinase on immunoreactions in lymphocyte-predominant breast cancer (LPBC), particularly its role in triple negative breast cancer (TNBC), 194 cases of LPBC were identified with pertinent clinical information retrieved. The expressions of ATM, activated ATM (P-ATM), Fas ligand (FASL), tumor necrosis factor-related apoptosis-induced ligand (TRAIL), major histocompatibility complex class I chain-related protein A (MICA), CD8, and Forkhead box P3 (FOXP3) were assessed by immunohistochemically. We found that ATM expressed on tumor cells was correlated with upregulated expression of P-ATM and MICA (P < 0.05), down-regulated expression of FASL and TRAIL (P < 0.01), and decreased Ki-67 tumor labeling (P < 0.05). However, within the TNBC group, only a negative correlation with FASL expression was found (P = 0.001). ATM and MICA expressions were significantly down -regulated in TNBC (P < 0.01) compared to non-TNBC, while TRAIL was significantly upregulated (P < 0.01). Tregs were increased in TNBC (P < 0.05), with CD8 + TILs decreased (P < 0.01). Ki-67 index was higher in TNBC than in non-TNBC (P < 0.01). ATM may play an important role in immunoreaction of LPBC, probably through upregulation of MICA and down-regulation of FASL and TRAIL. The down-regulated ATM expression in TNBC might be responsible for impaired tumor immunoactivity, rapid tumor growth, and aggressive clinical course.
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Affiliation(s)
- Peng Xu
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Yuanyuan Sun
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Yuanming Song
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Jiao Jiao
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Beibei Shen
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Weidong Li
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Chengying Jiang
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Yaqing Li
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Xinmin Zhang
- Department of Pathology, Cooper Medical School of Rowan University, Camden, NJ, USA
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Key Laboratory of Cancer Immunology and Biotherapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Li Fu
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China
| | - Xiaojing Guo
- Department of Breast Pathology and Lab, Key Laboratory of Breast Cancer of Breast Cancer Prevention and Therapy, National Clinical Research Center of Cancer, Tianjin Medical University Cancer Institute and Hospital, West Huanhu Road, Tianjin, 300060, China.
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Melanoma and Vitiligo: In Good Company. Int J Mol Sci 2019; 20:ijms20225731. [PMID: 31731645 PMCID: PMC6888090 DOI: 10.3390/ijms20225731] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 11/10/2019] [Accepted: 11/13/2019] [Indexed: 12/24/2022] Open
Abstract
Cutaneous melanoma represents the most aggressive form of skin cancer, whereas vitiligo is an autoimmune disorder that leads to progressive destruction of skin melanocytes. However, vitiligo has been associated with cutaneous melanoma since the 1970s. Most of the antigens recognized by the immune system are expressed by both melanoma cells and normal melanocytes, explaining why the autoimmune response against melanocytes that led to vitiligo could be also present in melanoma patients. Leukoderma has been also observed as a side effect of melanoma immunotherapy and has always been associated with a favorable prognosis. In this review, we discuss several characteristics of the immune system responses shared by melanoma and vitiligo patients, as well as the significance of occurrence of leukoderma during immunotherapy, with special attention to check-point inhibitors.
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41
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Li B, Chan HL, Chen P. Immune Checkpoint Inhibitors: Basics and Challenges. Curr Med Chem 2019; 26:3009-3025. [PMID: 28782469 DOI: 10.2174/0929867324666170804143706] [Citation(s) in RCA: 307] [Impact Index Per Article: 51.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 04/26/2017] [Accepted: 07/25/2017] [Indexed: 12/15/2022]
Abstract
Cancer is one of the most deadly diseases in the modern world. The last decade has witnessed dramatic advances in cancer treatment through immunotherapy. One extremely promising means to achieve anti-cancer immunity is to block the immune checkpoint pathways - mechanisms adopted by cancer cells to disguise themselves as regular components of the human body. Many review articles have described a variety of agents that are currently under extensive clinical evaluation. However, while checkpoint blockade is universally effective against a broad spectrum of cancer types and is mostly unrestricted by the mutation status of certain genes, only a minority of patients achieve a complete response. In this review, we summarize the basic principles of immune checkpoint inhibitors in both antibody and smallmolecule forms and also discuss potential mechanisms of resistance, which may shed light on further investigation to achieve higher clinical efficacy for these inhibitors.
