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Beypınar İ, Urvay S, Ürün M, Erçek B, Demir H, Yıldız C, Araz M, Oruç A, Özilice U, Balçık OY. Prognostic value of IMDC score in non-small cell lung cancer receiving immunotherapy: old dog, new tricks? : IMDC in lung cancer immunotherapy. Eur J Clin Pharmacol 2025; 81:561-570. [PMID: 39971806 DOI: 10.1007/s00228-025-03810-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/10/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Although there are multiple treatment options, oncologists lack appropriate biomarkers for determining the efficacy and toxicity of immunotherapy. In this study, we aimed to use a combination of the clinical parameters of IMDC risk groups at the time of diagnosis to predict the effectiveness of immunotherapy. METHODS This multicenter cross-sectional study retrospectively analyzed non-small cell lung cancer (NSCLC) patients receiving nivolumab for the prognostic effects of clinical factors, including the IMDC score. RESULTS Two hundred and five patients were enrolled in this study. There was no favorable group because the TTI was less than 1 year in the entire study group in the IMDC. The IMDC score and IMDC groups showed significant differences in PFS (p < 0.001; p < 0.001, respectively). Intermediate and poor-risk groups had PFS of 8 and 3 months PFS, respectively. The IMDC group showed a significant effect on OS (p = 0.002). The intermediate- and poor-risk groups had 12- and 4-month OS, respectively. The TTI risk factor excluded patient numbers in the favorable, intermediate, and poor risk groups were 47, 129, and 29, respectively, in the revised IMDC group (rIMDC). The prognostic effect of the rIMDC score and groups remained significant (p < 0.001 and p < 0.001, respectively). The classical IMDC had a significant effect on PFS in the multivariate analysis (p = 0.016). Also, rIMDC score in multivariate analysis resulted with significant effect on OS (p = 0.035). CONCLUSION To date, this is the first study to prove that the IMDC may be a valuable option for predicting both prognosis and treatment efficacy in NSCLC patients receiving especially second or further lines nivolumab treatment.
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Affiliation(s)
- İsmail Beypınar
- Department of Oncology, Alanya Alaaddin Keykubat University, Kestel, Merines Cd., Alanya, 07450, Antalya, Turkey.
| | - Semiha Urvay
- Department of Medical Oncology, Kayseri Acıbadem Hospital, Kayseri, Turkey
| | - Müslih Ürün
- Department of Medical Oncology, Van Yüzüncü Yıl University, Van, Turkey
| | - Berrak Erçek
- Department of Medical Oncology, Van Yüzüncü Yıl University, Van, Turkey
| | - Hacer Demir
- Department of Medical Oncology, Afyonkarahisar Health Sciences University, Afyon, Turkey
| | - Canan Yıldız
- Department of Medical Oncology, Afyonkarahisar Health Sciences University, Afyon, Turkey
| | - Murat Araz
- Department of Medical Oncology, Necmettin Erbakan University, Konya, Turkey
| | - Ahmet Oruç
- Department of Medical Oncology, Necmettin Erbakan University, Konya, Turkey
| | - Utku Özilice
- Department of Internal Medicine, Alanya Alaaddin Keykubat University, Alanya, Turkey
| | - Onur Yazdan Balçık
- Department of Oncology, Alanya Alaaddin Keykubat University, Kestel, Merines Cd., Alanya, 07450, Antalya, Turkey
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2
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Nie P, Chen K, Tian C, Xu E, Xue Q, Song J, Wang P. Tetrahedral DNA-Enhanced Interparticle Rolling Machine for High-Efficiency Human Neutrophil Elastase SERS Ratiometric Sensing in Serum and Tissue. ACS Sens 2025; 10:2367-2377. [PMID: 40047041 DOI: 10.1021/acssensors.5c00228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
The development of DNA rolling machines with high rolling efficiency for ratiometric biosensing is of great significance for the accurate diagnosis and evaluation of diseases. Herein, an interparticle DNA rolling machine constructed by well-oriented and ordered DNA nanorollers guided by tetrahedral DNA was exploited for high-efficiency lung tumor-related human neutrophil elastase (HNE) SERS ratiometric sensing. In this design, tetrahedral DNA with blocked DNAzyme was assembled on AuNPs to engineer well-oriented and ordered walking DNA nanorollers (WDNs) endowed with high collision efficiency and accessibility, significantly improving the reaction kinetics and rolling efficiency. When the DNAzyme "leg DNA" on WDNs were activated through the multivalent DNA converted by target HNE, the activated WDNs with polyoriented walkers rolled efficiently along directional hairpin "track DNA" on magnetic NPs (H1@MNPs) that served as continuously "cleaving-rolling-assembly" specific substrates (CRAS), constructing an interparticle rolling machine and finally converting HNE into a ratiometric SERS signal in a nanogap-rich silver nanoisland substrate. The CRAS increased the reaction direction and local concentration, improving the accessibility and signal. The interparticle relative motion with nonplanar polyoriented walking arms weakens the derailment of rolling "leg DNA", improves the processivity, and amplifies capability. Moreover, nanogap-rich silver nanoisland SERS substrates promote the formation of high-density hot spot domains, further improving the detection sensitivity. Of note, the rolling machine ratiometric biosensor successfully measures the HNE with a detection limit of 0.25 pM and can screen inhibitors and discriminate the HNE levels in serum and tissue of normal and lung tumor patients, suggesting that the biosensor provides an effective tool for early diagnosis, prognostic evaluation, and drug discovery of lung tumor.
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Affiliation(s)
- Ping Nie
- Department of Chemistry, Liaocheng University, Liaocheng 252059, Shandong, P. R. China
| | - Ke Chen
- Department of Biotechnology, College of Engineering, The University of Suwon, Hwaseong 18323, Korea
| | - Chengxin Tian
- Department of Chemistry, Liaocheng University, Liaocheng 252059, Shandong, P. R. China
| | - Ensheng Xu
- Department of Chemistry, Liaocheng University, Liaocheng 252059, Shandong, P. R. China
| | - Qingwang Xue
- Department of Chemistry, Liaocheng University, Liaocheng 252059, Shandong, P. R. China
| | - Jibin Song
- State Key Laboratory of Chemical Resource Engineering, College of Chemistry, Beijing University of Chemical Technology, Beijing 10010, P. R. China
| | - Pin Wang
- Neurology of Department, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250033, P. R. China
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Zhong R, He H, Wang X. Novel neutrophil targeting platforms in treating Glioblastoma: Latest evidence and therapeutic approaches. Int Immunopharmacol 2025; 150:114173. [PMID: 39938169 DOI: 10.1016/j.intimp.2025.114173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 01/22/2025] [Accepted: 01/23/2025] [Indexed: 02/14/2025]
Abstract
Glioblastoma (GBM) is the most aggressive and lethal type of primary brain tumor, characterized by its rapid growth, resistance to conventional therapies, and a highly immunosuppressive tumor microenvironment (TME). Recent studies have highlighted the critical role of neutrophils in the progression of GBM, where they contribute to tumor growth, invasion, and treatment resistance. As a result, neutrophils have emerged as a promising target for therapeutic intervention in GBM. Various strategies are being investigated to specifically target neutrophils within the GBM environment, including using small molecules, antibodies, and nanoparticle-based methods. These approaches aim to regulate neutrophils' recruitment, activation, and functions. This study reviews the latest findings regarding the involvement of neutrophils in GBM, explores potential techniques targeting neutrophils for therapeutic purposes, and discusses current clinical studies and prospects in this rapidly evolving field. By studying the diverse functions of neutrophils in GBM, these innovative therapeutic strategies can help address some of the most significant challenges in treating this malignancy.
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Affiliation(s)
- Rui Zhong
- Department of Neurosurgery, The First People's Hospital of Lin'an District, Hangzhou 311300, China
| | - Hongmei He
- Department of Neurosurgery, The First People's Hospital of Lin'an District, Hangzhou 311300, China
| | - Xiande Wang
- Department of Neurosurgery, The First People's Hospital of Lin'an District, Hangzhou 311300, China.
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Li H, Chen N, Wang W, Ye L, Fan Y, Xu X. Investigating the impact of the inflammatory immune microenvironment and steroids or COX-2 inhibitors usage on immunotherapy in advanced esophageal squamous cell carcinoma (ESCC): a propensity score matched analysis. Clin Transl Oncol 2025; 27:1105-1117. [PMID: 39177940 DOI: 10.1007/s12094-024-03668-1] [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: 05/18/2024] [Accepted: 08/07/2024] [Indexed: 08/24/2024]
Abstract
PURPOSE The research aimed to evaluate the connection between pre-treatment inflammatory biomarkers and clinical results in advanced esophageal squamous cell carcinoma (ESCC) receiving immune checkpoint inhibitors. MATERIALS AND METHODS Between 2019 and 2022, we analyzed 354 individuals diagnosed with metastatic ESCC who underwent immunotherapy. The study sought to evaluate the impact of specific inflammatory biomarkers (Neutrophil/Lymphocyte Ratio (NLR), C-reactive protein to albumin ratio (CRP/ALB) and Glasgow Prognostic Score (GPS), Cyclooxygenase-2 (COX-2) inhibitors or steroids usage on the effectiveness and survival outcomes of immunotherapy in advanced ESCC. The research utilized Kaplan‒Meier and Cox regression models alongside propensity score matching for analysis. RESULTS The findings revealed that elevated pre-treatment NLR (11.0 vs. 14.6 months, p = 0.021) and CRP/ALB (11.4 vs. 14.6 months, p = 0.022) levels were significantly associated with poorer overall survival (OS) outcomes, while the use of steroids did not show a significant difference in OS (15.5 vs. 15.4 months, p = 0.685) between groups. Similarly, no notable disparity in OS was observed between patients treated withCOX-2 inhibitors and those who were not (13.8 vs. 11.0 months, p = 0.054). CONCLUSION Lower levels of NLR and CRP/ALB prior to treatment were linked to better effectiveness and OS in immunotherapy for advanced ESCC. The study did not identify a significant relationship between OS in patients with esophageal cancer and the use of either steroids or COX-2 inhibitors.
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Affiliation(s)
- Huihui Li
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Road, Yangpu District, Shanghai, 200433, China
- Postgraduate Training Base Alliance, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Ning Chen
- Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, No. 1 Banshan East Road, Gongshu District, Hangzhou, 310022, Zhejiang, China
- Department of Oncology, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Wenjing Wang
- Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, No. 1 Banshan East Road, Gongshu District, Hangzhou, 310022, Zhejiang, China
- Postgraduate Training Base Alliance, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Lisha Ye
- Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, No. 1 Banshan East Road, Gongshu District, Hangzhou, 310022, Zhejiang, China
- Postgraduate Training Base Alliance, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Yun Fan
- Department of Medical Thoracic Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, No. 1 Banshan East Road, Gongshu District, Hangzhou, 310022, Zhejiang, China.
- Department of Oncology, The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
| | - Xiaoling Xu
- Department of Radiation Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, 507 Zhengmin Road, Yangpu District, Shanghai, 200433, China.
- Postgraduate Training Base Alliance, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
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Jędrzejewski T, Sobocińska J, Maciejewski B, Spisz P, Walczak-Skierska J, Pomastowski P, Wrotek S. In vitro treatment of triple-negative breast cancer cells with an extract from the Coriolus versicolor mushroom changes macrophage properties related to tumourigenesis. Immunol Res 2024; 73:14. [PMID: 39680299 DOI: 10.1007/s12026-024-09574-6] [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: 05/06/2024] [Accepted: 10/21/2024] [Indexed: 12/17/2024]
Abstract
Macrophages, the most abundant cells that participate in tumour progression, are the subject of a number of anticancer therapy approaches. Our previous results revealed that an extract of the fungus Coriolus versicolor (CV) has anti-cancer and immunomodulatory properties. The aim of the present study was to investigate whether CV extract-treated triple-negative breast cancer (TNBC) cells can release factors that can reprogram macrophages from pro-tumourigenic to anti-cancer subtypes. RAW 264.7 macrophages were cultured in a conditioned medium (CM) from non-treated 4T1 breast cancer cells (CM-NT) or CV extract-stimulated cells (CM-CV). After treatment, the following macrophage properties were evaluated: cell viability; M1/M2 phenotype (enzyme activities: iNOS and arginase 1; and expression of CD molecules: CD80 and CD163); cytokine concentrations: IL-6, TNF-α, IL-10, TGF-β, MCP-1 and VEGF; migration level; and ROS production. The results revealed that, compared with normal cells, TNBC cells stimulated with CV extract create a microenvironment that promotes a decrease in macrophage viability and migration, intracellular ROS production, and pro-angiogenic cytokine production (VEGF and MCP-1). Moreover, CM-CV decreased the expression of M2 macrophage markers (arginase 1 and CD163; IL-10 and TGF-β) but upregulated the expression of M1 cell markers (iNOS and CD80; IL-6 and TNF-α). We concluded that CV extract modifies the tumour microenvironment and changes macrophage polarisation toward functioning as an anti-tumour agent. Therefore, it is promising to use in the treatment of TNBC-associated macrophages.
