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Garner H, Martinovic M, Liu NQ, Bakker NAM, Velilla IQ, Hau CS, Vrijland K, Kaldenbach D, Kok M, de Wit E, de Visser KE. Understanding and reversing mammary tumor-driven reprogramming of myelopoiesis to reduce metastatic spread. Cancer Cell 2025:S1535-6108(25)00166-7. [PMID: 40345190 DOI: 10.1016/j.ccell.2025.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 10/11/2024] [Accepted: 04/15/2025] [Indexed: 05/11/2025]
Abstract
Tumor-induced systemic accumulation and polarization of neutrophils to an immunosuppressive phenotype is a potent driver of metastasis formation. Yet, how mammary tumors reprogram granulopoiesis at the molecular level and when tumor imprinting occurs during neutrophil development remains underexplored. Here, we combined single-cell, chromatin and functional analyses to unravel the tumor-driven reprogramming of granulopoiesis in the bone marrow, along with intervention studies aimed at reversing this process. We observe that mammary tumors accelerate commitment to the neutrophil lineage at the expense of lymphopoiesis and erythropoiesis without stimulating the development of a novel myeloid lineage. Moreover, tumor-directed immunosuppressive imprinting of neutrophils starts early in hematopoiesis. Treatment with anti-IL-1β normalizes tumor-induced granulopoiesis, reducing neutrophil immunosuppressive phenotype and mitigating metastatic spread. Together, these data provide molecular insights into the aberrant, tumor-driven neutrophil differentiation pathway leading to metastasis-promoting chronic inflammation and how it can be reversed to reduce metastatic spread.
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Affiliation(s)
- Hannah Garner
- Department of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands.
| | - Moreno Martinovic
- Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Ning Qing Liu
- Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Noor A M Bakker
- Department of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Irene Querol Velilla
- Department of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, the Netherlands
| | - Cheei-Sing Hau
- Department of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Kim Vrijland
- Department of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Daphne Kaldenbach
- Department of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands
| | - Marleen Kok
- Department of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands
| | - Elzo de Wit
- Division of Gene Regulation, Netherlands Cancer Institute, Amsterdam, the Netherlands.
| | - Karin E de Visser
- Department of Tumor Biology & Immunology, Netherlands Cancer Institute, Amsterdam, the Netherlands; Oncode Institute, Utrecht, the Netherlands; Department of Immunology, Leiden University Medical Centre, Leiden, the Netherlands.
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Hansen N, Peña-Martínez P, Skoog P, Reinbach K, Hansen FC, Faria SL, Grönberg C, Abdilleh K, Magnusson S, von Wachenfeldt K, Millrud CR, Liberg D, Järås M. Blocking IL1RAP on cancer-associated fibroblasts in pancreatic ductal adenocarcinoma suppresses IL-1-induced neutrophil recruitment. J Immunother Cancer 2024; 12:e009523. [PMID: 39694705 DOI: 10.1136/jitc-2024-009523] [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] [Accepted: 11/12/2024] [Indexed: 12/20/2024] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) represents a major clinical challenge due to its tumor microenvironment, which exhibits immune-suppressive properties that facilitate cancer progression, metastasis, and therapy resistance. Interleukin 1 (IL-1) signaling has been implicated as a driver in this process. Mechanistically, both IL-1α and IL-1β bind to the IL-1 receptor type 1, forming a complex with IL-1-receptor accessory protein (IL1RAP), which triggers downstream signaling pathways. The IL1RAP blocking antibody nadunolimab is currently in clinical development, but the precise consequences of inhibiting IL-1 signaling in PDAC remains elusive. METHODS To evaluate the biological relevance of blocking IL1RAP using nadunolimab in a PDAC animal model, human PDAC cells and cancer-associated fibroblasts (CAFs) were co-transplanted into mice. To study the underlying mechanisms of IL1RAP blockade ex vivo, co-cultured PDAC cells and CAFs were treated with nadunolimab prior to RNA sequencing. Migration assays were performed to assess how nadunolimab affects interactions between CAFs and myeloid immune cells. Finally, to establish a clinical correlation between IL1RAP expression and nadunolimab treatment effects, we analyzed tumor biopsies from a clinical phase I/II study in which nadunolimab was administered to patients. RESULTS In the xenograft mouse model, nadunolimab exhibited antitumor effects only when human CAFs were co-transplanted with PDAC cells. IL-1 stimulation induced CAFs to secrete chemokines that recruited neutrophils and monocytes. The secretion of this chemokine and the migration of myeloid cells were inhibited by nadunolimab. Media conditioned by IL-1-stimulated CAFs sustained a neutrophil population with a tissue invasion phenotype, an effect that was reversed by nadunolimab. In a cohort of metastatic late-stage PDAC patients receiving nadunolimab as monotherapy, high IL1RAP expression in tumors was associated with extended progression-free survival. CONCLUSIONS Our study demonstrates that targeting IL1RAP on CAFs inhibits IL-1-induced chemokine secretion and recruitment of neutrophils and monocytes, thereby counteracting the immunosuppressive microenvironment in PDAC. These findings highlight the therapeutic potential of targeting IL1RAP in PDAC.