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Affiliation(s)
- Bin Li
- University of Miami, Miller School of Medicine, Miami, Florida 33156, United States
| | - Ho Lam Chan
- University of Miami, Miller School of Medicine, Miami, Florida 33156, United States
| | - Pingping Chen
- University of Miami, Miller School of Medicine, Miami, Florida 33156, United States
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42
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He W, Zhang W, Zheng Q, Wei Z, Wang Y, Hu M, Ma F, Tao N, Luo C. Cinnamaldehyde causes apoptosis of myeloid-derived suppressor cells through the activation of TLR4. Oncol Lett 2019; 18:2420-2426. [PMID: 31402944 PMCID: PMC6676727 DOI: 10.3892/ol.2019.10544] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2017] [Accepted: 11/16/2018] [Indexed: 01/01/2023] Open
Abstract
Malignant tumors are among the most life-threatening diseases in the world. Although many different types of antitumor agents are available, severe side effects and toxicity limit their applications. Myeloid-derived suppressor cells (MDSCs) inhibit the antitumor immune response by suppressing the proliferation of T cells, the production of cytokines and the killing of tumor cells. As MDSCs have become novel targets in cancer therapy, this research focused on the anti-MDSC function of cinnamaldehyde (CA), which is extracted from cinnamon, a traditional Chinese spice. In the present study, MDSCs isolated from the spleens of mice with colon cancer were used as an in vitro model to assess the efficacy of CA. Treatment of MDSCs with CA significantly decreased cell proliferation and induced apoptotic cell death. Subsequent experiments demonstrated that CA treatment enhanced the expression of Bax and caspase-9 and inhibited the expression of Bcl-2, suggesting that CA induced apoptosis in the MDSCs via the intrinsic pathway. Taken together, the results demonstrated that CA exhibited significant anti-MDSC activity and attenuated the suppression of the antitumor immune response, indicating a potential use for CA in cancer therapy.
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Affiliation(s)
- Wanzhuo He
- College of Life Sciences, Peking University, Beijing 100871, P.R. China
| | - Wensheng Zhang
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
| | - Qilin Zheng
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
| | - Zheng Wei
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
| | - Yuanyuan Wang
- Infinitus Chinese Herbal Immunity Research Centre, Infinitus China Company Ltd., Guangzhou, Guangdong 510663, P.R. China
| | - Minghua Hu
- Infinitus Chinese Herbal Immunity Research Centre, Infinitus China Company Ltd., Guangzhou, Guangdong 510663, P.R. China
| | - Fangli Ma
- Infinitus Chinese Herbal Immunity Research Centre, Infinitus China Company Ltd., Guangzhou, Guangdong 510663, P.R. China
| | - Ning Tao
- Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P.R. China
| | - Cong Luo
- Department of Abdominal Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, P.R. China
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Hanna BS, Öztürk S, Seiffert M. Beyond bystanders: Myeloid cells in chronic lymphocytic leukemia. Mol Immunol 2019; 110:77-87. [DOI: 10.1016/j.molimm.2017.11.014] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2017] [Revised: 11/07/2017] [Accepted: 11/14/2017] [Indexed: 12/31/2022]
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Wang L, Li S, Yu X, Han Y, Wu Y, Wang S, Chen X, Zhang J, Wang S. α2,6-Sialylation promotes immune escape in hepatocarcinoma cells by regulating T cell functions and CD147/MMP signaling. J Physiol Biochem 2019; 75:199-207. [PMID: 30972697 DOI: 10.1007/s13105-019-00674-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 03/07/2019] [Indexed: 10/27/2022]
Abstract
Altered glycosylation is a common feature of cancer cells and plays an important role in tumor progression. β-Galactoside α2-6-sialyltransferase 1 (ST6Gal-I) is the critical sialyltransferase responsible for the addition of α2-6-sialic acid to the terminal N-glycans on the cell surface. However, the functions and mechanism of ST6Gal-I in tumor immune escape remain poorly understood. Here, we found that ST6Gal-I overexpression promoted hepatocarcinoma cell proliferation, migration, and immune escape by increasing the levels of CD147, MMP9, MMP2, and MMP7. When CD8+ T cells were co-cultured with cell lines expressing different levels of ST6Gal-I, we found that ST6Gal-I upregulation inhibited the T cell proliferation and increased the secretion of IL-10 and TGF-β1, while secretion of IFN-γ and TNF-α was diminished. In a syngeneic tumor transplant model, ST6Gal-I upregulated Hca-P. In addition, Hepa1-6 cells formed significantly larger tumors and suppressed intratumoral penetration by CD8+ T cells. In combination, these results suggest that ST6Gal-I promotes the immune escape of hepatocarcinoma cells in the tumor microenvironment and highlight the importance of assessing ST6Gal-I status for immunotherapies.