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Affiliation(s)
- Tomasz Jędrzejewski
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland.
| | - Justyna Sobocińska
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland
| | - Bartosz Maciejewski
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland
| | - Paulina Spisz
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland
| | - Justyna Walczak-Skierska
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University in Toruń, Wileńska 4 Street, 87-100, Toruń, Poland
| | - Paweł Pomastowski
- Centre for Modern Interdisciplinary Technologies, Nicolaus Copernicus University in Toruń, Wileńska 4 Street, 87-100, Toruń, Poland
- Department of Inorganic and Coordination Chemistry, Nicolaus Copernicus University in Toruń, Gagarina 7 Street, 87-100, Toruń, Poland
| | - Sylwia Wrotek
- Department of Immunology, Faculty of Biological and Veterinary Sciences, Nicolaus Copernicus University, Lwowska 1 Street, 87-100, Toruń, Poland
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Weerasinghe HN, Burrage PM, Jr DVN, Burrage K. Agent-based modeling for the tumor microenvironment (TME). MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2024; 21:7621-7647. [PMID: 39696854 DOI: 10.3934/mbe.2024335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2024]
Abstract
Cancer is a disease that arises from the uncontrolled growth of abnormal (tumor) cells in an organ and their subsequent spread into other parts of the body. If tumor cells spread to surrounding tissues or other organs, then the disease is life-threatening due to limited treatment options. This work applies an agent-based model to investigate the effect of intra-tumoral communication on tumor progression, plasticity, and invasion, with results suggesting that cell-cell and cell-extracellular matrix (ECM) interactions affect tumor cell behavior. Additionally, the model suggests that low initial healthy cell densities and ECM protein densities promote tumor progression, cell motility, and invasion. Furthermore, high ECM breakdown probabilities of tumor cells promote tumor invasion. Understanding the intra-tumoral communication under cellular stress can potentially lead to the design of successful treatment strategies for cancer.
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Affiliation(s)
- Hasitha N Weerasinghe
- School of Mathematical Sciences, Queensland University of Technology, Queensland, Brisbane, Australia
| | - Pamela M Burrage
- School of Mathematical Sciences, Queensland University of Technology, Queensland, Brisbane, Australia
| | - Dan V Nicolau Jr
- School of Immunology and Microbial Sciences, King's College London, London, United Kingdom
| | - Kevin Burrage
- School of Mathematical Sciences, Queensland University of Technology, Queensland, Brisbane, Australia
- Department of Computer Science, University of Oxford, United Kingdom
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7
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Wang K, Wang X, Song L. Unraveling the complex role of neutrophils in lymphoma: From pathogenesis to therapeutic approaches (Review). Mol Clin Oncol 2024; 21:85. [PMID: 39347476 PMCID: PMC11428085 DOI: 10.3892/mco.2024.2783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Accepted: 08/21/2024] [Indexed: 10/01/2024] Open
Abstract
Lymphoma, a malignancy of the lymphatic system, which is critical for maintaining the body's immune defenses, has become a focal point in recent research due to its intricate interplay with neutrophils-white blood cells essential for combating infections and inflammation. Unlike prior perceptions associating neutrophils only with tumor support, contemporary studies underscore their intricate and multifaceted involvement in the immune response to lymphoma. Recognizing the nuanced participation of neutrophils in lymphoma is crucial for developing innovative treatments to improve patient outcomes.
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Affiliation(s)
- Ke Wang
- Department of Cell Engineering, School of Life Sciences and Biotechnology, Sanquan College of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
| | - Xiao Wang
- Reproduction Medicine Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, Guangdong 524002, P.R. China
| | - Li Song
- Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Sanquan College of Xinxiang Medical University, Xinxiang, Henan 453003, P.R. China
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Du H, Xu E, Xu Y, Xue Q, Xu H, Song J. 3D DNAzyme Motor Nanodevice With Self-Powered FRET Amplifier and Self-Supplied H 2O 2 for Enhancing Human Neutrophil Elastase Profiling and Chemodynamic Therapy in Lung Tumor. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2406599. [PMID: 39348241 PMCID: PMC11600284 DOI: 10.1002/advs.202406599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 08/05/2024] [Indexed: 10/02/2024]
Abstract
The development of theragnostic nanosystems integrating FRET (fluorescence resonance energy transfer) imaging and chemodynamic therapy (CDT) for accurate diagnosis and effective treatment of lung tumors is still a big challenge. Herein, a peptide-assembled 3D DNAzyme motor nanodevice is engineered for a self-powered FRET amplifier profiling human neutrophil elastase (HNE) and self-supplied H2O2 enhancing CDT. The nanodevice is prepared by depositing AuNPs on ZIF-8, in which ZIF-8 co-loaded the lysosomal targeting peptide-modified copper peroxides (PCPs) and hairpins (H1, H2, and H3), AuNPs are co-labeled by DNAzyme-peptide (DP) conjugate and H3. In the tumor micro-environment, HNE driven 3D DNAzyme walker followed by an exponential amplification constructed by a synergistic cross-activation between hybridization chain reaction and DNAzyme, generating a self-powered FRET amplifier. The FRET amplifier specifically measures HNE with a sensitivity of 0.026 pM, and successfully images exogenous HNE in living cells and monitors HNE in mouse models. Moreover, the PCPs can target lysosomes, reducing lysosome escape. The self-supplying H2O2 undertaken by PCPs improves the Cu (II)-catalyzed Fenton-like reaction, effectively causing cell apoptosis to inhibit tumor growth. Significantly, the nanodevice successfully screens inhibitors and discriminates the HNE level in normal and lung cancer tissues, suggesting that the nanodevice provides an effective tool for the diagnosis and treatment of lung tumors.
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Affiliation(s)
- Huiyan Du
- Department of ChemistryLiaocheng UniversityLiaochengShandong252059P. R. China
| | - Ensheng Xu
- Department of ChemistryLiaocheng UniversityLiaochengShandong252059P. R. China
| | - Yihan Xu
- Department of ChemistryLiaocheng UniversityLiaochengShandong252059P. R. China
| | - Qingwang Xue
- Department of ChemistryLiaocheng UniversityLiaochengShandong252059P. R. China
| | - Hongxia Xu
- Department of Clinical LaboratoryThe Third People's Hospital of LiaochengLiaochengShandong252059P. R. China
| | - Jibin Song
- State Key Laboratory of Chemical Resource EngineeringCollege of ChemistryBeijing University of Chemical TechnologyBeijing10010P. R. China
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Huang J, Lin L, Mao D, Hua R, Guan F. Prognostic value of neutrophil-to-lymphocyte ratio in patients with non-muscle-invasive bladder cancer with intravesical Bacillus Calmette-Guérin immunotherapy: a systematic review and meta-analysis. Front Immunol 2024; 15:1464635. [PMID: 39507536 PMCID: PMC11538002 DOI: 10.3389/fimmu.2024.1464635] [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: 07/16/2024] [Accepted: 10/03/2024] [Indexed: 11/08/2024] Open
Abstract
Background The predictive accuracy of the preoperative neutrophil-to-lymphocyte ratio (NLR) on the prognosis of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical Bacillus Calmette-Guérin immunotherapy (BCG) after transurethral resection of the bladder tumor (TURBT) remains unknown. Therefore, the current study performed a systematic review and meta-analysis to examine the relationship between preoperative NLR and the prognosis of patients with NMIBC with intravesical BCG immunotherapy. Methods For this systematic review and meta-analysis, articles were retrieved from PubMed, Cochrane Library, Web of Science, and Embase databases from their inception to 14 May 2024. The role of NLR in predicting recurrence and progression in NMIBC was determined using pooled hazard ratios (HRs) and 95% confidence intervals (CIs). Results Seven articles were included in this meta-analysis, involving 4,187 patients. An elevated NLR was significantly associated with recurrence (HR = 2.67, 95% CI = 1.34-5.32, P < 0.001) and progression (HR = 1.72, 95% CI = 1.13-2.60, P = 0.004) in patients with NMIBC with intravesical BCG immunotherapy. Conclusion This meta-analysis demonstrated that elevated preoperative NLR levels were significantly associated with recurrence and disease progression in patients with NMIBC who underwent intravesical BCG immunotherapy after TURBT. Systematic review registration https://inplasy.com/inplasy-2024-7-0058/, identifier 202470058.
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Affiliation(s)
- Jiaguo Huang
- Department of Urology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Li Lin
- Department of Science and Education, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Dikai Mao
- Department of Urology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Runmiao Hua
- Department of Urology, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
| | - Feifei Guan
- Physical Examination Center, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, China
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Fan Q, Fu ZW, Xu M, Lv F, Shi JS, Zeng QQ, Xiong DH. Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer. World J Gastrointest Oncol 2024; 16:4064-4079. [DOI: 10.4251/wjgo.v16.i10.4064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 08/03/2024] [Accepted: 08/16/2024] [Indexed: 09/26/2024] Open
Abstract
The relevant mechanism of tumor-associated macrophages (TAMs) in the treatment of colorectal cancer patients with immune checkpoint inhibitors (ICIs) is discussed, and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies. As a class of drugs widely used in clinical tumor immunotherapy, ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system. The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly. The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs. ICIs can regulate the phenotypic function of TAMs, and TAMs can also affect the tolerance of colorectal cancer to ICI therapy. TAMs play an important role in ICI resistance, and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.
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Affiliation(s)
- Qi Fan
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Zheng-Wei Fu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Ming Xu
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Feng Lv
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Jia-Song Shi
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
| | - Qi-Qi Zeng
- Department of Gastroenterology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
| | - De-Hai Xiong
- Intestinal Center, Chongqing University Three Gorges Hospital, Chongqing 404000, China
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11
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Laplane L, Maley CC. The evolutionary theory of cancer: challenges and potential solutions. Nat Rev Cancer 2024; 24:718-733. [PMID: 39256635 PMCID: PMC11627115 DOI: 10.1038/s41568-024-00734-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/24/2024] [Indexed: 09/12/2024]
Abstract
The clonal evolution model of cancer was developed in the 1950s-1970s and became central to cancer biology in the twenty-first century, largely through studies of cancer genetics. Although it has proven its worth, its structure has been challenged by observations of phenotypic plasticity, non-genetic forms of inheritance, non-genetic determinants of clone fitness and non-tree-like transmission of genes. There is even confusion about the definition of a clone, which we aim to resolve. The performance and value of the clonal evolution model depends on the empirical extent to which evolutionary processes are involved in cancer, and on its theoretical ability to account for those evolutionary processes. Here, we identify limits in the theoretical performance of the clonal evolution model and provide solutions to overcome those limits. Although we do not claim that clonal evolution can explain everything about cancer, we show how many of the complexities that have been identified in the dynamics of cancer can be integrated into the model to improve our current understanding of cancer.
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Affiliation(s)
- Lucie Laplane
- UMR 8590 Institut d'Histoire et Philosophie des Sciences et des Techniques, CNRS, University Paris I Pantheon-Sorbonne, Paris, France
- UMR 1287 Hematopoietic Tissue Aging, Gustave Roussy Cancer Campus, Villejuif, France
| | - Carlo C Maley
- Arizona Cancer Evolution Center, Arizona State University, Tempe, AZ, USA.
- School of Life Sciences, Arizona State University, Tempe, AZ, USA.
- Biodesign Center for Biocomputing, Security and Society, Arizona State University, Tempe, AZ, USA.
- Center for Evolution and Medicine, Arizona State University, Tempe, AZ, USA.