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Affiliation(s)
- Nils Hansen
- Lund Stem Cell Center, Lund University, Lund, Sweden
| | | | | | | | | | | | | | - Kawther Abdilleh
- Pancreatic Cancer Action Network, Manhattan Beach, California, USA
| | | | | | | | | | - Marcus Järås
- Lund Stem Cell Center, Lund University, Lund, Sweden
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Koc DC, Mănescu IB, Mănescu M, Dobreanu M. A Review of the Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Nonhematologic Malignancies. Diagnostics (Basel) 2024; 14:2057. [PMID: 39335736 PMCID: PMC11431542 DOI: 10.3390/diagnostics14182057] [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: 07/01/2024] [Revised: 09/09/2024] [Accepted: 09/12/2024] [Indexed: 09/30/2024] Open
Abstract
Biomarkers are crucial in cancer diagnostics, prognosis, and surveillance. Extensive research has been dedicated to identifying biomarkers that are broadly applicable across multiple cancer types and can be easily obtained from routine investigations such as blood cell counts. One such biomarker, the neutrophil-to-lymphocyte ratio (NLR), has been established as a prognostic marker in cancer. However, due to the dynamic nature of cancer diagnosis and treatment, periodic updates are necessary to keep abreast of the vast amount of published data. In this review, we searched the PubMed database and analyzed and synthesized recent literature (2018-February 2024) on the role of NLR in predicting clinical outcomes in nonhematologic malignancies. The search was conducted using the PubMed database. We included a total of 88 studies, encompassing 28,050 human subjects, and categorized the findings into four major groups: gastrointestinal cancer, cancers of the urinary tract and reproductive system, lung cancer, and breast cancer. Our analysis confirms that NLR is a reliable prognostic indicator in cancer, and we discuss the specific characteristics, limitations, and exceptions associated with its use. The review concludes with a concise Q&A section, presenting the most relevant take-home messages in response to five key practical questions on this topic.
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Affiliation(s)
- Defne Cigdem Koc
- Medical Campus Hamburg, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 11-15 Albert-Einstein-Ring, 22761 Hamburg, Germany; (D.C.K.); (I.B.M.)
| | - Ion Bogdan Mănescu
- Medical Campus Hamburg, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 11-15 Albert-Einstein-Ring, 22761 Hamburg, Germany; (D.C.K.); (I.B.M.)
- Department of Laboratory Medicine, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 38 Gheorghe Marinescu, 540142 Targu Mures, Romania
| | - Măriuca Mănescu
- Department of Pediatrics, Emergency County Clinical Hospital of Targu Mures, 50 Gheorghe Marinescu, 540136 Targu Mures, Romania
| | - Minodora Dobreanu
- Department of Laboratory Medicine, Faculty of Medicine, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Targu Mures, 38 Gheorghe Marinescu, 540142 Targu Mures, Romania
- Clinical Laboratory, Emergency County Clinical Hospital of Targu Mures, 50 Gheorghe Marinescu, 540136 Targu Mures, Romania
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Li YN, Su JL, Tan SH, Chen XL, Cheng TL, Jiang Z, Luo YZ, Zhang LM. Machine learning based on metabolomics unveils neutrophil extracellular trap-related metabolic signatures in non-small cell lung cancer patients undergoing chemoimmunotherapy. World J Clin Cases 2024; 12:4091-4107. [PMID: 39015934 PMCID: PMC11235537 DOI: 10.12998/wjcc.v12.i20.4091] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 05/10/2024] [Accepted: 05/28/2024] [Indexed: 06/30/2024] Open
Abstract
BACKGROUND Non-small cell lung cancer (NSCLC) is the primary form of lung cancer, and the combination of chemotherapy with immunotherapy offers promising treatment options for patients suffering from this disease. However, the emergence of drug resistance significantly limits the effectiveness of these therapeutic strategies. Consequently, it is imperative to devise methods for accurately detecting and evaluating the efficacy of these treatments. AIM To identify the metabolic signatures associated with neutrophil extracellular traps (NETs) and chemoimmunotherapy efficacy in NSCLC patients. METHODS In total, 159 NSCLC patients undergoing first-line chemoimmunotherapy were enrolled. We first investigated the characteristics influencing clinical efficacy. Circulating levels of NETs and cytokines were measured by commercial kits. Liquid chromatography tandem mass spectrometry quantified plasma metabolites, and differential metabolites were identified. Least absolute shrinkage and selection operator, support vector machine-recursive feature elimination, and random forest algorithms were employed. By using plasma metabolic profiles and machine learning algorithms, predictive metabolic signatures were established. RESULTS First, the levels of circulating interleukin-8, neutrophil-to-lymphocyte ratio, and NETs were closely related to poor efficacy of first-line chemoimmunotherapy. Patients were classed into a low NET group or a high NET group. A total of 54 differential plasma metabolites were identified. These metabolites were primarily involved in arachidonic acid and purine metabolism. Three key metabolites were identified as crucial variables, including 8,9-epoxyeicosatrienoic acid, L-malate, and bis(monoacylglycerol)phosphate (18:1/16:0). Using metabolomic sequencing data and machine learning methods, key metabolic signatures were screened to predict NET level as well as chemoimmunotherapy efficacy. CONCLUSION The identified metabolic signatures may effectively distinguish NET levels and predict clinical benefit from chemoimmunotherapy in NSCLC patients.
