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Thoraval L, Tang-Fichaux M, Guillaume C, Varin-Simon J, Dumortier C, Sergheraert J, Lamret F, Bonhomme M, Laurent F, Josse J, Gangloff SC, Mongaret C, Reffuveille F, Velard F. Cutibacterium acnes strains associated with bone prosthesis infections cannot evade the host immune system. Front Immunol 2024; 15:1468709. [PMID: 39664373 PMCID: PMC11632127 DOI: 10.3389/fimmu.2024.1468709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 10/31/2024] [Indexed: 12/13/2024] Open
Abstract
Introduction Cutibacterium acnes is a commensal skin bacterium that is involved in bone prosthesis infections (BPIs) and presents low-grade clinical symptoms. C. acnes has been thought to escape the immune system at bone sites. Material and methods Our study was carried out on a laboratory strain and two BPI-related clinical strains, one of which surprisingly induced clinical symptoms of inflammation in the patient. We investigated the ability of these C. acnes strains to trigger in vitro human primary neutrophils (PMN) response through inflammatory mediators measurements (antibody arrays, ELISA, RT-qPCR, zymography) and activation status assessment (flow cytometry), and to induce in vivo PMN recruitment from the bloodstream in mice air-pouch model. PMN-mediated inflammation was also studied in an original in vitro model mimetic of an infected bone site that combine titanium alloy, human primary osteoblasts, human primary neutrophils and C. acnes strains. Results We demonstrated for the first time that both C. acnes planktonic and biofilm cultures, triggered an effective immune response by neutrophils in vitro and their recruitment in vivo. This host response was enhanced when using a strain from a patient with inflammatory signs. In an original infected prosthesis mimetic model, osteoblasts and neutrophils were able to detect C. acnes, but their response to the clinical C. acnes inflammatory strain decreased. Conclusion This work provides the first evidence showing that the immune cell response to pathogenic C. acnes may be tuned by nonimmune cells at the infected site, such as osteoblasts, which may promote bacterial persistence.
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Affiliation(s)
- Léa Thoraval
- Université de Reims Champagne-Ardenne, BIOS, Reims, France
| | | | | | | | | | - Johan Sergheraert
- Université de Reims Champagne-Ardenne, CHU Reims, BIOS, Pôle de Médecine Bucco-Dentaire, UFR Odontologie, Reims, France
| | - Fabien Lamret
- Université de Reims Champagne-Ardenne, BIOS, Reims, France
| | - Mélanie Bonhomme
- Centre International de Recherche en Infectiologie (CIRI), Université de Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Frédéric Laurent
- Centre International de Recherche en Infectiologie (CIRI), Université de Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Jérôme Josse
- Centre International de Recherche en Infectiologie (CIRI), Université de Lyon, Inserm, U1111, Université Claude Bernard Lyon 1, CNRS, UMR5308, ENS de Lyon, Lyon, France
| | - Sophie C. Gangloff
- Université de Reims Champagne-Ardenne, BIOS, UFR Pharmacie, Reims, France
| | - Céline Mongaret
- Université de Reims Champagne-Ardenne, CHU Reims, BIOS, Service Pharmacie, Reims, France
| | - Fany Reffuveille
- Université de Reims Champagne-Ardenne, BIOS, UFR Pharmacie, Reims, France
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Shen X, Niu X. Gamma-Glutamyl Transpeptidase to Neutrophil Ratio as Prognostic Indicator for Hepatocellular Carcinoma Patients Post-Curative Resection. J Hepatocell Carcinoma 2024; 11:2077-2085. [PMID: 39483455 PMCID: PMC11526730 DOI: 10.2147/jhc.s478186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 10/23/2024] [Indexed: 11/03/2024] Open
Abstract
Background The close association between inflammation and the clinical outcomes of hepatocellular carcinoma (HCC) has been extensively documented. This study aims to analyze the association between a novel inflammatory indicator, the gamma-glutamyl transpeptidase to neutrophil ratio (GNR), and HCC prognosis following curative resection. Methods A cohort of 204 eligible HCC cases were included. Based on an optimal cut-off value determined utilizing the X-tile software, patients were categorized into low- and high-GNR groups. The overall survival (OS) and recurrence-free survival (RFS) rates were assessed using the Kaplan-Meier analysis method with Log rank tests. Multivariate Cox proportional hazard regression was used to investigate the independent association between GNR and HCC prognosis. Restricted cubic splines were used to explore the nonlinear relationship between GNR and the risk of death or recurrence. Results The low GNR group exhibited significantly higher 3-year OS and RFS rates than the high GNR group. Multivariate Cox analysis indicated that a high GNR level was independently associated with poor OS and RFS. A linear correlation between GNR and the risk of death, as well as a nonlinear inverted "U" shape correlation between GNR and the risk of recurrence, were observed. Conclusion The findings provide evidence supporting the independent association of GNR with HCC prognosis. These results offer promise for enhancing prognosis assessments and guiding active monitoring strategies for patients with HCC post-curative resection.