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Baj J, Kołodziej M, Kobak J, Januszewski J, Syty K, Portincasa P, Forma A. Significance of Immune and Non-Immune Cell Stroma as a Microenvironment of Hepatocellular Carcinoma-From Inflammation to Hepatocellular Carcinoma Progression. Int J Mol Sci 2024; 25:10233. [PMID: 39408564 PMCID: PMC11475949 DOI: 10.3390/ijms251910233] [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: 07/28/2024] [Revised: 09/19/2024] [Accepted: 09/20/2024] [Indexed: 10/20/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common liver cancer as well as the most prevalent cause of death in the adult patient population with cirrhosis. The occurrence of HCC is primarily caused by chronic liver inflammation that might occur because of a viral infection, non-alcoholic fatty liver disease (NAFLD), or various lifestyle-associated factors. The objective of this review was to summarize the current knowledge regarding the microenvironment of HCC, indicating how immune- and non-immune-cell stroma might affect the onset and progression of HCC. Therefore, in the following narrative review, we described the role of tumor-infiltrating neutrophils, bone-marrow-derived cells, tumor-associated mast cells, cancer-associated fibroblasts, tumor-associated macrophages, liver-sinusoidal endothelial cells, lymphocytes, and certain cytokines in liver inflammation and the further progression to HCC. A better understanding of the HCC microenvironment might be crucial to introducing novel treatment strategies or combined therapies that could lead to more effective clinical outcomes.
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Affiliation(s)
- Jacek Baj
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Magdalena Kołodziej
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Joanna Kobak
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
| | - Jacek Januszewski
- Department of Correct, Clinical and Imaging Anatomy, Chair of Fundamental Sciences, Medical University of Lublin, Jaczewskiego 4, 20-090 Lublin, Poland; (J.B.); (J.J.)
| | - Kinga Syty
- Institute of Health Sciences, John Paul the II Catholic University of Lublin, Konstantynów 1G, 20-708 Lublin, Poland;
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, 70124 Bari, Italy;
| | - Alicja Forma
- Chair and Department of Forensic Medicine, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; (M.K.); (J.K.)
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13
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Shao Y, Han S, Hou Z, Yang C, Zhao Y. Tumor-associated macrophages within the immunological milieu: An emerging focal point for therapeutic intervention. Heliyon 2024; 10:e36839. [PMID: 39281573 PMCID: PMC11401039 DOI: 10.1016/j.heliyon.2024.e36839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 08/21/2024] [Accepted: 08/22/2024] [Indexed: 09/18/2024] Open
Abstract
Tumor-associated macrophages play an important role in the tumor immune microenvironment, and regulating the function of tumor-associated macrophages has important therapeutic potential in tumor therapy. Mature macrophages could migrate to the tumor microenvironment, influencing multiple factors such as tumor cell proliferation, invasion, metastasis, extracellular matrix remodeling, immune suppression, and drug resistance. As a major component of the tumor microenvironment, tumor-associated macrophages crosstalk with other immune cells. Currently, tumor-associated macrophages have garnered considerable attention in tumor therapy, broadening the spectrum of drug selection to some extent, thereby aiding in mitigating the prevailing clinical drug resistance dilemma. This article summarizes the recent advances in tumor-associated macrophages concerning immunology, drug targeting mechanisms for tumor-associated macrophages treatment, new developments, and existing challenges, offering insights for future therapeutic approaches. In addition, this paper summarized the impact of tumor-associated macrophages on current clinical therapies, discussed the advantages and disadvantages of targeted tumor-associated macrophages therapy compared with existing tumor therapies, and predicted and discussed the future role of targeted tumor-associated macrophages therapy and the issues that need to be focused on.
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Affiliation(s)
- Yanchi Shao
- Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Song Han
- The First Hospital of Jilin University, Changchun, China
| | - Zhenxin Hou
- Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Chen Yang
- Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
| | - Yanbin Zhao
- Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China
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14
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Iwata K, Suzawa K, Hashimoto K, Tanaka S, Shien K, Miyoshi K, Yamamoto H, Okazaki M, Sugimoto S, Toyooka S. Utility of neutrophil-to-lymphocyte ratio as an indicator of tumor immune status in non-small cell lung cancer. Jpn J Clin Oncol 2024; 54:895-902. [PMID: 38704243 PMCID: PMC11322889 DOI: 10.1093/jjco/hyae058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Accepted: 04/17/2024] [Indexed: 05/06/2024] Open
Abstract
BACKGROUND Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic biomarker in non-small cell lung cancer (NSCLC); however, the underlying biological rationale remains unclear. The present study aimed to explore the potential utility of NLR as a surrogate biomarker for immune response to cancer and to elucidate the underlying mechanism. METHODS This retrospective study included the medical records of 120 patients with NSCLC who underwent surgery at the study institution in 2012. NLR in peripheral blood was determined from blood test within 30 days before surgery. Tumor immune status was evaluated using immunohistochemical staining to identify CD3+, CD8+ and FOXP3+ tumor-infiltrating lymphocytes (TILs), and the relationship of NLR, with clinicopathologic characteristics including 5-year overall survival (OS), and the tumor immune status was investigated. The median values of NLR and TIL count were used as cutoff points. RESULTS The 5-year OS was significantly better in patients with low NLR (<2.2) than in those with high NLR (≥2.2) (70.1% vs. 56.8%, P = 0.042) and in patients with high CD3+ TIL count (≥242) than in those with low CD3+ TIL count (<242) (70% vs. 56.8%, P = 0.019). Additionally, the CD3+ TIL count was negatively correlated with preoperative NLR (P = 0.005). CONCLUSION NLR might potentially reflect the immune status of tumor microenvironment, explaining its impact on prognosis of patients with NSCLC.
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Affiliation(s)
- Kazuma Iwata
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Ken Suzawa
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
- Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Kohei Hashimoto
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
- Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Shin Tanaka
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
- Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Kazuhiko Shien
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
- Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Kentaroh Miyoshi
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
- Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Hiromasa Yamamoto
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
- Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Mikio Okazaki
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
- Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Seiichiro Sugimoto
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
- Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
| | - Shinichi Toyooka
- Department of General Thoracic Surgery and Brest and Endocrinological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
- Department of Thoracic Surgery, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan
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15
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Trocchia M, Ventrici A, Modestino L, Cristinziano L, Ferrara AL, Palestra F, Loffredo S, Capone M, Madonna G, Romanelli M, Ascierto PA, Galdiero MR. Innate Immune Cells in Melanoma: Implications for Immunotherapy. Int J Mol Sci 2024; 25:8523. [PMID: 39126091 PMCID: PMC11313504 DOI: 10.3390/ijms25158523] [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: 07/12/2024] [Revised: 07/31/2024] [Accepted: 08/01/2024] [Indexed: 08/12/2024] Open
Abstract
The innate immune system, composed of neutrophils, basophils, eosinophils, myeloid-derived suppressor cells (MDSCs), macrophages, dendritic cells (DCs), mast cells (MCs), and innate lymphoid cells (ILCs), is the first line of defense. Growing evidence demonstrates the crucial role of innate immunity in tumor initiation and progression. Several studies support the idea that innate immunity, through the release of pro- and/or anti-inflammatory cytokines and tumor growth factors, plays a significant role in the pathogenesis, progression, and prognosis of cutaneous malignant melanoma (MM). Cutaneous melanoma is the most common skin cancer, with an incidence that rapidly increased in recent decades. Melanoma is a highly immunogenic tumor, due to its high mutational burden. The metastatic form retains a high mortality. The advent of immunotherapy revolutionized the therapeutic approach to this tumor and significantly ameliorated the patients' clinical outcome. In this review, we will recapitulate the multiple roles of innate immune cells in melanoma and the related implications for immunotherapy.
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Affiliation(s)
- Marialuisa Trocchia
- Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, 80138 Naples, Italy; (M.T.); (A.V.); (A.L.F.); (F.P.); (S.L.)
| | - Annagioia Ventrici
- Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, 80138 Naples, Italy; (M.T.); (A.V.); (A.L.F.); (F.P.); (S.L.)
| | - Luca Modestino
- Department of Internal Medicine and Clinical Immunology, University Hospital of Naples Federico II, 80138 Naples, Italy;
| | - Leonardo Cristinziano
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80138 Naples, Italy;
| | - Anne Lise Ferrara
- Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, 80138 Naples, Italy; (M.T.); (A.V.); (A.L.F.); (F.P.); (S.L.)
| | - Francesco Palestra
- Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, 80138 Naples, Italy; (M.T.); (A.V.); (A.L.F.); (F.P.); (S.L.)
| | - Stefania Loffredo
- Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, 80138 Naples, Italy; (M.T.); (A.V.); (A.L.F.); (F.P.); (S.L.)
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80138 Naples, Italy;
| | - Mariaelena Capone
- Melanoma, Cancer Immunotherapy, and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, 80138 Naples, Italy; (M.C.); (G.M.); (M.R.); (P.A.A.)
| | - Gabriele Madonna
- Melanoma, Cancer Immunotherapy, and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, 80138 Naples, Italy; (M.C.); (G.M.); (M.R.); (P.A.A.)
| | - Marilena Romanelli
- Melanoma, Cancer Immunotherapy, and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, 80138 Naples, Italy; (M.C.); (G.M.); (M.R.); (P.A.A.)
| | - Paolo Antonio Ascierto
- Melanoma, Cancer Immunotherapy, and Development Therapeutics Unit, Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale”, 80138 Naples, Italy; (M.C.); (G.M.); (M.R.); (P.A.A.)
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences (DiSMeT), University of Naples Federico II, 80138 Naples, Italy; (M.T.); (A.V.); (A.L.F.); (F.P.); (S.L.)
- Department of Internal Medicine and Clinical Immunology, University Hospital of Naples Federico II, 80138 Naples, Italy;
- Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, 80138 Naples, Italy;
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16
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Martínez-López MF, de Almeida CR, Fontes M, Mendes RV, Kaufmann SHE, Fior R. Macrophages directly kill bladder cancer cells through TNF signaling as an early response to BCG therapy. Dis Model Mech 2024; 17:dmm050693. [PMID: 39114912 PMCID: PMC11554267 DOI: 10.1242/dmm.050693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Accepted: 06/09/2024] [Indexed: 11/13/2024] Open
Abstract
The Bacillus Calmette-Guérin (BCG) vaccine is the oldest cancer immunotherapeutic agent in use. Despite its effectiveness, its initial mechanisms of action remain largely unknown. Here, we elucidate the earliest cellular mechanisms involved in BCG-induced tumor clearance. We developed a fast preclinical in vivo assay to visualize in real time and at single-cell resolution the initial interactions among bladder cancer cells, BCG and innate immunity using the zebrafish xenograft model. We show that BCG induced the recruitment and polarization of macrophages towards a pro-inflammatory phenotype, accompanied by induction of the inflammatory cytokines tnfa, il1b and il6 in the tumor microenvironment. Macrophages directly induced apoptosis of human cancer cells through zebrafish TNF signaling. Macrophages were crucial for this response as their depletion completely abrogated the BCG-induced phenotype. Contrary to the general concept that macrophage anti-tumoral activities mostly rely on stimulating an effective adaptive response, we demonstrate that macrophages alone can induce tumor apoptosis and clearance. Thus, our results revealed an additional step to the BCG-induced tumor immunity model, while providing proof-of-concept experiments demonstrating the potential of this unique model to test innate immunomodulators.