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Affiliation(s)
- Yu-Ning Li
- School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, Hunan Province, China
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Jia-Lin Su
- School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, Hunan Province, China
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Shu-Hua Tan
- School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, Hunan Province, China
| | - Xing-Long Chen
- School of Life and Health Sciences, Hunan University of Science and Technology, Xiangtan 411201, Hunan Province, China
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Tian-Li Cheng
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Zhou Jiang
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Yong-Zhong Luo
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
| | - Le-Meng Zhang
- Department of Thoracic Medicine, Hunan Cancer Hospital, Changsha 410013, Hunan Province, China
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5
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Pang J, Ding N, Yin N, Xiao Z. Systemic immune-inflammation index as a prognostic marker in HER2-positive breast cancer patients undergoing trastuzumab therapy. Sci Rep 2024; 14:6578. [PMID: 38503890 PMCID: PMC10951263 DOI: 10.1038/s41598-024-57343-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Accepted: 03/18/2024] [Indexed: 03/21/2024] Open
Abstract
The prognostic value of SII (Systemic Immune-Inflammation Index) in HER-2-positive breast cancer (BC) patients, regardless of whether they receive trastuzumab treatment, and its potential value to distinguish patients who may benefit from trastuzumab therapy, warrant further investigation. Clinical data was collected from 797 HER-2-positive BC patients between July 2013 and March 2018. Baseline data differences were adjusted with propensity score matching. Univariate and multivariate analyses explored the correlation between clinical pathological factors, SII, and DFS. Four groups were established. Based on the baseline SII values of the participants, patients who did not receive trastuzumab treatment were divided into Group 1 (Low-SII) and Group 2 (High-SII), where SII had no predictive value for prognosis between groups. Participants who received trastuzumab treatment were also divided into two groups: the Low-SII group (Group 3) and the High-SII group (Group 4). The 5-year DFS was significantly higher in Group 3 than in Group 4 (91.76% vs. 82.76%, P = 0.017). Furthermore, multivariate analysis demonstrated a significant association between high SII and shorter DFS (HR = 3.430, 95% CI = 1.830-6.420, P < 0.001). In HER-2-positive BC patients treated with trastuzumab, those with lower SII showed a longer DFS, suggesting that SII may help in identifying patients who benefit from trastuzumab therapy.
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Affiliation(s)
- Jian Pang
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Nianhua Ding
- Department of Clinical Laboratory, The Affiliated Changsha Hospital of Xiangya School of Medicine, Central South University, Changsha, China
| | - Nana Yin
- Department of Operating Room, First People's Hospital of Changde, Changde, China
| | - Zhi Xiao
- Department of Breast Surgery, Xiangya Hospital, Central South University, 87# Xiangya Road, Changsha, 410008, Hunan, China.
- Clinical Research Center for Breast Cancer in Hunan Province, Changsha, China.
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Murphy O, Forget P, Ma D, Buggy DJ. Tumour excisional surgery, anaesthetic-analgesic techniques, and oncologic outcomes: a narrative review. Br J Anaesth 2023; 131:989-1001. [PMID: 37689540 DOI: 10.1016/j.bja.2023.07.027] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/28/2023] [Accepted: 07/28/2023] [Indexed: 09/11/2023] Open
Abstract
Cancer is a growing global burden; there were an estimated 18 million new cancer diagnoses worldwide in 2020. Excisional surgery remains one of the main treatments for solid organ tumours in cancer patients and is potentially curative. Cancer- and surgery-induced inflammatory processes can facilitate residual tumour cell survival, growth, and subsequent recurrence. However, it has been hypothesised that anaesthetic and analgesic techniques during surgery might influence the risk of cancer recurrence. This narrative review aims to provide an updated summary of recent observational studies and new randomised controlled clinical trials on whether certain specific anaesthetic and analgesic techniques or perioperative interventions during tumour resection surgery of curative intent materially affect long-term oncologic outcomes.
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Affiliation(s)
- Orla Murphy
- Department of Anaesthesiology and Perioperative Medicine, Mater University Hospital, School of Medicine, University College Dublin, Dublin, Ireland
| | - Patrice Forget
- Epidemiology Group, Institute of Applied Health Sciences, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK; Department of Anaesthesia, NHS Grampian, Aberdeen, UK; Euro-Periscope, The ESA-IC OncoAnaesthesiology Research Group
| | - Daqing Ma
- Euro-Periscope, The ESA-IC OncoAnaesthesiology Research Group; Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, UK
| | - Donal J Buggy
- Department of Anaesthesiology and Perioperative Medicine, Mater University Hospital, School of Medicine, University College Dublin, Dublin, Ireland; Euro-Periscope, The ESA-IC OncoAnaesthesiology Research Group; Outcomes Research, Cleveland Clinic, Cleveland, OH, USA.
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7
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Gong YT, Zhang LJ, Liu YC, Tang M, Lin JY, Chen XY, Chen YX, Yan Y, Zhang WD, Jin JM, Luan X. Neutrophils as potential therapeutic targets for breast cancer. Pharmacol Res 2023; 198:106996. [PMID: 37972723 DOI: 10.1016/j.phrs.2023.106996] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 11/06/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023]
Abstract
Breast cancer (BC) remains the foremost cause of cancer mortality globally, with neutrophils playing a critical role in its pathogenesis. As an essential tumor microenvironment (TME) component, neutrophils are emerging as pivotal factors in BC progression. Growing evidence has proved that neutrophils play a Janus- role in BC by polarizing into the anti-tumor (N1) or pro-tumor (N2) phenotype. Clinical trials are evaluating neutrophil-targeted therapies, including Reparixin (NCT02370238) and Tigatuzumab (NCT01307891); however, their clinical efficacy remains suboptimal. This review summarizes the evidence regarding the close relationship between neutrophils and BC, emphasizing the critical roles of neutrophils in regulating metabolic and immune pathways. Additionally, we summarize the existing therapeutic approaches that target neutrophils, highlighting the challenges, and affirming the rationale for continuing to explore neutrophils as a viable therapeutic target in BC management.