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Affiliation(s)
- Xueqin Shen
- Department of Clinical Nutrition, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
| | - Xiaoping Niu
- Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China
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Barril S, Acebo P, Millan-Billi P, Luque A, Sibila O, Tarín C, Tazi A, Castillo D, Hortelano S. Bronchoalveolar cytokine profile differentiates Pulmonary Langerhans cell histiocytosis patients from other smoking-related interstitial lung diseases. Respir Res 2023; 24:320. [PMID: 38111019 PMCID: PMC10729426 DOI: 10.1186/s12931-023-02622-z] [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: 06/26/2023] [Accepted: 11/29/2023] [Indexed: 12/20/2023] Open
Abstract
BACKGROUND Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease (ILD) associated with smoking, whose definitive diagnosis requires the exclusion of other forms of ILD and a compatible surgical lung biopsy. Bronchoalveolar lavage (BAL) is commonly proposed for the diagnosis of ILD, including PLCH, but the diagnostic value of this technique is limited. Here, we have analyzed the levels of a panel of cytokines and chemokines in BAL from PLCH patients, in order to identify a distinct immune profile to discriminate PLCH from other smoking related-ILD (SR-ILD), and comparing the results with idiopathic pulmonary fibrosis (IPF) as another disease in which smoking is considered a risk factor. METHODS BAL samples were collected from thirty-six patients with different ILD, including seven patients with PLCH, sixteen with SR-ILD and thirteen with IPF. Inflammatory profiles were analyzed using the Human Cytokine Membrane Antibody Array. Principal component analysis (PCA) was performed to reduce dimensionality and protein-protein interaction (PPI) network analysis using STRING 11.5 database were conducted. Finally, Random forest (RF) method was used to build a prediction model. RESULTS We have found significant differences (p < 0.05) on thirty-two cytokines/chemokines when comparing BAL from PLCH patients with at least one of the other ILD. Four main groups of similarly regulated cytokines were established, identifying distinct sets of markers for each cluster. Exploratory analysis using PCA (principal component analysis) showed clustering and separation of patients, with the two first components capturing 69.69% of the total variance. Levels of TARC/CCL17, leptin, oncostatin M (OSM) and IP-10/CXCL10 were associated with lung function parameters, showing positive correlation with FVC. Finally, random forest (RF) algorithm demonstrates that PLCH patients can be differentiated from the other ILDs based solely on inflammatory profile (accuracy 96.25%). CONCLUSIONS Our results show that patients with PLCH exhibit a distinct BAL immune profile to SR-ILD and IPF. PCA analysis and RF model identify a specific immune profile useful for discriminating PLCH.
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Affiliation(s)
- Silvia Barril
- Respiratory Department, Institut de Recerca Biomèdica de Lleida (IRBLleida), Hospital Universitari Arnau de Vilanova-Santa María, Lleida, Spain
| | - Paloma Acebo
- Unidad de Terapias Farmacológicas, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Paloma Millan-Billi
- Respiratory Department, Hospital de la Santa Creu i Sant Pau, Sant Pau Biomedical Research Institute (IIB-Sant Pau, Barcelona, Spain
- Hospital Universitario Germans Trias I Pujol, Barcelona, Spain
| | - Alfonso Luque
- Unidad de Endotelio Funcional, Unidad Funcional de Investigación de Enfermedades Crónicas (UFIEC), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Oriol Sibila
- Respiratory Department, Hospital de la Santa Creu i Sant Pau, Sant Pau Biomedical Research Institute (IIB-Sant Pau, Barcelona, Spain
| | | | - Abdellatif Tazi
- R75006, INSERM U976 Human Immunology Pathophysiology and Immunotherapy (HIPI), Institut de Recherche Saint-Louis, Université Paris Cité, Paris, France
- National Reference Center for Histiocytoses, Department of Pulmonology, AP-HP, Hôpital Saint-Louis, Paris, France
| | - Diego Castillo
- Respiratory Department, Hospital de la Santa Creu i Sant Pau, Sant Pau Biomedical Research Institute (IIB-Sant Pau, Barcelona, Spain.
| | - Sonsoles Hortelano
- Unidad de Terapias Farmacológicas, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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Carnevale S, Di Ceglie I, Grieco G, Rigatelli A, Bonavita E, Jaillon S. Neutrophil diversity in inflammation and cancer. Front Immunol 2023; 14:1180810. [PMID: 37180120 PMCID: PMC10169606 DOI: 10.3389/fimmu.2023.1180810] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 04/11/2023] [Indexed: 05/15/2023] Open
Abstract
Neutrophils are the most abundant circulating leukocytes in humans and the first immune cells recruited at the site of inflammation. Classically perceived as short-lived effector cells with limited plasticity and diversity, neutrophils are now recognized as highly heterogenous immune cells, which can adapt to various environmental cues. In addition to playing a central role in the host defence, neutrophils are involved in pathological contexts such as inflammatory diseases and cancer. The prevalence of neutrophils in these conditions is usually associated with detrimental inflammatory responses and poor clinical outcomes. However, a beneficial role for neutrophils is emerging in several pathological contexts, including in cancer. Here we will review the current knowledge of neutrophil biology and heterogeneity in steady state and during inflammation, with a focus on the opposing roles of neutrophils in different pathological contexts.
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Affiliation(s)
| | | | - Giovanna Grieco
- IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | | | | | - Sebastien Jaillon
- IRCCS Humanitas Research Hospital, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
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Liu M, Wang G, Wang L, Wang Y, Bian Y, Shi H, Liu J. Immunoregulatory functions of mature CD10 + and immature CD10 - neutrophils in sepsis patients. Front Med (Lausanne) 2023; 9:1100756. [PMID: 36687441 PMCID: PMC9846122 DOI: 10.3389/fmed.2022.1100756] [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: 11/17/2022] [Accepted: 12/02/2022] [Indexed: 01/05/2023] Open
Abstract
Introduction Neutrophil plays a more and more important role in sepsis with paralysis of immunoregulation. Till now, there was no biomarker to identify and isolate the mature and immature neutrophils in sepsis patients. CD10 shows on mature neutrophils at the latest stages of its differentiation. Our study aimed to investigate whether CD10 was a valid biomarker for distinguishing immature and mature neutrophil subgroups under septic conditions and their immunoregulatory effects on lymphocytes. Methods Totally 80 healthy volunteers and 107 sepsis patients were recruited in this study. Fluorescence-conjugated anti-CD66b, and anti-CD10 monoclonal antibodies followed by incubation with specific anti-fluorochrome microbeads was used to isolate different subgroups of neutrophils. T cell apoptotic assays and T cell proliferation assays followed by flow cytometry analysis were used to evaluate the immunoregulatory effect of each subgroup of neutrophils. Results (1) The cytological morphology of CD10+ neutrophils was mature and that of CD10- neutrophils was immature in sepsis patients. (2) Mature CD10+ neutrophils inhibited the proliferation of T cell and immature CD10- neutrophils promoted the T cell proliferation. Conclusion (1) CD10 was a good biomarker to distinguish mature from immature neutrophils in sepsis patients. (2) Mature CD10+ and immature CD10- neutrophils displayed opposite immunoregulatory effects on T cells in sepsis patients.