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Affiliation(s)
- Liping Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China.,School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, Liaoning, China
| | - Shijun Li
- Department of inspection, First Affiliated Hospital of Dalian Medical University, Dalian, 116011, Liaoning Province, China
| | - Xiao Yu
- Department of Pathology, Dalian Medical University, Dalian, 116044, Liaoning Province, China
| | - Yang Han
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China
| | - Yinshuang Wu
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China
| | - Shidan Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China
| | - Xixi Chen
- School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, Liaoning, China
| | - Jianing Zhang
- School of Life Science and Medicine, Dalian University of Technology, Panjin, 124221, Liaoning, China.
| | - Shujing Wang
- Department of Biochemistry and Molecular Biology, Institute of Glycobiology, Dalian Medical University, Dalian, 116044, China.
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Liu W, Wu TC, Hong DM, Hu Y, Fan T, Guo WJ, Xu Q. Carnosic acid enhances the anti-lung cancer effect of cisplatin by inhibiting myeloid-derived suppressor cells. Chin J Nat Med 2019; 16:907-915. [PMID: 30595215 DOI: 10.1016/s1875-5364(18)30132-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Indexed: 02/07/2023]
Abstract
Cisplatin and other platinum-based drugs are used frequently for treatment of lung cancer. However, their clinical performance are usually limited by drug resistance or toxic effects. Carnosic acid, a polyphenolic diterpene isolated from Rosemary (Rosemarinus officinalis), has been reported to have several pharmacological and biological activities. In the present study, the combination effect of cisplatin plus carnosic acid on mouse LLC (Lewis lung cancer) xenografts and possible underlying mechanism of action were examined. LLC-bearing mice were treated with intraperitoneal injection with cisplatin, oral gavage with carnosic acid, or combination with cisplatin and carnosic acid, respectively. Combination of carnosic acid and cisplatin yielded significantly better anti-growth and pro-apoptotic effects on LLC xenografts than drugs alone. Mechanistic study showed that carnosic acid treatment boosted the function of CD8+ T cells as evidenced by higher IFN-γ secretion and higher expression of FasL, perforin as well as granzyme B. In the meantime, the proportion of MDSC (myeloid-derived suppressor cells) in tumor tissues were reduced by carnosic acid treatment and the mRNA levels of iNOS2, Arg-1, and MMP9, which are the functional markers for MDSC, were reduced. In conclusion, our study proved that the functional suppression of MDSC by carnosic acid promoted the lethality of CD8+ T cells, which contributed to the enhancement of anti-lung cancer effect of cisplatin.
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Affiliation(s)
- Wen Liu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China
| | - Tian-Cong Wu
- Department of Radiation Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China
| | - Dong-Mei Hong
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China
| | - Yue Hu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China
| | - Ting Fan
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China
| | - Wen-Jie Guo
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China.
| | - Qiang Xu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Science, Nanjing University, Nanjing 210093, China.