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Affiliation(s)
- Yi-Ting Gong
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China
| | - Li-Jun Zhang
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yi-Chen Liu
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Min Tang
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jia-Yi Lin
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xin-Yi Chen
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yi-Xu Chen
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue Yan
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wei-Dong Zhang
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Pharmacy, Second Military Medical University, Shanghai 201203, China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China.
| | - Jin-Mei Jin
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Xin Luan
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Su X, Brassard A, Bartolomucci A, Dhoparee‐Doomah I, Qiu Q, Tsering T, Rohanizadeh R, Koufos O, Giannias B, Bourdeau F, Feng L, Messina‐Pacheco J, Leo S, Sangwan V, Quail D, Tankel J, Spicer J, Burnier JV, Bailey SD, Ferri L, Cools‐Lartigue J. Tumour extracellular vesicles induce neutrophil extracellular traps to promote lymph node metastasis. J Extracell Vesicles 2023; 12:e12341. [PMID: 37563798 PMCID: PMC10415595 DOI: 10.1002/jev2.12341] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 06/15/2023] [Indexed: 08/12/2023] Open
Abstract
Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastatic status. However, there is evidence suggesting that LN metastasis is facilitated by the formation of a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. Earlier work has demonstrated that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition diminishes LN metastases in animal models. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Finally, we showed that lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings reveal the role of EV-induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities that may occur early in the metastatic cascade.
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Affiliation(s)
- Xin Su
- Department of Experimental SurgeryMcGill UniversityMontrealQuebecCanada
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Department of PathologyMcGill UniversityMontrealQuebecCanada
| | - Ariane Brassard
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Department of Microbiology and ImmunologyMcGill UniversityMontrealQuebecCanada
| | - Alexandra Bartolomucci
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Department of PathologyMcGill UniversityMontrealQuebecCanada
| | - Iqraa Dhoparee‐Doomah
- Department of Experimental SurgeryMcGill UniversityMontrealQuebecCanada
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
| | - Qian Qiu
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
| | - Thupten Tsering
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Department of PathologyMcGill UniversityMontrealQuebecCanada
| | - Ramin Rohanizadeh
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
| | - Olivia Koufos
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
| | - Betty Giannias
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
| | - France Bourdeau
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
| | - Lixuan Feng
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Department of Microbiology and ImmunologyMcGill UniversityMontrealQuebecCanada
| | - Julia Messina‐Pacheco
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Department of PathologyMcGill UniversityMontrealQuebecCanada
| | - Sabrina Leo
- Department of Experimental SurgeryMcGill UniversityMontrealQuebecCanada
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
| | - Veena Sangwan
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
| | - Daniela Quail
- The Rosalind and Morris Goodman Cancer InstituteMcGill UniversityMontrealQuebecCanada
| | - James Tankel
- Division of Thoracic and Upper Gastrointestinal SurgeryMcGill UniversityMontrealQuebecCanada
| | - Jonathan Spicer
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Division of Thoracic and Upper Gastrointestinal SurgeryMcGill UniversityMontrealQuebecCanada
| | - Julia Valdemarin Burnier
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Department of PathologyMcGill UniversityMontrealQuebecCanada
| | - Swneke Donovan Bailey
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
| | - Lorenzo Ferri
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Division of Thoracic and Upper Gastrointestinal SurgeryMcGill UniversityMontrealQuebecCanada
| | - Jonathan Cools‐Lartigue
- Cancer Research ProgramResearch Institute of McGill University Health CenterMontrealQuebecCanada
- Division of Thoracic and Upper Gastrointestinal SurgeryMcGill UniversityMontrealQuebecCanada
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Shahverdi M, Masoumi J, Ghorbaninezhad F, Shajari N, Hajizadeh F, Hassanian H, Alizadeh N, Jafarlou M, Baradaran B. The modulatory role of dendritic cell-T cell cross-talk in breast cancer: Challenges and prospects. Adv Med Sci 2022; 67:353-363. [PMID: 36116207 DOI: 10.1016/j.advms.2022.09.001] [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: 05/01/2022] [Revised: 07/05/2022] [Accepted: 09/04/2022] [Indexed: 11/16/2022]
Abstract
Antigen recognition and presentation are highlighted as the first steps in developing specialized antigen responses. Dendritic cells (DCs) are outstanding professional antigen-presenting cells (APCs) responsible for priming cellular immunity in pathological states, including cancer. However, the diminished or repressed function of DCs is thought to be a substantial mechanism through which tumors escape from the immune system. In this regard, DCs obtained from breast cancer (BC) patients represent a notably weakened potency to encourage specific T-cell responses. Additionally, impaired DC-T-cell cross-talk in BC facilitates the immune evade of cancer cells and is connected with tumor advancement, immune tolerance, and adverse prognosis for patients. In this review we aim to highlight the available knowledge on DC-T-cell interactions in BC aggressiveness and show its therapeutic potential in BC treatment.