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Affiliation(s)
- Ming Liu
- Department of Anesthesia, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Guan Wang
- Department of Anesthesia, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Lin Wang
- Department of Anesthesia, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuqi Wang
- Department of Anesthesia, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuqing Bian
- Department of Anesthesia, The Second Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hang Shi
- Department of Dermatology, The First Affiliated Hospital of Dalian Medical University, Dalian, China,*Correspondence: Hang Shi,
| | - Jie Liu
- Department of Anesthesia, The Second Affiliated Hospital of Dalian Medical University, Dalian, China,Jie Liu,
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Mahmud Z, Rahman A, Mishu ID, Kabir Y. Mechanistic insights into the interplays between neutrophils and other immune cells in cancer development and progression. Cancer Metastasis Rev 2022; 41:405-432. [PMID: 35314951 DOI: 10.1007/s10555-022-10024-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 03/09/2022] [Indexed: 12/12/2022]
Abstract
Cancer is considered a major public health concern worldwide and is characterized by an uncontrolled division of abnormal cells. The human immune system recognizes cancerous cells and induces innate immunity to destroy those cells. However, sustained tumors may protect themselves by developing immune escape mechanisms through multiple soluble and cellular mediators. Neutrophils are the most plenteous leukocytes in the human blood and are crucial for immune defense in infection and inflammation. Besides, neutrophils emancipate the antimicrobial contents, secrete different cytokines or chemokines, and interact with other immune cells to combat and successfully kill cancerous cells. Conversely, many clinical and experimental studies signpost that being a polarized and heterogeneous population with plasticity, neutrophils, particularly their subpopulations, act as a modulator of cancer development by promoting tumor metastasis, angiogenesis, and immunosuppression. Studies also suggest that tumor infiltrating macrophages, neutrophils, and other innate immune cells support tumor growth and survival. Additionally, neutrophils promote tumor cell invasion, migration and intravasation, epithelial to mesenchymal transition, survival of cancer cells in the circulation, seeding, and extravasation of tumor cells, and advanced growth and development of cancer cells to form metastases. In this manuscript, we describe and review recent studies on the mechanisms for neutrophil recruitment, activation, and their interplay with different immune cells to promote their pro-tumorigenic functions. Understanding the detailed mechanisms of neutrophil-tumor cell interactions and the concomitant roles of other immune cells will substantially improve the clinical utility of neutrophils in cancer and eventually may aid in the identification of biomarkers for cancer prognosis and the development of novel therapeutic approaches for cancer treatment.
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Affiliation(s)
- Zimam Mahmud
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Atiqur Rahman
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | | | - Yearul Kabir
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
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Tecchio C, Cassatella MA. Uncovering the multifaceted roles played by neutrophils in allogeneic hematopoietic stem cell transplantation. Cell Mol Immunol 2021; 18:905-918. [PMID: 33203938 PMCID: PMC8115169 DOI: 10.1038/s41423-020-00581-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a life-saving procedure used for the treatment of selected hematological malignancies, inborn errors of metabolism, and bone marrow failures. The role of neutrophils in alloHSCT has been traditionally evaluated only in the context of their ability to act as a first line of defense against infection. However, recent evidence has highlighted neutrophils as key effectors of innate and adaptive immune responses through a wide array of newly discovered functions. Accordingly, neutrophils are emerging as highly versatile cells that are able to acquire different, often opposite, functional capacities depending on the microenvironment and their differentiation status. Herein, we review the current knowledge on the multiple functions that neutrophils exhibit through the different stages of alloHSCT, from the hematopoietic stem cell (HSC) mobilization in the donor to the immunological reconstitution that occurs in the recipient following HSC infusion. We also discuss the influence exerted on neutrophils by the immunosuppressive drugs delivered in the course of alloHSCT as part of graft-versus-host disease (GVHD) prophylaxis. Finally, the potential involvement of neutrophils in alloHSCT-related complications, such as transplant-associated thrombotic microangiopathy (TA-TMA), acute and chronic GVHD, and cytomegalovirus (CMV) reactivation, is also discussed. Based on the data reviewed herein, the role played by neutrophils in alloHSCT is far greater than a simple antimicrobial role. However, much remains to be investigated in terms of the potential functions that neutrophils might exert during a highly complex procedure such as alloHSCT.
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Affiliation(s)
- Cristina Tecchio
- Department of Medicine, Section of Hematology and Bone Marrow Transplant Unit, University of Verona, Verona, Italy.
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Tang J, Yan Z, Feng Q, Yu L, Wang H. The Roles of Neutrophils in the Pathogenesis of Liver Diseases. Front Immunol 2021; 12:625472. [PMID: 33763069 PMCID: PMC7982672 DOI: 10.3389/fimmu.2021.625472] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 01/25/2021] [Indexed: 01/30/2023] Open
Abstract
Neutrophils are the largest population of circulating leukocytes and the first responder against invading pathogens or other danger signals. Sophisticated machineries help them play critical roles in immunity and inflammation, including phagocytosis, superoxide production, cytokine and chemokine production, degranulation, and formation of neutrophil extracellular traps (NETs). After maturation and release from the bone marrow, neutrophils migrate to inflamed tissues in response to many stimuli. Increasing evidences indicate that neutrophils are critically involved in the pathogenesis of liver diseases, including liver cancer, thus making them promising target for the treatment of liver diseases. Here, we would like to provide the latest finding about the role of neutrophils in liver diseases and discuss the potentiality of neutrophils as target for liver diseases.