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Affiliation(s)
| | | | - Márcia Fontes
- Champalimaud Research, Champalimaud Foundation, Av. Brasilia, Lisbon 1400-038, Portugal
| | - Raquel Valente Mendes
- Champalimaud Research, Champalimaud Foundation, Av. Brasilia, Lisbon 1400-038, Portugal
| | - Stefan H. E. Kaufmann
- Max Planck Institute for Infection Biology, Berlin 10117, Germany
- Max Planck Institute for Multidisciplinary Sciences, Göttingen 37077, Germany
- Hagler Institute for Advanced Study, Texas A&M University, College Station, TX 77843, USA
| | - Rita Fior
- Champalimaud Research, Champalimaud Foundation, Av. Brasilia, Lisbon 1400-038, Portugal
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17
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Teng HW, Wang TY, Lin CC, Tong ZJ, Cheng HW, Wang HT. Interferon Gamma Induces Higher Neutrophil Extracellular Traps Leading to Tumor-Killing Activity in Microsatellite Stable Colorectal Cancer. Mol Cancer Ther 2024; 23:1043-1056. [PMID: 38346939 DOI: 10.1158/1535-7163.mct-23-0744] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Revised: 01/18/2024] [Accepted: 02/05/2024] [Indexed: 07/03/2024]
Abstract
Many patients with colorectal cancer do not respond to immune checkpoint blockade (ICB) therapy, highlighting the urgent need to understand tumor resistance mechanisms. Recently, the link between the IFNγ signaling pathway integrity and ICB resistance in the colorectal cancer tumor microenvironment has been revealed. The immunosuppressive microenvironment poses a significant challenge to antitumor immunity in colorectal cancer development. Tumor-associated neutrophils found in tumor tissues exhibit an immunosuppressive phenotype and are associated with colorectal cancer patient prognosis. Neutrophil extracellular traps (NET), DNA meshes containing cytotoxic enzymes released into the extracellular space, may be promising therapeutic targets in cancer. This study showed increased NETs in tumor tissues and peripheral neutrophils of high levels of microsatellite instability (MSI-H) patients with colorectal cancer compared with microsatellite stable (MSS) patients with colorectal cancer. IFNγ response genes were enriched in MSI-H patients with colorectal cancer compared with patients with MSS colorectal cancer. Co-culturing neutrophils with MSI-H colorectal cancer cell lines induced more NET formation and higher cellular apoptosis than MSS colorectal cancer cell lines. IFNγ treatment induced more NET formation and apoptosis in MSS colorectal cancer cell lines. Using subcutaneous or orthotopic CT-26 (MSS) tumor-bearing mice models, IFNγ reduced tumor size and enhanced PD-1 antibody-induced tumor-killing activity, accompanied by upregulated NETs and cellular apoptosis. These findings suggest that IFNγ could be a therapeutic strategy for MSS colorectal cancer.
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Affiliation(s)
- Hao-Wei Teng
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Tean-Ya Wang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Chun-Chi Lin
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Division of Colon and Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Zhen-Jie Tong
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsiao-Wei Cheng
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Hsiang-Tsui Wang
- Institute of Pharmacology, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Food Safety and Health Risk Assessment, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Doctor degree program in Toxicology, Kaohsiung Medical University, Kaohsiung, Taiwan
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18
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Zhang H, Li Y, Liu YW, Liu YG, Chen X. Predictive value of lymphocyte subsets and lymphocyte-to-monocyte ratio in assessing the efficacy of neoadjuvant therapy in breast cancer. Sci Rep 2024; 14:12799. [PMID: 38834662 DOI: 10.1038/s41598-024-61632-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 05/08/2024] [Indexed: 06/06/2024] Open
Abstract
Lymphocyte subsets are the most intuitive expression of the body's immune ability, and the lymphocyte-to-monocyte ratio (LMR) also clearly reflect the degree of chronic inflammation activity. The purpose of this study is to investigate their predictive value of lymphocyte subsets and LMR to neoadjuvant therapy (NAT) efficacy in breast cancer patients. In this study, lymphocyte subsets and LMR were compared between breast cancer patients (n = 70) and benign breast tumor female populations (n = 48). Breast cancer patients were treated with NAT, and the chemotherapy response of the breast was evaluated using established criteria. The differences in lymphocyte subsets and LMR were also compared between pathological complete response (pCR) and non-pCR patients before and after NAT. Finally, data were analyzed using SPSS. The analytical results demonstrated that breast cancer patients showed significantly lower levels of CD3 + T cells, CD4 + T cells, CD4 + /CD8 + ratio, NK cells, and LMR compared to benign breast tumor women (P < 0.05). Among breast cancer patients, those who achieved pCR had higher levels of CD4 + T cells, NK cells, and LMR before NAT (P < 0.05). NAT increased CD4 + /CD8 + ratio and decreased CD8 + T cells in pCR patients (P < 0.05). Additionally, both pCR and non-pCR patients exhibited an increase in CD3 + T cells and CD4 + T cells after treatment, but the increase was significantly higher in pCR patients (P < 0.05). Conversely, both pCR and non-pCR patients experienced a decrease in LMR after treatment. However, this decrease was significantly lower in pCR patients (P < 0.05). These indicators demonstrated their predictive value for therapeutic efficacy. In conclusion, breast cancer patients experience tumor-related immunosuppression and high chronic inflammation response. But this phenomenon can be reversed to varying degrees by NAT. It has been found that lymphocyte subsets and LMR have good predictive value for pCR. Therefore, these markers can be utilized to identify individuals who are insensitive to NAT early on, enabling the adjustment of treatment plans and achieving precise breast cancer treatment.
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Affiliation(s)
- Hao Zhang
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yan Li
- School of Public Health, Chongqing Medical University, Chongqing, China
| | - Ya-Wen Liu
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Ye-Gang Liu
- Department of General Surgery, People's Hospital of Tongzi County, Zunyi, Guizhou Province, China
| | - Xin Chen
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
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19
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Redmer T, Raigel M, Sternberg C, Ziegler R, Probst C, Lindner D, Aufinger A, Limberger T, Trachtova K, Kodajova P, Högler S, Schlederer M, Stoiber S, Oberhuber M, Bolis M, Neubauer HA, Miranda S, Tomberger M, Harbusch NS, Garces de Los Fayos Alonso I, Sternberg F, Moriggl R, Theurillat JP, Tichy B, Bystry V, Persson JL, Mathas S, Aberger F, Strobl B, Pospisilova S, Merkel O, Egger G, Lagger S, Kenner L. JUN mediates the senescence associated secretory phenotype and immune cell recruitment to prevent prostate cancer progression. Mol Cancer 2024; 23:114. [PMID: 38811984 PMCID: PMC11134959 DOI: 10.1186/s12943-024-02022-x] [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: 11/29/2023] [Accepted: 05/10/2024] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Prostate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. METHODS We analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. RESULTS Elevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1β production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1β and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1β, TNF-α, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both the senescence-associated secretory phenotype and senescence-associated immune cell infiltration but had no impact on cell cycle arrest. As a result, JUN depletion in Pten-deficient prostates interfered with the senescence-associated immune clearance and accelerated tumor growth. CONCLUSIONS Our results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.
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Affiliation(s)
- Torben Redmer
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria.
| | - Martin Raigel
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
| | - Christina Sternberg
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Biochemical Institute, University of Kiel, Kiel, 24098, Germany
| | - Roman Ziegler
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Cell Biology, Charles University, Prague, Czech Republic and Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Vestec u Prahy, Czech Republic
| | - Clara Probst
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
| | - Desiree Lindner
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
| | - Astrid Aufinger
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Tanja Limberger
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Center for Biomarker Research in Medicine (CBmed) Vienna, Core-Lab2, Medical University of Vienna, Vienna, 1090, Austria
| | - Karolina Trachtova
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
- CEITEC-Central European Institute of Technology, Masaryk University, Brno, 625 00, Czech Republic
| | - Petra Kodajova
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Sandra Högler
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Michaela Schlederer
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Stefan Stoiber
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
- Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, 1090, Austria
- Christian Doppler Laboratory for Applied Metabolomics, Medical University of Vienna, Vienna, 1090, Austria
| | - Monika Oberhuber
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, 8010, Austria
| | - Marco Bolis
- Institute of Oncology Research, Bellinzona and Faculty of Biomedical Sciences, USI, Lugano, 6500, TI, Switzerland
- Computational Oncology Unit, Department of Oncology, Istituto di Richerche Farmacologiche 'Mario Negri' IRCCS, Milano, 20156, Italy
- Bioinformatics Core Unit, Swiss Institute of Bioinformatics, Bellinzona, 6500, TI, Switzerland
| | - Heidi A Neubauer
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Institute of Medical Biochemistry, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Sara Miranda
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Martina Tomberger
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, 8010, Austria
| | - Nora S Harbusch
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, 8010, Austria
| | - Ines Garces de Los Fayos Alonso
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Felix Sternberg
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
- Department of Nutritional Sciences, Faculty of Life Sciences, University of Vienna, Vienna, 1090, Austria
| | - Richard Moriggl
- Department of Biosciences and Medical Biology, Cancer Cluster Salzburg, Paris-Lodron University of Salzburg, Salzburg, 5020, Austria
| | - Jean-Philippe Theurillat
- Institute of Oncology Research, Bellinzona and Faculty of Biomedical Sciences, USI, Lugano, 6500, TI, Switzerland
| | - Boris Tichy
- CEITEC-Central European Institute of Technology, Masaryk University, Brno, 625 00, Czech Republic
| | - Vojtech Bystry
- CEITEC-Central European Institute of Technology, Masaryk University, Brno, 625 00, Czech Republic
| | - Jenny L Persson
- Department of Molecular Biology, Umeå University, Umeå, 901 87, Sweden
- Department of Biomedical Sciences, Malmö Universitet, Malmö, 206 06, Sweden
| | - Stephan Mathas
- Charité-Universitätsmedizin Berlin, Hematology, Oncology and Tumor Immunology, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, 10117, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Group Biology of Malignant Lymphomas, Berlin, 13125, Germany
- Experimental and Clinical Research Center (ECRC), a cooperation between the MDC and the Charité, Berlin, Germany
| | - Fritz Aberger
- Department of Biosciences and Medical Biology, Cancer Cluster Salzburg, Paris-Lodron University of Salzburg, Salzburg, 5020, Austria
| | - Birgit Strobl
- Institute of Animal Breeding and Genetics, University of Veterinary Medicine Vienna, Vienna, 1210, Austria
| | - Sarka Pospisilova
- CEITEC-Central European Institute of Technology, Masaryk University, Brno, 625 00, Czech Republic
| | - Olaf Merkel
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Gerda Egger
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria
| | - Sabine Lagger
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria.
| | - Lukas Kenner
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, 1210, Austria.
- Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria.
- Christian Doppler Laboratory for Applied Metabolomics, Medical University of Vienna, Vienna, 1090, Austria.
- Center for Biomarker Research in Medicine, CBmed GmbH, Graz, 8010, Austria.
- Comprehensive Cancer Center, Medical University Vienna, Vienna, 1090, Austria.
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20
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Yang Y, Yang R, Deng F, Yang L, Yang G, Liu Y, Tian Q, Wang Z, Li A, Shang L, Cheng G, Zhang L. Immunoactivation by Cutaneous Blue Light Irradiation Inhibits Remote Tumor Growth and Metastasis. ACS Pharmacol Transl Sci 2024; 7:1055-1068. [PMID: 38633599 PMCID: PMC11019738 DOI: 10.1021/acsptsci.3c00355] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 03/01/2024] [Accepted: 03/06/2024] [Indexed: 04/19/2024]
Abstract
An improved innate immunity will respond quickly to pathogens and initiate efficient adaptive immune responses. However, up to now, there have been limited clinical ways for effective and rapid consolidation of innate immunity. Here, we report that cutaneous irradiation with blue light of 450 nm rapidly stimulates the innate immunity through cell endogenous reactive oxygen species (ROS) regulation in a noninvasive way. The iron porphyrin-containing proteins, mitochondrial cytochrome c (Cyt-c), and cytochrome p450 (CYP450) can be mobilized by blue light, which boosts electron transport and ROS production in epidermal and dermal tissues. As a messenger of innate immune activation, the increased level of ROS activates the NF-κB signaling pathway and promotes the secretion of immunomodulatory cytokines in skin. Initiated from skin, a regulatory network composed of cytokines and immune cells is established through the circulation system for innate immune activation. The innate immunity activated by whole-body blue light irradiation inhibits tumor growth and metastasis by increasing the infiltration of antitumor neutrophils and tumor-associated macrophages. Our results elucidate the remote immune modulation mechanism of blue light and provide a clinically applicable way for innate immunity activation.