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Affiliation(s)
- Mahshid Shahverdi
- Department of Medical Biotechnology, Arak University of Medical Sciences, Arak, Iran
| | - Javad Masoumi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farid Ghorbaninezhad
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Neda Shajari
- Department of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Farnaz Hajizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Hamidreza Hassanian
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nazila Alizadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahdi Jafarlou
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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10
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Deng ZL, Zhou DZ, Cao SJ, Li Q, Zhang JF, Xie H. Development and Validation of an Inflammatory Response-Related Gene Signature for Predicting the Prognosis of Pancreatic Adenocarcinoma. Inflammation 2022; 45:1732-1751. [PMID: 35322324 DOI: 10.1007/s10753-022-01657-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 02/27/2022] [Accepted: 03/01/2022] [Indexed: 11/05/2022]
Abstract
Pancreatic adenocarcinoma (PAAD) is a highly dangerous malignant tumor of the digestive tract, and difficult to diagnose, treat, and predict the prognosis. As we all know, tumor and inflammation can affect each other, and thus the inflammatory response in the microenvironment can be used to affect the prognosis. So far, the prognostic value of inflammatory response-related genes in PAAD is still unclear. Therefore, this study aimed to explore the inflammatory response-related genes for predicting the prognosis of PAAD. In this study, the mRNA expression profiles of PAAD patients and the corresponding clinical characteristics data of PAAD patients were downloaded from the public database. The least absolute shrinkage and selection operator (LASSO) Cox analysis model was used to identify and construct the prognostic gene signature in The Cancer Genome Atlas (TCGA) cohort. The PAAD patients used for verification are from the International Cancer Genome Consortium (ICGC) cohort. The Kaplan-Meier method was used to compare the overall survival (OS) between the high- and low-risk groups. Univariate and multivariate Cox analyses were performed to identify the independent predictors of OS. Gene set enrichment analysis (GSEA) was performed to obtain gene ontology (GO) terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the correlation between gene expression and immune infiltrates was investigated via single sample gene set enrichment analysis (ssGSEA). The GEPIA database was performed to examine prognostic genes in PAAD. LASSO Cox regression analysis was used to construct a model of inflammatory response-related gene signature. Compared with the low-risk group, patients in the high-risk group had significantly lower OS. The receiver operating characteristic curve (ROC) analysis confirmed the signature's predictive capacity. Multivariate Cox analysis showed that risk score is an independent predictor of OS. Functional analysis shows that the immune status between the two risk groups is significantly different, and the cancer-related pathways were abundant in the high-risk group. Moreover, the risk score is significantly related to tumor grade, stage, and immune infiltration types. It was also obtained that the expression level of prognostic genes was significantly correlated with the sensitivity of cancer cells to anti-tumor drugs. In addition, there are significant differences in the expression of PAAD tissues and adjacent non-tumor tissues. The novel signature constructed from five inflammatory response-related genes can be used to predict prognosis and affect the immune status of PAAD. In addition, suppressing these genes may be a treatment option.
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Affiliation(s)
- Zu-Liang Deng
- Department of Radiation Oncology, Affiliated Hospital (Clinical College) of Xiangnan University, Chenzhou, 423000, People's Republic of China
| | - Ding-Zhong Zhou
- Department of Interventional Vascular Surgery, Affiliated Hospital (Clinical College) of Xiangnan University, Chenzhou, 423000, People's Republic of China
| | - Su-Juan Cao
- Department of Oncology, Affiliated Hospital (Clinical College) of Xiangnan University, Chenzhou, 423000, People's Republic of China
| | - Qing Li
- Department of Interventional Vascular Surgery, Affiliated Hospital (Clinical College) of Xiangnan University, Chenzhou, 423000, People's Republic of China
| | - Jian-Fang Zhang
- Department of Physical Examination, Beihu Centers for Disease Control and Prevention, Chenzhou, 423000, People's Republic of China
| | - Hui Xie
- Department of Radiation Oncology, Affiliated Hospital (Clinical College) of Xiangnan University, Chenzhou, 423000, People's Republic of China.
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11
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Kim GT, Kim EY, Shin SH, Lee H, Lee SH, Sohn KY, Kim JW. Improving anticancer effect of aPD-L1 through lowering neutrophil infiltration by PLAG in tumor implanted with MB49 mouse urothelial carcinoma. BMC Cancer 2022; 22:727. [PMID: 35787261 PMCID: PMC9251917 DOI: 10.1186/s12885-022-09815-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Accepted: 06/21/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The PD-L1 antibody is an immune checkpoint inhibitor (ICI) attracting attention. The third-generation anticancer drug has been proven to be very effective due to fewer side effects and higher tumor-specific reactions than conventional anticancer drugs. However, as tumors produce additional resistance in the host immune system, the effectiveness of ICI is gradually weakening. Therefore, it is very important to develop a combination therapy that increases the anticancer effect of ICI by removing anticancer resistance factors present around the tumor. METHODS The syngeneic model was used (n = 6) to investigate the enhanced anti-tumor effect of PD-L1 antibody with the addition of PLAG. MB49 murine urothelial cancer cells were implanted into the C57BL/6 mice subcutaneously. PLAG at different dosages (50/100 mpk) was daily administered orally for another 4 weeks with or without 5 mpk PD-L1 antibody (10F.9G2). PD-L1 antibody was delivered via IP injection once a week. RESULTS The aPD-L1 monotherapy group inhibited tumor growth of 56% compared to the positive group, while the PLAG and aPD-L1 co-treatment inhibited by 89%. PLAG treatment effectively reduced neutrophils infiltrating localized in tumor and converted to a tumor microenvironment with anti-tumor effective T-cells. PLAG increased tumor infiltration of CD8 positive cytotoxic T-cell populations while effectively inhibiting the infiltration of neoplastic T-cells such as CD4/FoxP3. Eventually, neutrophil-induced tumor ICI resistance was resolved by restoring the neutrophil-to-lymphocyte ratio to the normal range. In addition, regulation of cytokine and chemokine factors that inhibit neutrophil infiltration and increase the killing activity of cytotoxic T cells was observed in the tumors of mice treated with PLAG + aPD-L1. CONCLUSIONS PLAG effectively turned the tumor-promoting microenvironment into a tumor-suppressing microenvironment. As a molecule that increases the anti-tumor effectiveness of aPD-L1, PLAG has the potential to be an essential and effective ICI co-therapeutic agent.