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Affiliation(s)
- Jiaojiao Tang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zijun Yan
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- Graduate Management Unit, Shanghai Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Qiyu Feng
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Lexing Yu
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
| | - Hongyang Wang
- Division of Life Sciences and Medicine, Cancer Research Center, The First Affiliated Hospital of University of Science and Technology of China, Hefei, China
- International Cooperation Laboratory on Signal Transduction, Ministry of Education Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer, Shanghai Key Laboratory of Hepato-Biliary Tumor Biology, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
- National Center for Liver Cancer, Shanghai, China
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Wu L, Saxena S, Goel P, Prajapati DR, Wang C, Singh RK. Breast Cancer Cell-Neutrophil Interactions Enhance Neutrophil Survival and Pro-Tumorigenic Activities. Cancers (Basel) 2020; 12:E2884. [PMID: 33049964 PMCID: PMC7599756 DOI: 10.3390/cancers12102884] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 10/02/2020] [Accepted: 10/05/2020] [Indexed: 12/14/2022] Open
Abstract
Breast cancer remains the most prevalent cancer in women with limited treatment options for patients suffering from therapy-resistance and metastatic disease. Neutrophils play an important role in breast cancer progression and metastasis. We examined the pro-tumorigenic nature of the breast cancer cell-neutrophil interactions and delineated the differences in neutrophil properties between the chemotherapy-resistant and the parent tumor microenvironment. Our data demonstrated that high neutrophil infiltration is associated with disease aggressiveness and therapy resistance. In the human breast cancer dataset, expression of neutrophil-related signature gene expression was higher in tumors from therapy-resistant patients than therapy-sensitive patients. We observed that breast cancer-derived factors significantly enhanced neutrophil survival, polarization, and pro-inflammatory cytokine expression. Breast cancer cell-derived supernatant treated neutrophils significantly expressed high levels of interleukin-1β (IL-1β), CC-chemokine ligand-2-4 (CCL2, CCL3, CCL4), inducible nitric oxide synthase (iNOS), and matrix metallopeptidase-9 (MMP9), and formed extracellular traps (NETs). Moreover, neutrophils showed increased secretion of MMP9 when cultured with the supernatant of chemotherapy-resistant Cl66-Doxorubicin (Cl66-Dox) and Cl66-Paclitaxel (Cl66-Pac) cells in comparison with the supernatant of Cl66-parent cells. Together, these data suggest an important role of breast cancer cell-neutrophil interactions in regulating pro-tumor characteristics in neutrophils and its modulation by therapy resistance.
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Affiliation(s)
- Lingyun Wu
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 UNMC, Omaha, NE 68198-5900, USA; (L.W.); (S.S.); (P.G.); (D.R.P.); (C.W.)
- Vascular Biology and Therapeutics Program and Department of Pharmacology, Yale University, Yale School of Medicine, New Haven, CT 06520-8089, USA
| | - Sugandha Saxena
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 UNMC, Omaha, NE 68198-5900, USA; (L.W.); (S.S.); (P.G.); (D.R.P.); (C.W.)
| | - Paran Goel
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 UNMC, Omaha, NE 68198-5900, USA; (L.W.); (S.S.); (P.G.); (D.R.P.); (C.W.)
| | - Dipakkumar R. Prajapati
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 UNMC, Omaha, NE 68198-5900, USA; (L.W.); (S.S.); (P.G.); (D.R.P.); (C.W.)
| | - Cheng Wang
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 UNMC, Omaha, NE 68198-5900, USA; (L.W.); (S.S.); (P.G.); (D.R.P.); (C.W.)
| | - Rakesh K. Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985900 UNMC, Omaha, NE 68198-5900, USA; (L.W.); (S.S.); (P.G.); (D.R.P.); (C.W.)
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Jia Y, Liu L, Shan B. Future of immune checkpoint inhibitors: focus on tumor immune microenvironment. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1095. [PMID: 33145314 PMCID: PMC7575936 DOI: 10.21037/atm-20-3735] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Immunotherapy has become a powerful clinical strategy in cancer treatment. Immune checkpoint inhibitors (ICIs) have opened a new era for cancer immunotherapy. Nowadays, the number of immunotherapy drug approvals has increased, with numerous treatment options in clinical and preclinical development. However, there remain some obstacles to improve the efficacy of ICIs further. The tumor immune microenvironment (TIME) consists of cancer cell, immune cells and cytokines, et cetera. The dynamics of TIME determine the efficacies of ICIs. Although the ICIs showed manageable toxicity, immune-related adverse effects (irAEs) are still unignorable for clinicians. Since some primary resistance mechanisms exist in TIME, ICIs can only show effects in individual cancer patients. Even for the patients who responded, acquired resistance will occur to neutralize the effect of ICIs. Understanding how to increase the response rates and overcome the resistance to various classes of ICIs is the key to improving clinical efficacy. Besides the novel ICIs in development, there are some approaches to establish combination therapies are underway to improve further the efficacies of ICIs in treating cancer patients. Here, we describe the complicated TIME and state quo of ICIs to prospect the future of ICIs in cancer treatment.
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Affiliation(s)
- Yunlong Jia
- Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Lihua Liu
- Department of Tumor Immunotherapy, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.,Hebei Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Baoen Shan
- Hebei Cancer Institute, Fourth Hospital of Hebei Medical University, Shijiazhuang, China.,Research Center, Fourth Hospital of Hebei Medical University, Shijiazhuang, China
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Wu L, Saxena S, Singh RK. Neutrophils in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1224:1-20. [PMID: 32036601 DOI: 10.1007/978-3-030-35723-8_1] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Neutrophils are the first responders to inflammation, infection, and injury. As one of the most abundant leukocytes in the immune system, neutrophils play an essential role in cancer progression, through multiple mechanisms, including promoting angiogenesis, immunosuppression, and cancer metastasis. Recent studies demonstrating elevated neutrophil to lymphocyte ratios suggest neutrophil as a potential therapeutic target and biomarker for disease status in cancer. This chapter will discuss the phenotypic and functional changes in the neutrophil in the tumor microenvironment, the underlying mechanism(s) of neutrophil facilitated cancer metastasis, and clinical potential of neutrophils as a prognostic/diagnostic marker and therapeutic target.