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Affiliation(s)
- Yingchun Yang
- Key
Laboratory for Space Bioscience & Biotechnology, School of Life
Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Rong Yang
- Key
Laboratory for Space Bioscience & Biotechnology, School of Life
Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Fangqing Deng
- Key
Laboratory for Space Bioscience & Biotechnology, School of Life
Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Luqiu Yang
- Key
Laboratory for Space Bioscience & Biotechnology, School of Life
Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Guanghao Yang
- Key
Laboratory for Space Bioscience & Biotechnology, School of Life
Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Yanyan Liu
- Key
Laboratory for Space Bioscience & Biotechnology, School of Life
Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Qing Tian
- Key
Laboratory for Space Bioscience & Biotechnology, School of Life
Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Zixi Wang
- Key
Laboratory for Space Bioscience & Biotechnology, School of Life
Sciences, Northwestern Polytechnical University, Xi’an 710072, China
| | - Aipeng Li
- School
of Chemical Engineering and Technology, Xi’an Jiaotong University, Xi’an 710049, China
| | - Li Shang
- School
of Materials Science and Engineering, Northwestern
Polytechnical University, Xi’an 710072, China
| | - Genyang Cheng
- Department
of Nephrology, the First Affiliated Hospital
of Zhengzhou University, Zhengzhou 450052, China
| | - Lianbing Zhang
- Key
Laboratory for Space Bioscience & Biotechnology, School of Life
Sciences, Northwestern Polytechnical University, Xi’an 710072, China
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21
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Chen Y, Liu H, Sun Y. Effect of acute inflammatory reaction induced by biopsy on tumor microenvironment. J Cancer Res Clin Oncol 2024; 150:177. [PMID: 38578317 PMCID: PMC10997701 DOI: 10.1007/s00432-024-05704-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 12/04/2023] [Indexed: 04/06/2024]
Abstract
When it comes to the diagnosis of solid tumors, biopsy is always the gold standard. However, traumatic and inflammatory stimuli are so closely related to tumor initiation and development that the acute inflammatory response induced by biopsy can give rise to changes in the tumor microenvironment, including recruitment of immunosuppressive cells (M2 macrophages, Treg cells, Tumor-associated neutrophils) and secretion of inflammation-associated cytokines, to create immunosuppressive conditions that enable the increase of circulating tumor cells in the peripheral circulation and promote the metastatic spread of tumors after surgery. In this review, we discuss dynamic changes and inhibitory characteristics of biopsy on tumor microenvironment. By investigating its mechanism of action and summarizing the current therapeutic strategies for biopsy-induced tumor immunosuppressive microenvironment, the future of using biopsy-induced inflammation to improve the therapeutic effects and prognosis of patients is prospected.
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Affiliation(s)
- Yuanyuan Chen
- Department of Stomatology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Hualian Liu
- Department of Stomatology, The Third Affiliated Hospital of Soochow University, Changzhou, China.
| | - Yadong Sun
- Department of General Practice, Unit 94587 of the Chinese People's Liberation Army, Lianyungang, China
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22
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Tan J, Egelston CA, Guo W, Stark JM, Lee PP. STING signalling compensates for low tumour mutation burden to drive anti-tumour immunity. EBioMedicine 2024; 101:105035. [PMID: 38401418 PMCID: PMC10904200 DOI: 10.1016/j.ebiom.2024.105035] [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: 05/20/2023] [Revised: 01/30/2024] [Accepted: 02/11/2024] [Indexed: 02/26/2024] Open
Abstract
BACKGROUND While mutation-derived neoantigens are well recognized in generating anti-tumour T cell response, increasing evidences highlight the complex association between tumour mutation burden (TMB) and tumour infiltrating lymphocytes (TILs). The exploration of non-TMB determinants of active immune response could improve the prognosis prediction and provide guidance for current immunotherapy. METHODS The transcriptomic and whole exome sequence data in The Cancer Genome Atlas were used to examine the relationship between TMB and exhausted CD8+ T cells (Tex), as an indicator of tumour antigen-specific T cells across nine major cancer types. Computational clustering analysis was performed on 4510 tumours to identify different immune profiles. NanoString gene expression analysis and single cell RNA-seq analysis using fresh human breast cancer were performed for finding validation. FINDINGS TMB was found to be poorly correlated with active immune response in various cancer types. Patient clustering analysis revealed a group of tumours with abundant Tex but low TMB. In those tumours, we observed significantly higher expression of the stimulator of interferon genes (STING) signalling. Dendritic cells, particularly those of BATF3+ lineage, were also found to be essential for accumulation of Tex within tumours. Mechanistically, loss of genomic and cellular integrity, marked by decreased DNA damage repair, defective replication stress response, and increased apoptosis were shown to drive STING activation. INTERPRETATION These results highlight that TMB alone does not fully predict tumour immune profiles, with STING signalling compensating for low TMB in non-hypermutated tumours to enhance anti-tumour immunity. Translating these results, STING agonists may benefit patients with non-hypermutated tumours. STING activation may serve as an additional biomarker to predict response to immune checkpoint blockades alongside TMB. Our research also unravelled the interplay between genomic instability and STING activation, informing potential combined chemotherapy targeting the axis of genomic integrity and immunotherapy. FUNDING City of Hope Christopher Family Endowed Innovation Fund for Alzheimer's Disease and Breast Cancer Research in honor of Vineta Christopher; Breast Cancer Alliance Early Career Investigator Award; National Cancer Institute of the National Institutes of Health under award number R01CA256989 and R01CA240392.
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Affiliation(s)
- Jiayi Tan
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA; Irell & Manella Graduate School of Biological Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Colt A Egelston
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Weihua Guo
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Jeremy M Stark
- Department of Cancer Genetics and Epigenetics, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Peter P Lee
- Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA, USA.
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23
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Abakumova TV, Antoneeva II, Gening TP. Killer Function of Circulating Neutrophils in Relation to Cytokines in Uterine Myoma and Endometrial Cancer. Bull Exp Biol Med 2024; 176:607-611. [PMID: 38730105 DOI: 10.1007/s10517-024-06077-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Indexed: 05/12/2024]
Abstract
The study presents the killer functions of circulating neutrophils: myeloperoxidase activity, the ability to generate ROS, phagocytic activity, receptor status, NETosis, as well as the level of cytokines IL-2, IL-4, IL-6, IL-17A, and IL-18, granulocyte CSF, monocyte chemotactic protein 1, and neutrophil elastase in the serum of patients with uterine myoma and endometrial cancer (FIGO stages I-III). The phagocytic ability of neutrophils in uterine myoma was influenced by serum levels of granulocyte CSF and IL-2 in 54% of the total variance. The degranulation ability of neutrophils in endometrial cancer was determined by circulating IL-18 in 50% of the total variance. In uterine myoma, 66% of the total variance in neutrophil myeloperoxidase activity was explained by a model dependent on blood levels of IL-17A, IL-6, and IL-4. The risk of endometrial cancer increases when elevated levels of monocyte chemotactic protein 1 in circulating neutrophils are associated with reduced ability to capture particles via extracellular traps (96% probability).
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Affiliation(s)
| | | | - T P Gening
- Ulyanovsk State University, Ulyanovsk, Russia
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24
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Witz A, Dardare J, Betz M, Gilson P, Merlin JL, Harlé A. Tumor-derived cell-free DNA and circulating tumor cells: partners or rivals in metastasis formation? Clin Exp Med 2024; 24:2. [PMID: 38231464 PMCID: PMC10794481 DOI: 10.1007/s10238-023-01278-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 11/20/2023] [Indexed: 01/18/2024]
Abstract
The origin of metastases is a topic that has sparked controversy. Despite recent advancements, metastatic disease continues to pose challenges. The first admitted model of how metastases develop revolves around cells breaking away from the primary tumor, known as circulating tumor cells (CTCs). These cells survive while circulating through the bloodstream and subsequently establish themselves in secondary organs, a process often referred to as the "metastatic cascade". This intricate and dynamic process involves various steps, but all the mechanisms behind metastatic dissemination are not yet comprehensively elucidated. The "seed and soil" theory has shed light on the phenomenon of metastatic organotropism and the existence of pre-metastatic niches. It is now established that these niches can be primed by factors secreted by the primary tumor before the arrival of CTCs. In particular, exosomes have been identified as important contributors to this priming. Another concept then emerged, i.e. the "genometastasis" theory, which challenged all other postulates. It emphasizes the intriguing but promising role of cell-free DNA (cfDNA) in metastasis formation through oncogenic formation of recipient cells. However, it cannot be ruled out that all these theories are intertwined. This review outlines the primary theories regarding the metastases formation that involve CTCs, and depicts cfDNA, a potential second player in the metastasis formation. We discuss the potential interrelationships between CTCs and cfDNA, and propose both in vitro and in vivo experimental strategies to explore all plausible theories.
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Affiliation(s)
- Andréa Witz
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France.
| | - Julie Dardare
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Margaux Betz
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Pauline Gilson
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Jean-Louis Merlin
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
| | - Alexandre Harlé
- Département de Biopathologie, Institut de Cancérologie de Lorraine, CNRS UMR 7039 CRAN-Université de Lorraine, 6 avenue de Bourgogne, 54519, Vandœuvre-lès-Nancy Cedex, France
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25
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Luo F, Li H, Ma W, Cao J, Chen Q, Lu F, Qiu M, Zhou P, Xia Z, Zeng K, Zhan J, Zhou T, Luo Q, Pan W, Zhang L, Lin C, Huang Y, Zhang L, Yang D, Zhao H. The BCL-2 inhibitor APG-2575 resets tumor-associated macrophages toward the M1 phenotype, promoting a favorable response to anti-PD-1 therapy via NLRP3 activation. Cell Mol Immunol 2024; 21:60-79. [PMID: 38062129 PMCID: PMC10757718 DOI: 10.1038/s41423-023-01112-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 10/12/2023] [Accepted: 11/13/2023] [Indexed: 01/01/2024] Open
Abstract
The main challenges in the use of immune checkpoint inhibitors (ICIs) are ascribed to the immunosuppressive tumor microenvironment and the lack of sufficient infiltration of activated CD8+ T cells. Transforming the tumor microenvironment (TME) from "cold" to "hot" and thus more likely to potentiate the effects of ICIs is a promising strategy for cancer treatment. We found that the selective BCL-2 inhibitor APG-2575 can enhance the antitumor efficacy of anti-PD-1 therapy in syngeneic and humanized CD34+ mouse models. Using single-cell RNA sequencing, we found that APG-2575 polarized M2-like immunosuppressive macrophages toward the M1-like immunostimulatory phenotype with increased CCL5 and CXCL10 secretion, restoring T-cell function and promoting a favorable immunotherapy response. Mechanistically, we demonstrated that APG-2575 directly binds to NF-κB p65 to activate NLRP3 signaling, thereby mediating macrophage repolarization and the activation of proinflammatory caspases and subsequently increasing CCL5 and CXCL10 chemokine production. As a result, APG-2575-induced macrophage repolarization could remodel the tumor immune microenvironment, thus improving tumor immunosuppression and further enhancing antitumor T-cell immunity. Multiplex immunohistochemistry confirmed that patients with better immunotherapeutic efficacy had higher CD86, p-NF-κB p65 and NLRP3 levels, accompanied by lower CD206 expression on macrophages. Collectively, these data provide evidence that further study on APG-2575 in combination with immunotherapy for tumor treatment is required.
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Affiliation(s)
- Fan Luo
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Han Li
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wenjuan Ma
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jiaxin Cao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qun Chen
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Feiteng Lu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Miaozhen Qiu
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Penghui Zhou
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Zengfei Xia
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Kangmei Zeng
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Jianhua Zhan
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Ting Zhou
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Qiuyun Luo
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Wentao Pan
- Ascentage Pharma (Suzhou) Co Ltd, 218 Xinghu Street, Suzhou, Jiangsu Province, China
| | - Lin Zhang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Chaozhuo Lin
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Yan Huang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Li Zhang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Dajun Yang
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
| | - Hongyun Zhao
- State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
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26
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Borlongan MC, Saha D, Wang H. Tumor Microenvironment: A Niche for Cancer Stem Cell Immunotherapy. Stem Cell Rev Rep 2024; 20:3-24. [PMID: 37861969 DOI: 10.1007/s12015-023-10639-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/02/2023] [Indexed: 10/21/2023]
Abstract
Tumorigenic Cancer Stem Cells (CSCs), often called tumor-initiating cells (TICs), represent a unique subset of cells within the tumor milieu. They stand apart from the bulk of tumor cells due to their exceptional self-renewal, metastatic, and differentiation capabilities. Despite significant progress in classifying CSCs, these cells remain notably resilient to conventional radiotherapy and chemotherapy, contributing to cancer recurrence. In this review, our objective is to explore novel avenues of research that delve into the distinctive characteristics of CSCs within their surrounding tumor microenvironment (TME). We will start with an overview of the defining features of CSCs and then delve into their intricate interactions with cells from the lymphoid lineage, namely T cells, B cells, and natural killer (NK) cells. Furthermore, we will discuss their dynamic interplay with myeloid lineage cells, including macrophages, neutrophils, and myeloid-derived suppressor cells (MDSCs). Moreover, we will illuminate the crosstalk between CSCs and cells of mesenchymal origin, specifically fibroblasts, adipocytes, and endothelial cells. Subsequently, we will underscore the pivotal role of CSCs within the context of the tumor-associated extracellular matrix (ECM). Finally, we will highlight pre-clinical and clinical studies that target CSCs within the intricate landscape of the TME, including CAR-T therapy, oncolytic viruses, and CSC-vaccines, with the ultimate goal of uncovering novel avenues for CSC-based cancer immunotherapy.