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Affiliation(s)
- Guen Tae Kim
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Eun Young Kim
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Su-Hyun Shin
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Hyowon Lee
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Se Hee Lee
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Ki-Young Sohn
- Enzychem Lifesciences, 10F aT Center 27 Gangnam-daero, Seoul, South Korea
| | - Jae Wha Kim
- grid.249967.70000 0004 0636 3099Division of Systems Biology and Bioengineering, Cell Factory Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), 125 Kwahak-ro, Daejeon, South Korea
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Li H, Hu Y, Liu D, Wang J, Han P, Zhang N, Li Y. Bioinformatic Characterization of Whole Blood Neutrophils in Pelvic Inflammatory Disease: A Potential Prognostic Indicator for Transumbilical Single-Port Laparoscopic Pelvic Abscess Surgery. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:2555603. [PMID: 35401780 PMCID: PMC8993565 DOI: 10.1155/2022/2555603] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/31/2021] [Accepted: 01/11/2022] [Indexed: 12/19/2022]
Abstract
The purpose of this research is to determine the prognosis of patients treated with transumbilical single-port laparoscopic surgery for acute pelvic inflammatory illness. Postoperative data on 129 patients treated with laparoscopic surgery for acute pelvic inflammatory illness were obtained retrospectively. It was observed that the shorter the time required for postoperative leukocyte recovery to normal, the shorter the time required for postoperative pain and diet recovery, as well as hospital stay, in such individuals. CIBERSORT was used to examine patient data from GEO. The most significant difference between the normal and pelvic inflammatory groups was in neutrophil content. Association study found a substantial positive correlation between the quantity of neutrophils infiltrating the immune system and the abundance of monocyte M0 infiltrating the immune system. Neutrophil immune infiltration was strongly inversely linked with plasma cells, activated CD8+ Tm cells, and active CD4+ Tm cells. Four mRNAs linked with pelvic inflammatory illness were revealed to be strongly associated with neutrophil immune infiltration, notably CALML4, COQ10B, DCPS, and PPP2R1A. The ROC revealed that CALML4 (area under the curve (AUC): 0.769, 95% confidence interval (CI): 0.638-0.881), COQ10B (AUC: 0.742, 95% CI: 0.587-0.881), PPP2R1A (AUC: 0.733 95% CI: 0.593-0.857), and DCPS (AUC: 0.745, 95% CI: 0.571-0.900) were potential markers for predicting pelvic inflammatory disease. CALML4, COQ10B, PPP2R1A, and DCPS may be critical determinants determining the amount of preoperative neutrophil infiltration and the time required for leukocyte recovery after single-port laparoscopy in acute pelvic inflammatory illness.
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Affiliation(s)
- Haining Li
- General Hospital of Ningxia Medical University, China
| | | | - Dan Liu
- General Hospital of Ningxia Medical University, China
| | | | | | | | - Yan Li
- General Hospital of Ningxia Medical University, China
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13
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Coagulome and the tumor microenvironment: an actionable interplay. Trends Cancer 2022; 8:369-383. [PMID: 35027336 DOI: 10.1016/j.trecan.2021.12.008] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 11/19/2021] [Accepted: 12/15/2021] [Indexed: 12/14/2022]
Abstract
Human tumors often trigger a hypercoagulable state that promotes hemostatic complications, including venous thromboembolism. The recent application of systems biology to the study of the coagulome highlighted its link to shaping the tumor microenvironment (TME), both within and outside of the vascular space. Addressing this link provides the opportunity to revisit the significance of biomarkers of hemostasis and assess the communication between vasculature and tumor parenchyma, an important topic considering the advent of immune checkpoint inhibitors and vascular normalization strategies. Understanding how the coagulome and TME influence each other offers exciting new prospects for predicting hemostatic complications and boosting the effectiveness of cancer treatment.