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Affiliation(s)
- Lingyun Wu
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sugandha Saxena
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
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Wang Y, Wang H, Yin W, Lin Y, Zhou L, Sheng X, Xu Y, Sha R, Lu J. Novel lymphocyte to red blood cell ratio (LRR), neutrophil to red blood cell ratio (NRR), monocyte to red blood cell ratio (MRR) as predictive and prognostic biomarkers for locally advanced breast cancer. Gland Surg 2019; 8:627-635. [PMID: 32042669 DOI: 10.21037/gs.2019.10.10] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Background Lymphocytes, neutrophils, and monocytes are vital effector cells in innate immunity. We postulated that lymphocyte to red blood cell ratio (LRR), neutrophil to red blood cell ratio (NRR), monocyte to red blood cell ratio (MRR) could represent the intensity of systemic inflammatory immunological reaction reflected through the lymphocyte, neutrophil and monocyte respectively. This study aimed to access the predictive and prognostic value of LRR, NRR, MRR and LRR-NRR-MRR score for locally advanced breast cancer. Methods A total of 137 patients from two clinical trials SHPD002 and SHPD003 were included. Logistic regression analysis was used to evaluate the association between ratios and pathological complete response (pCR). Disease-free survival (DFS) and overall survival (OS) were estimated by Kaplan-Meier method and cox regression analysis. Results Lower LRR-NRR-MRR score (OR =0.593; 95% CI: 0.369-0.954; P=0.031) was more easily to achieve pCR in multivariate analysis. Lower LRR (P=0.022), NRR (P=0.027) and MRR (P=0.024) were significantly associated with better DFS. LRR-NRR-MRR score was an independently prognostic factor for both DFS (HR =3.318; 95% CI: 1.601-6.876; P=0.001) and OS (HR =3.160; 95% CI: 1.030-9.696; P=0.044). Conclusions The LRR-NRR-MRR score could be identified as a new predictive biomarker for the therapeutic effect of neoadjuvant therapy and an independent prognostic factor for both DFS and OS for locally advanced breast cancer.
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Affiliation(s)
- Yaohui Wang
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Haofeng Wang
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Wenjin Yin
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Yanping Lin
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Liheng Zhou
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Xiaonan Sheng
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Yaqian Xu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Rui Sha
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
| | - Jinsong Lu
- Department of Breast Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200127, China
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13
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Tumor-Associated Neutrophils in Cancer: Going Pro. Cancers (Basel) 2019; 11:cancers11040564. [PMID: 31010242 PMCID: PMC6520693 DOI: 10.3390/cancers11040564] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/09/2019] [Accepted: 04/17/2019] [Indexed: 02/07/2023] Open
Abstract
The progression of cancer is not only about the tumor cell itself, but also about other involved players including cancer cell recruited immune cells, their released pro-inflammatory factors, and the extracellular matrix. These players constitute the tumor microenvironment and play vital roles in the cancer progression. Neutrophils—the most abundant white blood cells in the circulation system—constitute a significant part of the tumor microenvironment. Neutrophils play major roles linking inflammation and cancer and are actively involved in progression and metastasis. Additionally, recent data suggest that neutrophils could be considered one of the emerging targets for multiple cancer types. This review summarizes the most recent updates regarding neutrophil recruitments and functions in the tumor microenvironment as well as potential development of neutrophils-targeted putative therapeutic strategies.
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Zhang Q, Lou Y, Bai XL, Liang TB. Immunometabolism: A novel perspective of liver cancer microenvironment and its influence on tumor progression. World J Gastroenterol 2018; 24:3500-3512. [PMID: 30131656 PMCID: PMC6102497 DOI: 10.3748/wjg.v24.i31.3500] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 05/29/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
The initiation and progression of liver cancer, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, are dependent on its tumor microenvironment. Immune cells are key players in the liver cancer microenvironment and show complicated crosstalk with cancer cells. Emerging evidence has shown that the functions of immune cells are closely related to cell metabolism. However, the effects of metabolic changes of immune cells on liver cancer progression are largely undefined. In this review, we summarize the recent findings of immunometabolism and relate these findings to liver cancer progression. We also explore the translation of the understanding of immunometabolism for clinical use.
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Affiliation(s)
- Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, Zhejiang Province, China
| | - Yu Lou
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, Zhejiang Province, China
| | - Xue-Li Bai
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, Zhejiang Province, China
| | - Ting-Bo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, Zhejiang Province, China
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, Hangzhou 310009, Zhejiang Province, China
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15
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Identification of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the peripheral blood of Hodgkin and non-Hodgkin lymphoma patients. Oncotarget 2018; 7:27676-88. [PMID: 27050283 PMCID: PMC5053680 DOI: 10.18632/oncotarget.8507] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2016] [Accepted: 03/18/2016] [Indexed: 12/29/2022] Open
Abstract
Human granulocytic myeloid-derived suppressor cells (G-MDSCs) have been described as low-density immunosuppressive CD66b+CD33dimHLA-DR-granulocytes that co-purify with mononuclear cells after density gradient centrifugation of blood from cancer patients. The role of G-MDSCs in Hodgkin (HL) and non-Hodgkin lymphoma (NHL) remains unclear. The percentage and immunophenotype of CD66b+CD33dimHLA-DR-cells were analyzed in PBMCs from HL and B-cell NHL patients (n = 124) and healthy donors (n = 48). The immunosuppressive functions of these cells were tested in vitro. Correlations between CD66b+CD33dimHLA-DR-cells and patient clinicopathological features and outcome, were evaluated. CD66b+CD33dimHLA-DR-cells were increased in PBMCs from HL and B-cell NHL patients as compared to healthy donors: 2.18 (0.02–70.92) vs 0.42 (0.04–2.97), p < 0.0001. Their percentage remained significantly higher even considering HL (n = 31), indolent (n = 31) and aggressive (n = 62) B-cell NHL patients separately: 1.54 (0.28–26.34), 2.15 (0.02–20.08), and 2.96 (0.25–70.92), respectively, p < 0.0001. CD66b+CD33dimHLA-DR-cells in patient PBMCs were mostly composed of mature CD11b+CD16+ low-density neutrophils in an activated status, as revealed by their higher CD11b and CD66b expression as compared to conventionally isolated (normal-density) autologous or healthy donor neutrophils. The in vitro depletion of CD66b+ cells from patient PBMCs restored the proliferation of autologous T cells. Higher frequencies of CD66b+CD33dimHLA-DR− G-MDSCs correlated significantly with unfavorable prognostic index scores and a shorter freedom from disease progression. PBMCs from HL and B-cell NHL patients contain a population of CD66b+CD33dimHLA-DR− G-MDSCs, mostly composed of activated low-density neutrophils with immunosuppressive properties. These findings disclose a previously unknown G-MDSC-mediated mechanism of immune-escape in lymphomas, therefore anticipating possible targets for therapeutic interventions.