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Affiliation(s)
- Mia C Borlongan
- College of Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA
| | - Dipongkor Saha
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
| | - Hongbin Wang
- College of Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
- Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
- Master Program of Pharmaceutical Sciences College of Graduate Studies, Department of Pharmaceutical and Biomedical Sciences College of Pharmacy, Department of Basic Science College of Medicine, California Northstate University, 9700 West Taron Drive, Elk Grove, CA, 95757, USA.
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27
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Xie J, Guo Z, Zhu Y, Ma M, Jia G. Peripheral blood inflammatory indexes in breast cancer: A review. Medicine (Baltimore) 2023; 102:e36315. [PMID: 38050296 PMCID: PMC10695498 DOI: 10.1097/md.0000000000036315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/03/2023] [Indexed: 12/06/2023] Open
Abstract
Immune and inflammatory responses play an important role in tumorigenesis and metastasis. Inflammation is an important component of the tumor microenvironment, and the changes in inflammatory cells may affect the occurrence and development of tumors. Complete blood count at the time of diagnosis and treatment can reflect the inflammatory status within the tumor. Studies have shown that the number of certain inflammatory cells in peripheral blood and their ratios are important prognostic factors for many malignancies, including neutrophil, lymphocyte, monocyte, and platelet counts, as well as neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, systemic inflammation response index and pan-immune-inflammation-value. The value of peripheral blood inflammation indexes in predicting the efficacy and prognosis of breast cancer neoadjuvant therapy is worth recognizing. This review details the application of peripheral blood inflammation indexes in the evaluation of efficacy and prediction of prognosis in neoadjuvant therapy for breast cancer, aiming to provide a more comprehensive reference for the comprehensive diagnosis and treatment of breast cancer.
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Affiliation(s)
- Jiaqiang Xie
- Department of Breast and Thyroid Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan, China
- School of Clinical Medicine, Henan University, Kaifeng, Henan, China
| | - Zhenxi Guo
- Department of Breast and Thyroid Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan, China
- School of Clinical Medicine, Henan University, Kaifeng, Henan, China
| | - Yijing Zhu
- Department of Breast and Thyroid Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan, China
- School of Clinical Medicine, Henan University, Kaifeng, Henan, China
| | - Mingde Ma
- Department of Breast and Thyroid Surgery, Huaihe Hospital of Henan University, Kaifeng, Henan, China
| | - Guangwei Jia
- Department of Thyroid and Breast Surgery, Nanyang First People’s Hospital Affiliated to Henan University, Nanyang, Henan, China
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28
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Takahashi Y, Oyama H, Nakamura A, Minegishi Y, Tanaka K. Zinc supports liver regeneration after partial resection. Turk J Surg 2023; 39:344-353. [PMID: 38694520 PMCID: PMC11057933 DOI: 10.47717/turkjsurg.2023.6260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/20/2023] [Indexed: 05/04/2024]
Abstract
Objectives Safe removal of extensive liver tumor burdens depends on regeneration of the remnant liver, which requires a large amount of zinc over a short period of time. We studied how zinc influences regeneration. Material and Methods We measured perioperative serum zinc concentrations after liver cancer diagnosis in 77 patients undergoing hepatectomy to determine how serum zinc affected short-term outcomes and remnant liver regeneration. Results Serum zinc concentration at diagnosis showed no correlation with inflammatory or nutritional parameters except for a weak correlation with the lymphocyte-to-monocyte ratio. When patients were divided into a high pre-hepatectomy zinc group (≥75 µg/dL, n= 39, H group) and a low zinc group (<75 µg/dL, n= 38, L group), short-term results such as mortality (p> 0.999), morbidity (p= 0.490), and hospital stay (p= 0.591) did not differ between groups. However, hypertrophy in the future liver remnant after hepatectomy in the H group (127.7 ± 24.7% of original volume) was greater than in the L group (115.9 ± 16.7%, p= 0.024). In a subgroup of patients with extended hepatectomy, hypertrophy was 130.9 ± 26.8% in the H group vs. 116.4 ± 16.5% in the L group (p= 0.037). Conclusion Greater serum zinc at diagnosis was associated with greater hypertrophy in the future liver remnant.
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Affiliation(s)
- Yuki Takahashi
- Department of General and Gastroenterological Surgery, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Hideyuki Oyama
- Department of General and Gastroenterological Surgery, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Akihiro Nakamura
- Department of General and Gastroenterological Surgery, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Yuzo Minegishi
- Department of General and Gastroenterological Surgery, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Kuniya Tanaka
- Department of General and Gastroenterological Surgery, Showa University Fujigaoka Hospital, Yokohama, Japan
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Hasani S, Fathabadi F, Saeidi S, Mohajernoei P, Hesari Z. The role of NFATc1 in the progression and metastasis of prostate cancer: A review on the molecular mechanisms and signaling pathways. Cell Biol Int 2023; 47:1895-1904. [PMID: 37814550 DOI: 10.1002/cbin.12094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 08/27/2023] [Accepted: 09/26/2023] [Indexed: 10/11/2023]
Abstract
A common type of cancer among men is the prostate cancer that kills many people every year. The multistage of this disease and the involvement of the vital organs of the body have reduced the life span and quality of life of the people involved and turned the treatment process into a complex one. NFATc1 biomarker contributes significantly in the diagnosis and treatment of this disease by increasing its expression in prostate cancer and helping the proliferation, differentiation, and invasion of cancer cells through different signaling pathways. NFATc1 is also able to target the metabolism of cancer cells by inserting specific oncogene molecules such as c-myc that it causes cell growth and proliferation. Bone is a common tissue where prostate cancer cells metastasize. In this regard, the activity of NFATc1, through the regulation of different signaling cascades, including the RANKL/RANK signaling pathway, in turn, increases the activity of osteoclasts, and as a result, bone tissue is gradually ruined. Using Silibinin as a medicinal plant extract can inhibit the activity of osteoclasts related to prostate cancer by targeting NFATc. Undoubtedly, NFATc1 is one of the effective oncogenes related to prostate cancer, which has the potential to put this cancer on the path of progression and metastasis. In this review, we will highlight the role of NFATc1 in the progression and metastasis of prostate cancer. Furthermore, we will summarize signaling pathways and molecular mechanism, through which NFATc1 regulates the process of prostate cancer.
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Affiliation(s)
- Samaneh Hasani
- Department of Nursing, Faculty of Medical Sciences, Khalkhal University of Medical Sciences, Khalkhal, Iran
| | - Farshid Fathabadi
- Laboratory Sciences Research Center, Golestan University of Medical Sciences, Department of Laboratory Sciences, Faculty of Paramedicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Saman Saeidi
- Laboratory Sciences Research Center, Golestan University of Medical Sciences, Department of Laboratory Sciences, Faculty of Paramedicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Pouya Mohajernoei
- Department of Medicine and Surgery, Università degli Studi di Padova, Padua, Italy
| | - Zahra Hesari
- Laboratory Sciences Research Center, Golestan University of Medical Sciences, Department of Laboratory Sciences, Faculty of Paramedicine, Golestan University of Medical Sciences, Gorgan, Iran
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Gul S, Pang J, Yuan H, Chen Y, Yu Q, Wang H, Tang W. Stemness signature and targeted therapeutic drugs identification for Triple Negative Breast Cancer. Sci Data 2023; 10:815. [PMID: 37985782 PMCID: PMC10662149 DOI: 10.1038/s41597-023-02709-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Accepted: 10/31/2023] [Indexed: 11/22/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and carries the worst prognosis, characterized by the lack of progesterone, estrogen, and HER2 gene expression. This study aimed to analyze cancer stemness-related gene signature to determine patients' risk stratification and prognosis feature with TNBC. Here one-class logistic regression (OCLR) algorithm was applied to compute the stemness index of TNBC patients. Cox and LASSO regression analysis was performed on stemness-index related genes to establish 16 genes-based prognostic signature, and their predictive performance was verified in TCGA and METABERIC merged data cohort. We diagnosed the expression level of prognostic genes signature in the tumor immune microenvironment, analyzed the TNBC scRNA-seq GSE176078 dataset, and further validated the expression level of prognostic genes using the HPA database. Finally, the small molecular compounds targeted at the anti-tumor effect of predictive genes were screened by molecular docking; this novel stemness-based prognostic genes signature study could facilitate the prognosis of patients with TNBC and thus provide a feasible therapeutic target for TNBC.
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Affiliation(s)
- Samina Gul
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, 727 jingming south road, Kunming city, Yunnan province, 650500, China
| | - Jianyu Pang
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, 727 jingming south road, Kunming city, Yunnan province, 650500, China
| | - Hongjun Yuan
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, 727 jingming south road, Kunming city, Yunnan province, 650500, China
| | - Yongzhi Chen
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, 727 jingming south road, Kunming city, Yunnan province, 650500, China
| | - Qian Yu
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, 727 jingming south road, Kunming city, Yunnan province, 650500, China
| | - Hui Wang
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, 727 jingming south road, Kunming city, Yunnan province, 650500, China
| | - Wenru Tang
- Laboratory of Molecular Genetics of Aging & Tumor, Medical School, Kunming University of Science and Technology, 727 jingming south road, Kunming city, Yunnan province, 650500, China.
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Mireștean CC, Stan MC, Iancu RI, Iancu DPT, Bădulescu F. The Prognostic Value of Platelet-Lymphocyte Ratio, Neutrophil-Lymphocyte Ratio, and Monocyte-Lymphocyte Ratio in Head and Neck Squamous Cell Carcinoma (HNSCC)-A Retrospective Single Center Study and a Literature Review. Diagnostics (Basel) 2023; 13:3396. [PMID: 37998532 PMCID: PMC10670617 DOI: 10.3390/diagnostics13223396] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 10/28/2023] [Accepted: 10/30/2023] [Indexed: 11/25/2023] Open
Abstract
INTRODUCTION Neutrophil-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and pallets-to-lymphocyte ratio (PLR) are currently validated as cheap and accessible biomarkers in different types of solid tumors, including head and neck cancers (HNC). THE PURPOSE OF THE STUDY To evaluate the possible purposes and biomarker value of NLR, PLR, and MLR recorded pre-treatment (radiotherapy/chemotherapy) in HNC. MATERIALS AND METHODS From 190 patients with HNC included in the oncology records in the oncology outpatient clinic of the Craiova County Emergency Hospital (from January 2002 to December 2022), 39 cases met the inclusion criteria (squamous cell carcinoma and the possibility to calculate the pre-treatment (chemotherapy/radiotherapy) value of NLR, PLR, and MLR. Overall survival (OS) values were correlated with NLR, PLR, and MLR. RESULTS The median values for NLR, PLR, and MLR were 6.15 (1.24-69), 200.79 (61.3-1775.0), and 0.53 (0.12-5.5), respectively. In the study, the mean values for NLR, PLR, and MLR of 2.88, 142.97, and 0.36, respectively, were obtained. The median OS in the study group was 11 months (1-120). Although a negative Pearson's correlation was present, the relationship between the variables was only weak, with values of R = 0.07, p = 0.67, R = 0.02, p = 0.31, and R = 0.07, p = 0.62 being related to NLR, PLR, and MLR, respectively, in correlation with OS. The median values of NLR, PLR, and MLR were calculated (1.53, 90.32, and 0.18, respectively) for the HNC cases with pre-treatment values of NLR < 2 and for the HNC cases with NLR values ≥ 6 (23.5, 232.78, and 0.79, respectively). The median OS for cases with NLR < 2 and NLR ≥ 6 were 17.4 and 13 months, respectively. CONCLUSIONS The comparative analysis of the data highlights a benefit to OS for cases low values of NLR. The role of not only borderline NLR values (between 2 and 6) as a prognostic marker in HNSCC but also the inclusion of PLR and MLR in a prognostic score must also be defined in the future. Prospective studies with more uniformly selected inclusion criteria could demonstrate the value of pre-treatment NLR, PLR, and MLR for treatment stratification through the intensification or de-escalation of non-surgical curative treatment in HNSCC.