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Identification of Prognostic Metabolism-Related Genes in Clear Cell Renal Cell Carcinoma. JOURNAL OF ONCOLOGY 2021; 2021:2042114. [PMID: 34616452 PMCID: PMC8490028 DOI: 10.1155/2021/2042114] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 09/13/2021] [Indexed: 01/05/2023]
Abstract
Background Clear cell renal cell carcinoma (ccRCC) is a cancer with abnormal metabolism. The purpose of this study was to investigate the effect of metabolism-related genes on the prognosis of ccRCC patients. Methods The data of ccRCC patients were downloaded from the TCGA and the GEO databases and clustered using the nonnegative matrix factorization method. The limma software package was used to analyze differences in gene expression. A random forest model was used to screen for important genes. A novel Riskscore model was established using multivariate regression. The model was evaluated based on the metabolic pathway, immune infiltration, immune checkpoint, and clinical characteristics. Results According to metabolism-related genes, kidney clear cell carcinoma (KIRC) datasets downloaded from TCGA were clustered into two groups and showed significant differences in prognosis and immune infiltration. There were 667 differentially expressed genes between the two clusters, of which 408 were screened by univariate analysis. Finally, 12 differentially expressed genes (MDK, SLC1A1, SGCB, C4orf3, MALAT1, PILRB, IGHG1, FZD1, IFITM1, MUC20, KRT80, and SALL1) were filtered out using the random forest model. The model of Riskscore was obtained by multiplying the expression levels of these 12 genes with the corresponding coefficients of the multivariate regression. We found that the Riskscore correlated with the expression of these 12 genes; the high Riskscore matched the low survival rate verified in the verification set. The analysis found that the Riskscore model was associated with most of the metabolic processes, immune infiltration of cells such as plasma cells, immune checkpoints such as PD-1, and clinical characteristics such as M stage. Conclusion We established a new Riskscore model for the prognosis of ccRCC based on metabolism. The genes in the model provided several novel targets for the study of ccRCC.
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15
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Sionov RV. Leveling Up the Controversial Role of Neutrophils in Cancer: When the Complexity Becomes Entangled. Cells 2021; 10:cells10092486. [PMID: 34572138 PMCID: PMC8465406 DOI: 10.3390/cells10092486] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Revised: 09/12/2021] [Accepted: 09/15/2021] [Indexed: 12/13/2022] Open
Abstract
Neutrophils are the most abundant immune cell in the circulation of human and act as gatekeepers to discard foreign elements that have entered the body. They are essential in initiating immune responses for eliminating invaders, such as microorganisms and alien particles, as well as to act as immune surveyors of cancer cells, especially during the initial stages of carcinogenesis and for eliminating single metastatic cells in the circulation and in the premetastatic organs. Since neutrophils can secrete a whole range of factors stored in their many granules as well as produce reactive oxygen and nitrogen species upon stimulation, neutrophils may directly or indirectly affect carcinogenesis in both the positive and negative directions. An intricate crosstalk between tumor cells, neutrophils, other immune cells and stromal cells in the microenvironment modulates neutrophil function resulting in both anti- and pro-tumor activities. Both the anti-tumor and pro-tumor activities require chemoattraction towards the tumor cells, neutrophil activation and ROS production. Divergence is seen in other neutrophil properties, including differential secretory repertoire and membrane receptor display. Many of the direct effects of neutrophils on tumor growth and metastases are dependent on tight neutrophil–tumor cell interactions. Among them, the neutrophil Mac-1 interaction with tumor ICAM-1 and the neutrophil L-selectin interaction with tumor-cell sialomucins were found to be involved in the neutrophil-mediated capturing of circulating tumor cells resulting in increased metastatic seeding. On the other hand, the anti-tumor function of neutrophils was found to rely on the interaction between tumor-surface-expressed receptor for advanced glycation end products (RAGE) and Cathepsin G expressed on the neutrophil surface. Intriguingly, these two molecules are also involved in the promotion of tumor growth and metastases. RAGE is upregulated during early inflammation-induced carcinogenesis and was found to be important for sustaining tumor growth and homing at metastatic sites. Cathepsin G was found to be essential for neutrophil-supported lung colonization of cancer cells. These data level up the complexity of the dual role of neutrophils in cancer.
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Affiliation(s)
- Ronit Vogt Sionov
- Hadassah Medical School, The Hebrew University of Jerusalem, Ein Kerem Campus, P.O.B. 12272, Jerusalem 9112102, Israel
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16
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Wall TP, Buggy DJ. Perioperative Intravenous Lidocaine and Metastatic Cancer Recurrence - A Narrative Review. Front Oncol 2021; 11:688896. [PMID: 34408981 PMCID: PMC8365881 DOI: 10.3389/fonc.2021.688896] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/15/2021] [Indexed: 12/17/2022] Open
Abstract
Cancer is a major global health problem and the second leading cause of death worldwide. When detected early, surgery provides a potentially curative intervention for many solid organ tumours. Unfortunately, cancer frequently recurs postoperatively. Evidence from laboratory and retrospective clinical studies suggests that the choice of anaesthetic and analgesic agents used perioperatively may influence the activity of residual cancer cells and thus affect subsequent recurrence risk. The amide local anaesthetic lidocaine has a well-established role in perioperative therapeutics, whether used systemically as an analgesic agent or in the provision of regional anaesthesia. Under laboratory conditions, lidocaine has been shown to inhibit cancer cell behaviour and exerts beneficial effects on components of the inflammatory and immune responses which are known to affect cancer biology. These findings raise the possibility that lidocaine administered perioperatively as a safe and inexpensive intravenous infusion may provide significant benefits in terms of long term cancer outcomes. However, despite the volume of promising laboratory data, robust prospective clinical evidence supporting beneficial anti-cancer effects of perioperative lidocaine treatment is lacking, although trials are planned to address this. This review provides a state of the art summary of the current knowledge base and recent advances regarding perioperative lidocaine therapy, its biological effects and influence on postoperative cancer outcomes.