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16
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Personeni N, Giordano L, Abbadessa G, Porta C, Borbath I, Daniele B, Van Laethem JL, Van Vlierberghe H, Trojan J, De Toni EN, Gasbarrini A, Lencioni M, Lamar ME, Wang Y, Shuster D, Schwartz B, Santoro A, Rimassa L. Prognostic value of the neutrophil-to-lymphocyte ratio in the ARQ 197-215 second-line study for advanced hepatocellular carcinoma. Oncotarget 2017; 8:14408-14415. [PMID: 28122337 PMCID: PMC5362414 DOI: 10.18632/oncotarget.14797] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Accepted: 01/11/2017] [Indexed: 02/07/2023] Open
Abstract
The ARQ 197-215 study randomized patients to tivantinib or placebo and pre-specified efficacy analyses indicated the predictive value of MET expression as a marker of benefit from tivantinib in hepatocellular carcinoma (HCC). We aimed to explore the neutrophil-to-lymphocyte ratio (NLR) in 98 ARQ 197-215 patients with available absolute neutrophil count and absolute lymphocyte count at baseline. The cut-off value used to define high versus low NLR was 3.0. In univariate analysis, high NLR was associated with hazard ratio (HR) for overall survival (OS) of 1.58 [95% confidence interval (CI) 1.01; 2.47; P <0.046], corresponding to median OS of 5.1 months versus 7.8 months in patients with low NLR (P = 0.044). In contrast, time to progression was not significantly affected by NLR (P = 0.20). Multivariable model confirmed that both NLR >3 (P = 0.03) and presence of vascular invasion (P = 0.017) were negatively associated with OS. After adjustment for vascular invasion, NLR independently predicted survival in both the placebo and the tivantinib cohort. For OS, no interaction was detected between NLR status and treatment (Pinteraction = 0.40). Baseline NLR is an independent prognostic biomarker in patients with HCC and compensated liver function who are candidate for second-line treatments.
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Affiliation(s)
- Nicola Personeni
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.,Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Laura Giordano
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
| | - Giovanni Abbadessa
- Clinical Development & Translational Medicine, ArQule, Burlington, MA, United States
| | - Camillo Porta
- Fondazione IRCCS Policlinico Universitario San Matteo, Pavia, Italy
| | - Ivan Borbath
- Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | | | | | | | - Jörg Trojan
- Internal Medicine, J. W. Goethe University Hospital, Frankfurt, Germany
| | | | | | | | - Maria E Lamar
- Clinical Development & Translational Medicine, ArQule, Burlington, MA, United States
| | - Yunxia Wang
- Clinical Development & Translational Medicine, ArQule, Burlington, MA, United States
| | - Dale Shuster
- Clinical Development, Daiichi-Sankyo, Edison, NJ, United States
| | - Brian Schwartz
- Clinical Development & Translational Medicine, ArQule, Burlington, MA, United States
| | - Armando Santoro
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.,Humanitas University, Rozzano, Milan, Italy
| | - Lorenza Rimassa
- Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy
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17
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Liu XL, Wang LJ, Zhang S, Li MG, Jiang YY, Yang ZY. Changes in peripheral blood T, NK and B cells and thymus function in patients with HBV-related primary liver cancer. Shijie Huaren Xiaohua Zazhi 2016; 24:3381-3390. [DOI: 10.11569/wcjd.v24.i22.3381] [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] [Indexed: 02/06/2023] Open
Abstract
AIM: To explore changes in the distribution of peripheral blood T, NK and B cells and thymus function in the occurrence and progression of hepatitis B virus-related primary liver cancer (HBV-PLC).
METHODS: Clinical and laboratory data of 73 HBV-PLV patients, 50 liver cirrhosis (LC) patients and 37 chronic hepatitis B (CHB) patients were collected at Beijing Ditan Hospital, Capital Medical University. The distribution of CD3+ T, CD4+ T, CD8+ T, CD3-CD16+CD56+ NK, CD3-CD19+ B cells and the expression of CD31, CD45RA on T cells were detected in peripheral blood of all patients by flow cytometry.
RESULTS: Compared with CHB and LC patients, the percentage and absolute number of lymphocytes declined in HBV-PLC patients (P < 0.001). Compared with LC patients, the numbers of T, CD4+ T, CD8+ T, B (P < 0.001), and NK cells (P = 0.011) significantly decreased in HBV-PLC patients. With regard to Child-Pugh, Okuda, and BCLC stages, the numbers of lymphocytes, T, CD4+ T, and CD8+ T cells were significantly lower in advanced stages than in early stages (P < 0.05).
CONCLUSION: The immune cells that have anti-tumor effects decrease in the peripheral blood of HBV-PLC patients, which may be due to the reduced thymus function.
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18
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Tecchio C, Cassatella MA. Neutrophil-derived chemokines on the road to immunity. Semin Immunol 2016; 28:119-28. [PMID: 27151246 PMCID: PMC7129466 DOI: 10.1016/j.smim.2016.04.003] [Citation(s) in RCA: 174] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 04/04/2016] [Accepted: 04/05/2016] [Indexed: 12/12/2022]
Abstract
During recent years, it has become clear that polymorphonuclear neutrophils are remarkably versatile cells, whose functions go far beyond phagocytosis and killing. In fact, besides being involved in primary defense against infections-mainly through phagocytosis, generation of toxic molecules, release of toxic enzymes and formation of extracellular traps-neutrophils have been shown to play a role in finely regulating the development and the evolution of inflammatory and immune responses. These latter neutrophil-mediated functions occur by a variety of mechanisms, including the production of newly manufactured cytokines. Herein, we provide a general overview of the chemotactic cytokines/chemokines that neutrophils can potentially produce, either under inflammatory/immune reactions or during their activation in more prolonged processes, such as in tumors. We highlight recent observations generated from studying human or rodent neutrophils in vitro and in vivo models. We also discuss the biological significance of neutrophil-derived chemokines in the context of infectious, neoplastic and immune-mediated diseases. The picture that is emerging is that, given their capacity to produce and release chemokines, neutrophils exert essential functions in recruiting, activating and modulating the activities of different leukocyte populations.
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Affiliation(s)
- Cristina Tecchio
- Department of Medicine, Section of Hematology and Bone Marrow Transplant Unit, University of Verona, Verona, Italy.
| | - Marco A Cassatella
- Department of Medicine, Section of General Pathology, University of Verona, Verona, Italy.