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Affiliation(s)
- Camil Ciprian Mireștean
- Department of Medical Oncology and Radiotherapy, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; (C.C.M.); (F.B.)
- Department of Surgery, Railways Clinical Hospital, 700506 Iasi, Romania
| | - Mihai Cosmin Stan
- Department of Surgery, Railways Clinical Hospital, 700506 Iasi, Romania
- Department of Medical Oncology, Vâlcea County Emergency Hospital, 200300 Râmnicu Vâlcea, Romania
| | - Roxana Irina Iancu
- Faculty of Dental Medicine, Oral Pathology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Department of Clinical Laboratory, “Saint Spiridon” County Hospital, 700111 Iasi, Romania
| | - Dragoș Petru Teodor Iancu
- Oncology and Radiotherapy Department, Faculty of Medicine, “Gr. T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania
- Department of Radiation Oncology, Regional Institute of Oncology, 700483 Iași, Romania
| | - Florinel Bădulescu
- Department of Medical Oncology and Radiotherapy, University of Medicine and Pharmacy Craiova, 200349 Craiova, Romania; (C.C.M.); (F.B.)
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Din SRU, Saeed S, Khan SU, Arbi FM, Xuefang G, Zhong M. Bacteria-driven cancer therapy: Exploring advancements and challenges. Crit Rev Oncol Hematol 2023; 191:104141. [PMID: 37742883 DOI: 10.1016/j.critrevonc.2023.104141] [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: 08/08/2023] [Revised: 09/15/2023] [Accepted: 09/18/2023] [Indexed: 09/26/2023] Open
Abstract
Cancer, a serious fatal disease caused by the uncontrolled growth of cells, is the biggest challenge flagging around medicine and health fields. Conventionally, various treatments-based strategies such as radiotherapy, chemotherapy, and alternative cancer therapies possess drugs that cannot reach the cancerous tissues and make them toxic to noncancerous cells. Cancer immunotherapy has made outstanding achievements in reducing the chances of cancer. Our considerable attention towards cancer-directed immune responses and the mechanisms behind which immune cells kill cancer cells have progressively been helpful in the advancement of new therapies. Among them, bacteria-based cancer immunotherapy has achieved much more attention due to smart and robust mechanisms in activating the host anti-tumor response. Moreover, bacterial-based therapy can be utilized as a single monotherapy or in combination with multiple anticancer immunotherapies to accelerate productive clinical results. Herein, we comprehensively reviewed recent advancements, challenges, and future perspectives in developing bacterial-based cancer immunotherapies.
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Affiliation(s)
- Syed Riaz Ud Din
- Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China
| | - Sumbul Saeed
- School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia
| | - Shahid Ullah Khan
- Integrative Science Center of Germplasm Creation in Western China (CHONGQING) Science City and Southwest University, College of Agronomy and Biotechnology, Southwest University, Beibei, Chongqing 400715, China; Engineering Research Center of South Upland Agriculture, Ministry of Education, Chongqing 400715, China; Women Medical and Dental College, Khyber Medical University, Peshawar, KPK 22020, Pakistan
| | - Fawad Mueen Arbi
- Quaid-e-Azam Medical College, Bahawalpur, Punjab 63100, Pakistan
| | - Guo Xuefang
- Department of Medical Microbiology, Dalian Medical University, Dalian 116044, China
| | - Mintao Zhong
- Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian 116044, China.
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Nour SM, Abbasi N, Sadi S, Ravan N, Alipourian A, Yarizadeh M, Soofi A, Ataei A, Tehrany PM. miRNAs as key modulators between normal cells and tumor microenvironment interactions. Chem Biol Drug Des 2023; 102:939-950. [PMID: 37402595 DOI: 10.1111/cbdd.14285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 06/08/2023] [Accepted: 06/12/2023] [Indexed: 07/06/2023]
Abstract
The tumor microenvironment (TME) is well-defined target for understanding tumor progression and various cell types. Major elements of the tumor microenvironment are the followings: endothelial cells, fibroblasts, signaling molecules, extracellular matrix, and infiltrating immune cells. MicroRNAs (miRNAs) are a group of small noncoding RNAs with major functions in the gene expression regulation at post-transcriptional level that have also appeared to exerts key functions in the cancer initiation/progression in diverse biological processes and the tumor microenvironment. This study summarized various roles of miRNAs in the complex interactions between the tumor and normal cells in their microenvironment.
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Affiliation(s)
| | - Nadia Abbasi
- School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sima Sadi
- Medical Doctor, Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Navid Ravan
- Faculty of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Alipourian
- Sleep Disorders Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Mahsa Yarizadeh
- Tehran Medical Branch, Islamic Azad University, Tehran, Iran
| | - Asma Soofi
- Department of Physical Chemistry, School of Chemistry, College of Sciences, University of Tehran, Tehran, Iran
| | - Ali Ataei
- School of Medicine, Bam University of Medical Sciences, Bam, Iran
| | - Pooya M Tehrany
- Faculty of Medicine, National University of Malaysia, Bani, Malaysia
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Batheja S, Sahoo RK, Tarannum S, Vaiphei KK, Jha S, Alexander A, Goyal AK, Gupta U. Hepatocellular carcinoma: Preclinical and clinical applications of nanotechnology with the potential role of carbohydrate receptors. Biochim Biophys Acta Gen Subj 2023; 1867:130443. [PMID: 37573973 DOI: 10.1016/j.bbagen.2023.130443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 08/04/2023] [Accepted: 08/09/2023] [Indexed: 08/15/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common types of liver cancer; accounts for 75-85% of cases. The treatment and management of HCC involve different sanative options like surgery, chemotherapy, immunotherapy, etc. Recently, various advancements have been introduced for the diagnosis and targeting of hepatic tumor cells. Among these, biomarkers are considered the primary source for the diagnosis and differentiation of tumor cells. With the advancement in the field of nanotechnology, different types of nanocarriers have been witnessed in tumor targeting. Nanocarriers such as nanoparticles, liposomes, polymeric micelles, nanofibers, etc. are readily prepared for effective tumor targeting with minimal side-effects. The emergence of various approaches tends to improve the effectiveness of these nanocarriers as demonstrated in ample clinical trials. This review focuses on the significant role of carbohydrates such as mannose, galactose, fructose, etc. in the development, diagnosis, and therapy of HCC. Hence, the current focus of this review is to acknowledge various perspectives regarding the occurrence, diagnosis, treatment, and management of HCC.
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Affiliation(s)
- Sanya Batheja
- Nanopolymeric Drug Delivery Lab, Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan 305817, India
| | - Rakesh Kumar Sahoo
- Nanopolymeric Drug Delivery Lab, Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan 305817, India
| | - Sofiya Tarannum
- Nanopolymeric Drug Delivery Lab, Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan 305817, India
| | - Klaudi K Vaiphei
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sila Katamur, Changsari, Kamrup, Guwahati, Assam 781101, India
| | - Shikha Jha
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sila Katamur, Changsari, Kamrup, Guwahati, Assam 781101, India
| | - Amit Alexander
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Sila Katamur, Changsari, Kamrup, Guwahati, Assam 781101, India
| | - Amit Kumar Goyal
- Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan 305817, India
| | - Umesh Gupta
- Nanopolymeric Drug Delivery Lab, Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandarsindri, Ajmer, Rajasthan 305817, India.
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Wei C. The multifaceted roles of matrix metalloproteinases in lung cancer. Front Oncol 2023; 13:1195426. [PMID: 37766868 PMCID: PMC10520958 DOI: 10.3389/fonc.2023.1195426] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 08/08/2023] [Indexed: 09/29/2023] Open
Abstract
Background Though the matrix metalloproteinases (MMPs) are widely investigated in lung cancer (LC), however, almost no review systematically clarify their multi-faced roles in LC. Methods We investigated the expression of MMPs and their effects on survival of patients with LC, the resistance mechanisms of MMPs in anti-tumor therapy, the regulatory networks of MMPs involved, the function of MMPs inducing CSCLs, MMPs-related tumor immunity, and effects of MMP polymorphisms on risk of LC. Results High expression of MMPs was mainly related to poor survival, high clinical stages and cancer metastasis. Role of MMPs in LC are multi-faced. MMPs are involved in drug resistance, induced CSCLs, participated in tumor immunity. Besides, MMPs polymorphisms may increase risk of LC. Conclusions MMPs might be promising targets to restore the anti-tumor immune response and enhance the killing function of nature immune cells in LC.
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Affiliation(s)
- Cui Wei
- Department of Emergency, The Third Hospital of Changsha, Changsha, China
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Liu H, He R, Yang X, Huang B, Liu H. Mechanism of TCF21 Downregulation Leading to Immunosuppression of Tumor-Associated Macrophages in Non-Small Cell Lung Cancer. Pharmaceutics 2023; 15:2295. [PMID: 37765264 PMCID: PMC10536982 DOI: 10.3390/pharmaceutics15092295] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 08/22/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
Lung cancer, as one of the high-mortality cancers, seriously affects the normal life of people. Non-small cell lung cancer (NSCLC) accounts for a high proportion of the overall incidence of lung cancer, and identifying therapeutic targets of NSCLC is of vital significance. This study attempted to elucidate the regulatory mechanism of transcription factor 21 (TCF21) on the immunosuppressive effect of tumor-associated macrophages (TAM) in NSCLC. The experimental results revealed that the expression of TCF21 was decreased in lung cancer cells and TAM. Macrophage polarization affected T cell viability and tumor-killing greatly, and M2-type polarization reduced the viability and tumor-killing of CD8+T cells. Meanwhile, overexpression of TCF21 promoted the polarization of TAM to M1 macrophages and the enhancement of macrophages to the viability of T cells. Furthermore, there appears to be a targeting relationship between TCF21 and Notch, suggesting that TCF21 exerts its influence via the Notch signaling pathway. This study demonstrated the polarization regulation of TAM to regulate the immunosuppressive effect, which provides novel targets for the treatment of lung cancer.
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Affiliation(s)
- Hong Liu
- Department of Thyroid Oncology, Chongqing University Cancer Hospital, Chongqing 400030, China;
| | - Run He
- School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing 400067, China;
| | - Xuliang Yang
- Department of Thoracic Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400011, China; (X.Y.); (B.H.)
| | - Bo Huang
- Department of Thoracic Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400011, China; (X.Y.); (B.H.)
| | - Hongxiang Liu
- Department of Thoracic Surgery, Chongqing Hospital of Traditional Chinese Medicine, Chongqing 400011, China; (X.Y.); (B.H.)
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Ghaffari S, Rezaei N. Eosinophils in the tumor microenvironment: implications for cancer immunotherapy. J Transl Med 2023; 21:551. [PMID: 37587450 PMCID: PMC10433623 DOI: 10.1186/s12967-023-04418-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 08/05/2023] [Indexed: 08/18/2023] Open
Abstract
Despite being an integral part of the immune response in the tumor microenvironment (TME), few studies have mechanistically elucidated eosinophil functions in cancer outcomes. Eosinophils are a minor population of granulocytes that are mostly explored in asthma and allergic disorders. Their influence on primary and metastatic tumors, however, has recently come to light. Eosinophils' diverse armamentarium of mediators and receptors allows them to participate in innate and adaptive immunity, such as type 1 and type 2 immunity, and shape TME and tumor outcomes. Based on TME cells and cytokines, activated eosinophils drive other immune cells to ultimately promote or suppress tumor growth. Discovering exactly what conditions determine the pro-tumorigenic or anti-tumorigenic role of eosinophils allows us to take advantage of these signals and devise novel strategies to target cancer cells. Here, we first revisit eosinophil biology and differentiation as recognizing eosinophil mediators is crucial to their function in homeostatic and pathological conditions as well as tumor outcome. The bulk of our paper discusses eosinophil interactions with tumor cells, immune cells-including T cells, plasma cells, natural killer (NK) cells-and gut microbiota. Eosinophil mediators, such as IL-5, IL-33, granulocyte-macrophage colony-stimulating factor (GM-CSF), thymic stromal lymphopoietin (TSLP), and CCL11 also determine eosinophil behavior toward tumor cells. We then examine the implications of these findings for cancer immunotherapy approaches, including immune checkpoint blockade (ICB) therapy using immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cell therapy. Eosinophils synergize with CAR T cells and ICB therapy to augment immunotherapies.