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Affiliation(s)
- Thomas P Wall
- Department of Anaesthesiology, Mater Misericordiae University Hospital, School of Medicine, University College Dublin, Dublin, Ireland.,EU COST Action 15204, Euro-Periscope, Brussels, Belgium
| | - Donal J Buggy
- Department of Anaesthesiology, Mater Misericordiae University Hospital, School of Medicine, University College Dublin, Dublin, Ireland.,EU COST Action 15204, Euro-Periscope, Brussels, Belgium.,Outcomes Research, Cleveland Clinic, Cleveland, OH, United States
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Li WC, Wang Z, Gao J, Zhou H, Li J, Zhu XX. Clinical Outcomes and Prognostic Factors of Salvage Stereotactic Body Radiotherapy for Post-Surgical Thoracic Oligo-Recurrence/Metastasis of Non-Small-Cell Lung Cancer. Cancer Manag Res 2021; 13:1887-1896. [PMID: 33654433 PMCID: PMC7914053 DOI: 10.2147/cmar.s287993] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 01/21/2021] [Indexed: 12/25/2022] Open
Abstract
Purpose The study aimed to assess the efficacy and safety of stereotactic body radiotherapy (SBRT) using CyberKnife (CK) in patients with postoperative thoracic oligo-recurrence/metastasis of non-small-cell lung cancer (NLCLC), and to analyze the prognostic factors affecting overall survival after SBRT. Patients and Methods A total of 44 patients with postoperative thoracic oligo-recurrence/metastatic of NLCLC treated with SBRT were reviewed. Thoracic oligo-recurrence/was defined as 1–3 loco-regional confined to lung lobe, hilar/mediastinal lymph nodes, bronchial stump, or chest wall. Primary endpoints included local control (LC), overall survival (OS), progression-free survival (PFS) and toxicity. Prognostic factors that affected these patients were analyzed by the univariate and multivariate analysis by Kaplan–Meier methods and Cox regression models, respectively. Results The median follow-up time after salvage SBRT was 48.5 months. Measuring from the date of salvage SBRT, the median OS of the 44 patients was 52.60 (95% CI: 29.59–75.60) months. 1-,3-and 5-year OS rates were 97.7%, 65.3% and 47.7%, respectively. The 1-,3-year and 5-year LC rates were 97.7%, 85.1% and 80.1%, respectively. At 1, 3 and 5 years, the PFS rates were 77.1%, 28.8% and 5.3%, respectively. Multivariate analysis demonstrated that pre-SBRT neutrophil-to-lymphocyte ratio (NLR) and Charlson comorbidity index (CCI) were independent prognostic factors (p < 0.05). The treatment-related side-effects were well tolerated. No patients developed grade 3 or greater pulmonary toxicity. Conclusion SBRT is a promising salvage therapeutic option for postoperative thoracic oligo-recurrence/metastasis of non-small-cell lung cancer with acceptable toxicity. Low pre-SBRT neutrophil-to-lymphocyte ratio (NLR) and low Charlson comorbidity index (CCI) were associated with a better prognosis and longer survival and might be considered as reliable and independent prognostic factors in these patients treated with SBRT.
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Affiliation(s)
- Wen-Cai Li
- Department of Radiation Oncology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhen Wang
- Department of Medical Radiation Oncology, Jinling Hospital, Nanjing, Jiangsu, 210002, People's Republic of China
| | - Jie Gao
- Department of Medical Radiation Oncology, Jinling Hospital, Nanjing, Jiangsu, 210002, People's Republic of China
| | - Han Zhou
- Department of Medical Radiation Oncology, Jinling Hospital, Nanjing, Jiangsu, 210002, People's Republic of China
| | - Jing Li
- Department of Medical Radiation Oncology, Jinling Hospital, Nanjing, Jiangsu, 210002, People's Republic of China
| | - Xi-Xu Zhu
- Department of Medical Radiation Oncology, Jinling Hospital, First School of Clinical Medicine, Southern Medical University, Nanjing, Jiangsu, 210002, People's Republic of China
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Boulter L, Bullock E, Mabruk Z, Brunton VG. The fibrotic and immune microenvironments as targetable drivers of metastasis. Br J Cancer 2021; 124:27-36. [PMID: 33239677 PMCID: PMC7782519 DOI: 10.1038/s41416-020-01172-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2020] [Revised: 10/29/2020] [Accepted: 11/02/2020] [Indexed: 02/06/2023] Open
Abstract
Although substantial progress has been made over the past 40 years in treating patients with cancer, effective therapies for those who are diagnosed with advanced metastatic disease are still few and far between. Cancer cells do not exist in isolation: rather, they exist within a complex microenvironment composed of stromal cells and extracellular matrix. Within this tumour microenvironment exists an interplay between the two main stromal cell subtypes, cancer-associated fibroblasts (CAFs) and immune cells, that are important in controlling metastasis. A complex network of paracrine signalling pathways between CAFs, immune cells and tumour cells are involved at multiple stages of the metastatic process, from invasion and intravasation at the primary tumour site to extravasation and colonisation in the metastatic site. Heterogeneity and plasticity within stromal cell populations also contribute to the complexity. Although many of these processes are likely to be common to a number of metastatic sites, we will describe in detail the interplay within the liver, a preferred site of metastasis for many tumours. A greater understanding of these networks provides opportunities for the design of new therapeutic approaches for targeting the metastatic disease.
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Affiliation(s)
- Luke Boulter
- MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - Esme Bullock
- Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - Zeanap Mabruk
- Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK
| | - Valerie G Brunton
- Edinburgh Cancer Research UK Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Crewe Road South, Edinburgh, EH4 2XU, UK.
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