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19
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Liang CM, Chen L, Hu H, Ma HY, Gao LL, Qin J, Zhong CP. Chemokines and their receptors play important roles in the development of hepatocellular carcinoma. World J Hepatol 2015; 7:1390-1402. [PMID: 26052384 PMCID: PMC4450202 DOI: 10.4254/wjh.v7.i10.1390] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/08/2014] [Accepted: 04/07/2015] [Indexed: 02/06/2023] Open
Abstract
The chemokine system consists of four different subclasses with over 50 chemokines and 19 receptors. Their functions in the immune system have been well elucidated and research during the last decades unveils their new roles in hepatocellular carcinoma (HCC). The chemokines and their receptors in the microenvironment influence the development of HCC by several aspects including: inflammation, effects on immune cells, angiogenesis, and direct effects on HCC cells. Regarding these aspects, pre-clinical research by targeting the chemokine system has yielded promising data, and these findings bring us new clues in the chemokine-based therapies for HCC.
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20
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Zhang NB, Zhang JX. Advances in research of tumor microenvironment in hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2014; 22:4774-4784. [DOI: 10.11569/wcjd.v22.i31.4774] [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] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is not just composed of liver cancer cells; it contains several cell types and extracellular matrix that interact with each other, creating a complex interaction network within a permissive microenvironment. The tumor microenvironment in HCC can not only support liver cancer cell growth but also promote tumor invasion through the stimulation of cancer cell proliferation, migration, and invasion and activation of angiogenesis, which together determine the phenotype of HCC. In this review, we provide an overview of current knowledge on the role of the tumor microenvironment in HCC and its application in prognosis prediction and treatment.
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21
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Tecchio C, Micheletti A, Cassatella MA. Neutrophil-derived cytokines: facts beyond expression. Front Immunol 2014; 5:508. [PMID: 25374568 PMCID: PMC4204637 DOI: 10.3389/fimmu.2014.00508] [Citation(s) in RCA: 509] [Impact Index Per Article: 46.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2014] [Accepted: 09/29/2014] [Indexed: 12/21/2022] Open
Abstract
Polymorphonuclear neutrophils, besides their involvement in primary defense against infections - mainly through phagocytosis, generation of toxic molecules, release of enzymes, and formation of extracellular traps - are also becoming increasingly important for their contribution to the fine regulation in development of inflammatory and immune responses. These latter functions of neutrophils occur, in part, via their de novo production and release of a large variety of cytokines, including chemotactic cytokines (chemokines). Accordingly, the improvement in technologies for molecular and functional cell analysis, along with concomitant advances in cell purification techniques, have allowed the identification of a continuously growing list of neutrophil-derived cytokines, as well as the characterization of their biological implications in vitro and/or in vivo. This short review summarizes crucial concepts regarding the modalities of expression, release, and regulation of neutrophil-derived cytokines. It also highlights examples illustrating the potential implications of neutrophil-derived cytokines according to recent observations made in humans and/or in experimental animal models.
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Affiliation(s)
- Cristina Tecchio
- Section of Hematology, Department of Medicine, School of Medicine, University of Verona , Verona , Italy
| | - Alessandra Micheletti
- Section of General Pathology, Department of Pathology and Diagnostics, School of Medicine, University of Verona , Verona , Italy
| | - Marco A Cassatella
- Section of General Pathology, Department of Pathology and Diagnostics, School of Medicine, University of Verona , Verona , Italy
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22
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Serum CCL2 and CCL3 as potential biomarkers for the diagnosis of oral squamous cell carcinoma. Tumour Biol 2014; 35:10539-46. [PMID: 25060177 DOI: 10.1007/s13277-014-2306-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 07/03/2014] [Indexed: 10/25/2022] Open
Abstract
Monocyte chemotactic protein-1 (MCP-1/CCL2) and macrophage inflammatory protein-1α (MIP-1α/CCL3) are small chemotactic proteins that have been found in several kinds of tumor tissue samples and function as key regulators of cancer progression. However, the expression of CCL2 and CCL3 in serum samples of oral squamous cell carcinoma (OSCC) patients remains unknown. This study aimed to investigate the prognostic meaning of serum CCL2 and CCL3 in OSCC. The concentration of CCL2 and CCL3 was assessed by ELISA in serum of OSCC patients (n = 98), leukoplakia patients (n = 14), and healthy donors (n = 27). The results showed that the concentration of CCL2 in the OSCC group was significantly lower compared to that in the healthy controls (67.81 vs. 108.1 pg/ml, P < 0.0001). The CCL3 concentration was higher in leukoplakia patients than in OSCC patients and healthy donors (201.9 vs. 153.9 or 118.3 pg/ml, P < 0.05). No significant difference in CCL3 concentration was observed between OSCC patients and healthy donors. However, the OSCC group clearly presented two subclusters, i.e., CCL3 (LOW) and CCL3 (HIGH) OSCC subclusters, in which the serum level of CCL3 was positively related to the tumor size. Interestingly, the ratio of CCL2/CCL3 in OSCC patients was correlated to TNM (tumor, node, metastasis), smoking habits, and differentiation. The receiver operating characteristic (ROC) curve suggests that serum CCL2 is a good diagnostic marker to discriminate OSCC patients from healthy people (cutoff value, 101.1 pg/ml) and the ratio of CCL2/CCL3 also is a good diagnostic marker to discriminate leukoplakia patients and CCL3 (HIGH) OSCC patients from healthy people (cutoff values, 1.080 and 0.424, respectively). These results indicate that CCL2 and CCL3 are associated with progression of OSCC and may be potential biomarkers.
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The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment. CANCER MICROENVIRONMENT 2014; 8:125-58. [PMID: 24895166 DOI: 10.1007/s12307-014-0147-5] [Citation(s) in RCA: 319] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/01/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023]
Abstract
Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor (N1) and pro-tumor (N2) sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.