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Duan J, Gao Y, Zhang X, Wang X, Wang B, Meng X, Yoshikai Y, Wang Y, Sun X. CD30 ligand deficiency accelerates glioma progression by promoting the formation of tumor immune microenvironment. Int Immunopharmacol 2019; 71:350-360. [PMID: 30952099 DOI: 10.1016/j.intimp.2019.03.055] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 01/01/2023]
Abstract
CD30 ligand (CD30L, CD153), belonging to the tumor necrosis factor superfamily, has been reported to act as an immune regulator mainly in several autoimmune diseases and Hodgkin's lymphoma. However, little is known about its regulation in the glioma microenvironment. In this study, using a GL261 mouse glioma model, we showed that CD30L deficiency in the host accelerated glioma growth and reduced mouse survival, which might be associated with the accumulation of tumor-infiltrating immune cells, especially tumor-associated macrophages, myeloid-derived suppressor cells and CD8+ PD-1+ T cells. Moreover, CD30L deficiency resulted in distinct subsets of tumor-associated macrophages compared with those of wild-type mice. Furthermore, compared with those of wild-type mice, tumor-associated macrophages and microglia in CD30L-deficient mice adopted a more pro-tumorigenic phenotype within tumors. CD8+ T cells in CD30L-deficient mice decreased the expression of ki-67. Therefore, these results suggest that CD30L deficiency promotes the exhaustion of CD8+ T cells and the infiltration of tumor-associated macrophages and microglia. Our findings provide evidence for a new potential immunotherapy for glioma targeting CD30/CD30L signaling.
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Affiliation(s)
- Jin Duan
- Department of Immunology, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China
| | - Yaxian Gao
- Department of Immunology, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China; Department of Immunology, Chengde Medical College, Chengde 067000, Hebei Province, PR China
| | - Xiaoqing Zhang
- Department of Immunology, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China
| | - Xiao Wang
- Department of Immunology, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China
| | - Biao Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences of China Medical University, Shenyang, Liaoning Province, PR China
| | - Xin Meng
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences of China Medical University, Shenyang, Liaoning Province, PR China
| | - Yasunobu Yoshikai
- Division of Host Defense, Center for Prevention of Infectious Disease, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Yuanyuan Wang
- Department of Anesthesiology, The Fourth Affiliated Hospital, China Medical University, Shenyang, Liaoning Province, PR China.
| | - Xun Sun
- Department of Immunology, China Medical University, No.77 Puhe Road, Shenyang North New Area, Shenyang, Liaoning Province, PR China.
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Sarkar I, Pati S, Dutta A, Basak U, Sa G. T-memory cells against cancer: Remembering the enemy. Cell Immunol 2019; 338:27-31. [PMID: 30928016 DOI: 10.1016/j.cellimm.2019.03.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 03/14/2019] [Indexed: 12/24/2022]
Abstract
BACKGROUND Recently various types of immunotherapies have made immense progress in combating cancer. Adoptive cell therapy, being one of the most favorable forms of immunotherapy, is rapidly moving from bench to bed. MAIN BODY Different types of T-memory cells are being used as promising candidates for adoptive cell therapy: T effector memory (TEM) cells which are terminally differentiated memory cells and attain effector function soon after re-stimulation; T central memory (TCM) cells which differentiate into effector T-memory subsets and T-effector cells after antigenic stimulation; and tissue T resident memory (TRM) cells which fight the tumor insult at the peripheral tissues. Recently, a new subtype of T-memory cells, T stem cell memory (TSCM) have been identified as the most favorable candidate for adoptive cell therapy as they exhibit higher persistence, anti-tumor immunity and self-renewal capacity in the tumor-bearing host. CONCLUSION In this review, we briefly describe the concept and types of T-memory cells as well as their role as potential candidates for anti-cancer immunotherapy.
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Affiliation(s)
- Irene Sarkar
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Subhadip Pati
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Abhishek Dutta
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Udit Basak
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India
| | - Gaurisankar Sa
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India.