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24
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Xu R, Huang H, Zhang Z, Wang FS. The role of neutrophils in the development of liver diseases. Cell Mol Immunol 2014. [PMID: 24633014 DOI: 10.1038/cmi.204.2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Liver disease encompasses a wide variety of liver conditions, including liver failure, liver cirrhosis and a spectrum of acute and chronic hepatitis, such as alcoholic, fatty, drug, viral and chronic hepatitis. Liver injury is a primary causative factor in liver disease; generally, these factors include direct liver damage and immune-mediated liver injury. Neutrophils (also known as neutrophilic granulocytes or polymorphonuclear leukocytes (PMNs)) are the most abundant circulating white blood cell type in humans, and PMNs are a major innate immune cell subset. Inappropriate activation and homing of neutrophils to the microvasculature contributes to the pathological manifestations of many types of liver disease. This review summarizes novel concepts of neutrophil-mediated liver injury that are based on current clinical and animal model studies.
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Affiliation(s)
- Ruonan Xu
- The Institute of Translational Hepatology, Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
| | - Huihuang Huang
- The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China
| | - Zheng Zhang
- The Institute of Translational Hepatology, Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
| | - Fu-Sheng Wang
- The Institute of Translational Hepatology, Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
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25
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Xu R, Huang H, Zhang Z, Wang FS. The role of neutrophils in the development of liver diseases. Cell Mol Immunol 2014; 11:224-31. [PMID: 24633014 DOI: 10.1038/cmi.2014.2] [Citation(s) in RCA: 186] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 01/07/2014] [Accepted: 01/07/2014] [Indexed: 12/12/2022] Open
Abstract
Liver disease encompasses a wide variety of liver conditions, including liver failure, liver cirrhosis and a spectrum of acute and chronic hepatitis, such as alcoholic, fatty, drug, viral and chronic hepatitis. Liver injury is a primary causative factor in liver disease; generally, these factors include direct liver damage and immune-mediated liver injury. Neutrophils (also known as neutrophilic granulocytes or polymorphonuclear leukocytes (PMNs)) are the most abundant circulating white blood cell type in humans, and PMNs are a major innate immune cell subset. Inappropriate activation and homing of neutrophils to the microvasculature contributes to the pathological manifestations of many types of liver disease. This review summarizes novel concepts of neutrophil-mediated liver injury that are based on current clinical and animal model studies.
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Affiliation(s)
- Ruonan Xu
- The Institute of Translational Hepatology, Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
| | - Huihuang Huang
- The Institute of Intensive Care Unit, Beijing 302 Hospital, Beijing, China
| | - Zheng Zhang
- The Institute of Translational Hepatology, Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
| | - Fu-Sheng Wang
- The Institute of Translational Hepatology, Research Center for Biological Therapy, Beijing 302 Hospital, Beijing, China
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26
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Katsuno T, Ochi M, Tominaga K, Tanaka F, Sogawa M, Tanigawa T, Yamagami H, Shiba M, Watanabe K, Watanabe T, Fujiwara Y, Arakawa T. Mesenchymal stem cells administered in the early phase of tumorigenesis inhibit colorectal tumor development in rats. J Clin Biochem Nutr 2013; 53:170-5. [PMID: 24249972 PMCID: PMC3818273 DOI: 10.3164/jcbn.13-68] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 08/16/2013] [Indexed: 12/26/2022] Open
Abstract
To investigate the differences between the effects of mesenchymal stem cells (MSCs) administered in the early and late phases of tumorigenesis, MSCs were isolated from bone marrow and colorectal tumors were produced by exposing 7-week-old F344 rats to 1,2-dimethylhydrazine and dextran sulfate sodium. We evaluated tumor number and volume (week 25), MSC localization, number of aberrant crypt foci (ACF), transforming growth factor (TGF)-β1 protein levels in the rectum after administration of MSCs (week 5 or 15), and the effects of MSC-conditioned medium on ACL15 cell proliferation. Administered MSCs labeled with PKH26 were observed in the rectum. Administered MSCs in the early phase (week 5) before tumor occurrence (week 12) significantly decreased tumor number and volume (1.5 vs 4 and 21 mm3 vs 170 mm3; p<0.01), but not administered MSCs in the late phase (week 15). Administered MSCs in the early phase reduced ACF number on days 14 and 35 (1.9 vs 4.1 and 3.7 vs 7.3; p<0.01). Rectal TGF-β1 increased 1.3 fold on day 3, and MSC-conditioned medium containing TGF-β1 abundantly inhibited ACL15 cell proliferation. MSCs administered in the early phase but not late phase inhibited colorectal tumor development in a rat model.
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Affiliation(s)
- Takayuki Katsuno
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka 545-8585, Japan
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Nakashita S, Eguchi Y, Mizuta T, Kuroki S, Ono N, Eguchi T, Anzai K, Fujimoto K. Evaluation narcotic analgesic use and survival time in terminal stage liver diseases compared with lung cancer: a retrospective chart review. J Clin Biochem Nutr 2013; 52:241-3. [PMID: 23704814 PMCID: PMC3652303 DOI: 10.3164/jcbn.13-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2013] [Accepted: 01/29/2013] [Indexed: 11/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) and liver cirrhosis are fatal diseases. This study aimed to investigate survival time and palliative care in terminal HCC and/or liver cirrhosis compared with lung cancer. Between January 2004 and December 2010, we enrolled 116 patients with terminal cirrhosis and/or HCC or lung cancer admitted to a municipal hospital in Japan; 48 had liver cirrhosis, 35 HCC and 33 lung cancer. By retrospective chart review, we evaluated: (i) rate of usage of narcotic analgesics and (ii) survival time from onset of coma (Glasgow Coma Scale less than 8). Time between coma and death was significantly shorter in the liver disease patients (cirrhosis and/or HCC: 7.0 h) than in lung cancer (44.0 h, p = 0.045). Total bilirubin was higher in HCC compared with cirrhosis (p<0.01). Rate of usage of narcotic analgesics was higher in lung cancer (20/33: 60.6%) than in liver disease (17/83: 20.5%, p<0.01); analgesics were used more frequently in HCC than in liver cirrhosis (p<0.01). These results suggest that liver cirrhosis and HCC patients do not always require palliative care and that survival time from onset of coma due to liver disease was not prolonged compared with lung cancer.
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Affiliation(s)
- Shunya Nakashita
- Department of Internal Medicine, Saga Medical School, 5-1-1 Nabeshima, Saga 849-8501, Japan ; Eguchi Hospital, 1054-2 Kanada, Mikatsuki-cho, Ogi, Saga 845-0032, Japan
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