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Som A, Mandaliya R, Alsaadi D, Farshidpour M, Charabaty A, Malhotra N, Mattar MC. Immune checkpoint inhibitor-induced colitis: A comprehensive review. World J Clin Cases 2019; 7:405-418. [PMID: 30842952 PMCID: PMC6397821 DOI: 10.12998/wjcc.v7.i4.405] [Citation(s) in RCA: 189] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 01/21/2019] [Accepted: 01/26/2019] [Indexed: 02/05/2023] Open
Abstract
Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target down-regulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1. ICIs have revolutionized the treatment of a variety of malignancies. However, many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis (IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease, however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.
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Affiliation(s)
- Aniruddh Som
- Department of Internal Medicine, Medstar Washington Hospital Center, Washington, DC 20010, United States
| | - Rohan Mandaliya
- Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC 20007, United States
| | - Dana Alsaadi
- Department of Internal Medicine, MedStar Georgetown University Hospital, Washington, DC 20007, United States
| | - Maham Farshidpour
- Department of Internal Medicine, MedStar Union Memorial Hospital and Good Samaritan Hospital, Baltimore, MD 21218, United States
| | - Aline Charabaty
- Department of Gastroenterology, Sibley Memorial Hospital, Washington, DC 20007, United States
| | - Nidhi Malhotra
- Department of Gastroenterology, MedStar Washington Hospital Center, Washington, DC 20010, United States
| | - Mark C Mattar
- Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC 20007, United States
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Jennings JJ, Mandaliya R, Nakshabandi A, Lewis JH. Hepatotoxicity induced by immune checkpoint inhibitors: a comprehensive review including current and alternative management strategies. Expert Opin Drug Metab Toxicol 2019; 15:231-244. [PMID: 30677306 DOI: 10.1080/17425255.2019.1574744] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Immune checkpoint inhibitors (ICIs) block cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/PD ligand 1 (PD-L1) receptors that control antitumor activities of lymphocytes. While highly efficacious, these drugs have been associated with several immune-related adverse events (irAEs) due to the disruption of self-tolerance. Immune-mediated hepatitis (IMH) usually presents as mild elevations of liver enzymes though it can rarely be associated with life-threatening hepatic injury. Areas covered: A comprehensive review was performed to define the clinicopathologic forms of liver injury associated with ICIs, comparing the various ICI classes as well as comparing this form of IMH with idiopathic autoimmune hepatitis and drug-induced autoimmune hepatitis. Liver biopsy has proven very useful in selected patients. A specific form of fibrin ring granulomatous hepatitis appears to be associated with IMH. The current societal treatment algorithms and emerging data were reviewed to determine when to utilize corticosteroids. Expert opinion: Monitoring for severe ICI-IMH is recommended although acute liver failure remains rare. Most patients with grade 3-4 hepatotoxicity respond to corticosteroids, but a subset of patients with mild hepatitis on liver biopsy resolve without steroids and need to be carefully selected in concert with the consultation of a hepatologist.
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Affiliation(s)
- Joseph J Jennings
- a Department of Medicine, Division of Gastroenterology and Hepatology , MedStar Georgetown University Hospital , Washington , DC , USA
| | - Rohan Mandaliya
- a Department of Medicine, Division of Gastroenterology and Hepatology , MedStar Georgetown University Hospital , Washington , DC , USA
| | - Ahmad Nakshabandi
- b Department of Internal Medicine , Mercy Hospital and Medical Center , Chicago , IL , USA
| | - James H Lewis
- a Department of Medicine, Division of Gastroenterology and Hepatology , MedStar Georgetown University Hospital , Washington , DC , USA
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Lybaert L, Vermaelen K, De Geest BG, Nuhn L. Immunoengineering through cancer vaccines – A personalized and multi-step vaccine approach towards precise cancer immunity. J Control Release 2018; 289:125-145. [DOI: 10.1016/j.jconrel.2018.09.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 09/11/2018] [Accepted: 09/12/2018] [Indexed: 02/07/2023]
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