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Affiliation(s)
- Sasan Ghaffari
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Xiang L, Rao Q, He B, Guo XH, Xu YD, Luo BP, Zhao G, Wu FH. Role of Cyclin D1b in Inducing Macrophages Toward a Tumor-associated Macrophage-like Phenotype in Murine Breast Cancer. Curr Med Sci 2023; 43:655-667. [PMID: 37391677 DOI: 10.1007/s11596-023-2762-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 03/21/2023] [Indexed: 07/02/2023]
Abstract
OBJECTIVE Tumor-associated macrophages (TAMs) of the M2 phenotype are frequently associated with cancer progression. Invasive cancer cells undergoing epithelial-mesenchymal transition (EMT) have a selective advantage as TAM activators. Cyclin D1b is a highly oncogenic splice variant of cyclin D1. We previously reported that cyclin D1b enhances the invasiveness of breast cancer cells by inducing EMT. However, the role of cyclin D1b in inducing macrophage differentiation toward tumor-associated macrophage-like cells remains unknown. This study aimed to explore the relationship between breast cancer cells overexpressing cyclin D1b and TAMs. METHODS Mouse breast cancer 4T1 cells were transfected with cyclin D1b variant and co-cultured with macrophage cells in a Transwell coculture system. The expression of characteristic cytokines in differentiated macrophages was detected using qRT-PCR, ELISA and zymography assay. Tumor-associated macrophage distribution in a transplanted tumor was detected by immunofluorescence staining. The proliferation and migration ability of breast cancer cells was detected using the cell counting kit-8 (CCK-8) assay, wound healing assay, Transwell invasion assay, and lung metastasis assay. Expression levels of mRNAs were detected by qRT-PCR. Protein expression levels were detected by Western blotting. The integrated analyses of The Cancer Genome Atlas (TCGA) datasets and bioinformatics methods were adopted to discover gene expression, gene coexpression, and overall survival in patients with breast cancer. RESULTS After co-culture with breast cancer cells overexpressing cyclin D1b, RAW264.7 macrophages were differentiated into an M2 phenotype. Moreover, differentiated M2-like macrophages promoted the proliferation and migration of breast cancer cells in turn. Notably, these macrophages facilitated the migration of breast cancer cells in vivo. Further investigations indicated that differentiated M2-like macrophages induced EMT of breast cancer cells accompanied with upregulation of TGF-β1 and integrin β3 expression. CONCLUSION Breast cancer cells transfected with cyclin D1b can induce the differentiation of macrophages into a tumor-associated macrophage-like phenotype, which promotes tumor metastasis in vitro and in vivo.
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Affiliation(s)
- Lei Xiang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Qi Rao
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Bin He
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Xiao-Hong Guo
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Yun-Dan Xu
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, China
| | - Bao-Ping Luo
- Institute of Liver Diseases, Hubei Key Laboratory of the Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China
- Affiliated Hospital of Hubei University of Chinese Medicine, Wuhan, 430074, China
- Hubei Province Academy of Traditional Chinese Medicine, Wuhan, 430074, China
| | - Gang Zhao
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, China.
| | - Feng-Hua Wu
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, 430065, China.
- Institute of Liver Diseases, Hubei Key Laboratory of the Theory and Application Research of Liver and Kidney in Traditional Chinese Medicine, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, 430061, China.
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Ahmad A, Khan P, Rehman AU, Batra SK, Nasser MW. Immunotherapy: an emerging modality to checkmate brain metastasis. Mol Cancer 2023; 22:111. [PMID: 37454123 PMCID: PMC10349473 DOI: 10.1186/s12943-023-01818-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 07/06/2023] [Indexed: 07/18/2023] Open
Abstract
The diagnosis of brain metastasis (BrM) has historically been a dooming diagnosis that is nothing less than a death sentence, with few treatment options for palliation or prolonging life. Among the few treatment options available, brain radiotherapy (RT) and surgical resection have been the backbone of therapy. Within the past couple of years, immunotherapy (IT), alone and in combination with traditional treatments, has emerged as a reckoning force to combat the spread of BrM and shrink tumor burden. This review compiles recent reports describing the potential role of IT in the treatment of BrM in various cancers. It also examines the impact of the tumor microenvironment of BrM on regulating the spread of cancer and the role IT can play in mitigating that spread. Lastly, this review also focuses on the future of IT and new clinical trials pushing the boundaries of IT in BrM.
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Affiliation(s)
- Aatiya Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Parvez Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Asad Ur Rehman
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Surinder Kumar Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE-68198, USA
| | - Mohd Wasim Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE-68198, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Zhao C, Zhang Z, Zhou Y, Wang J, Liu C, Wang X, Liu H. Potential role of lnc-METRNL-1 in the occurrence and prognosis of oral squamous cell carcinoma. 3 Biotech 2023; 13:256. [PMID: 37396471 PMCID: PMC10313615 DOI: 10.1007/s13205-023-03674-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 06/13/2023] [Indexed: 07/04/2023] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors of the head and neck with poor prognosis. This study aimed to explore the role of lnc-METRNL-1 in occurrence and prognosis of OSCC patients. Expression of lnc-METRNL-1 was compared between OSCC samples and paracancerous samples from The Cancer Genome Atlas (TCGA) database. Additionally, the lnc-METRNL-1 expression in cell lines was detected by using qRT-PCR. The overall survival (OS) was estimated based on the Kaplan-Meier and the immune cell infiltration was evaluated using CIBERSORT. Significantly enriched biological pathways were identified by Gene-set enrichment analysis (GSEA). Differential expression analysis was done in edgeR package. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of differential expression genes were conducted using DAVID version 6.8. The lnc-METRNL-1 expression in OSCC was significantly lower than that in paracancerous samples, and patients with low lnc-METRNL-1 expression had poorer OS. Additionally, lnc-METRNL-1 was significantly down-regulated in OSCC cell lines compared with normal cell line. High expression of lnc-METRNL-1 was closely associated with the activation of several tumor metabolic and metabolism-related pathways. Besides, aberrant lnc-METRNL-1 expression was found to be related to the differential infiltration of immune cells in tumor tissue, such as regulatory T cells, and Macrophages. Low lnc-METRNL-1 expression was probably a poor prognostic biomarker for OSCC patients. Moreover, the potential role of lnc-METRNL-1 in the onset of OSCC was partly revealed. Supplementary Information The online version contains supplementary material available at 10.1007/s13205-023-03674-0.
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Affiliation(s)
- Chenguang Zhao
- Department of Emergency and General Dentistry, Tianjin Stomatology Hospital, Hospital of Stomatology, NanKai University·Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, No. 75 Dagubei Road, Heping District, Tianjin, 300041 China
| | - Zhiling Zhang
- Department of Oral and Maxillofacial Surgery, Tianjin Stomatology Hospital, Hospital of Stomatology, NanKai University·Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, No. 75 Dagubei Road, Heping District, Tianjin, 300041 China
| | - Yingrui Zhou
- Department of Emergency and General Dentistry, Tianjin Stomatology Hospital, Hospital of Stomatology, NanKai University·Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, No. 75 Dagubei Road, Heping District, Tianjin, 300041 China
| | - Jinhui Wang
- Department of Emergency and General Dentistry, Tianjin Stomatology Hospital, Hospital of Stomatology, NanKai University·Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, No. 75 Dagubei Road, Heping District, Tianjin, 300041 China
| | - Chunlin Liu
- Department of Emergency and General Dentistry, Tianjin Stomatology Hospital, Hospital of Stomatology, NanKai University·Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, No. 75 Dagubei Road, Heping District, Tianjin, 300041 China
| | - Xi Wang
- Department of Emergency and General Dentistry, Tianjin Stomatology Hospital, Hospital of Stomatology, NanKai University·Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, No. 75 Dagubei Road, Heping District, Tianjin, 300041 China
| | - Hao Liu
- Department of Oral and Maxillofacial Surgery, Tianjin Stomatology Hospital, Hospital of Stomatology, NanKai University·Tianjin Key Laboratory of Oral and Maxillofacial Function Reconstruction, No. 75 Dagubei Road, Heping District, Tianjin, 300041 China
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Hu Y, Paris S, Sahoo N, Bertolet G, Wang Q, Wang Q, Barsoumian HB, Da Silva J, Huang A, Doss DJ, Pollock DP, Hsu E, Selene N, Leyton CSK, Voss TA, Masrorpour F, Ganjoo S, Leuschner C, Pietz JT, Puebla-Osorio N, Gandhi S, Nguyen QN, Wang J, Cortez MA, Welsh JW. Nanoparticle-enhanced proton beam immunoradiotherapy drives immune activation and durable tumor rejection. JCI Insight 2023; 8:e167749. [PMID: 37345658 PMCID: PMC10371249 DOI: 10.1172/jci.insight.167749] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 05/16/2023] [Indexed: 06/23/2023] Open
Abstract
The combination of radiation therapy (RT) and immunotherapy has emerged as a promising treatment option in oncology. Historically, x-ray radiation (XRT) has been the most commonly used form of RT. However, proton beam therapy (PBT) is gaining recognition as a viable alternative, as it has been shown to produce similar outcomes to XRT while minimizing off-target effects. The effects of PBT on the antitumor immune response have only just begun to be described, and to our knowledge no studies to date have examined the effect of PBT as part of a combinatorial immunoradiotherapeutic strategy. Here, using a 2-tumor model of lung cancer in mice, we show that PBT in tandem with an anti-PD1 antibody substantially reduced growth in both irradiated and unirradiated tumors. This was accompanied by robust activation of the immune response, as evidenced by whole-tumor and single-cell RNA sequencing showing upregulation of a multitude of immune-related transcripts. This response was further significantly enhanced by the injection of the tumor to be irradiated with NBTXR3 nanoparticles. Tumors of mice treated with the triple combination exhibited increased infiltration and activation of cytotoxic immune cells. This triple combination eradicated both tumors in 37.5% of the treated mice and showed robust long-term immunity to cancer.
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Affiliation(s)
- Yun Hu
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Sébastien Paris
- Department of Translational Science, Nanobiotix, Paris, France
| | | | - Genevieve Bertolet
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Qi Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Qianxia Wang
- Department of Radiation Physics, and
- Department of Physics and Astronomy, Rice University, Houston, Texas, USA
| | - Hampartsoum B Barsoumian
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jordan Da Silva
- Department of Translational Science, Nanobiotix, Paris, France
| | - Ailing Huang
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | | | | | - Ethan Hsu
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Nanez Selene
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Claudia S Kettlun Leyton
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Tiffany A Voss
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Fatemeh Masrorpour
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Shonik Ganjoo
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Carola Leuschner
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jordan T Pietz
- Department of Strategic Communication, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Nahum Puebla-Osorio
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Saumil Gandhi
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Quynh-Nhu Nguyen
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Maria Angelica Cortez
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - James W Welsh
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Nigam M, Mishra AP, Deb VK, Dimri DB, Tiwari V, Bungau SG, Bungau AF, Radu AF. Evaluation of the association of chronic inflammation and cancer: Insights and implications. Biomed Pharmacother 2023; 164:115015. [PMID: 37321055 DOI: 10.1016/j.biopha.2023.115015] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Revised: 06/02/2023] [Accepted: 06/11/2023] [Indexed: 06/17/2023] Open
Abstract
Among the most extensively researched processes in the development and treatment of cancer is inflammatory condition. Although acute inflammation is essential for the wound healing and reconstruction of tissues that have been damaged, chronic inflammation may contribute to the onset and growth of a number of diseases, including cancer. By disrupting the signaling processes of cells, which result in cancer induction, invasion, and development, a variety of inflammatory molecules are linked to the development of cancer. The microenvironment surrounding the tumor is greatly influenced by inflammatory cells and their subsequent secretions, which also contribute significantly to the tumor's growth, survivability, and potential migration. These inflammatory variables have been mentioned in several publications as prospective diagnostic tools for anticipating the onset of cancer. Targeting inflammation with various therapies can reduce the inflammatory response and potentially limit or block the proliferation of cancer cells. The scientific medical literature from the past three decades has been studied to determine how inflammatory chemicals and cell signaling pathways related to cancer invasion and metastasis are related. The current narrative review updates the relevant literature while highlighting the specifics of inflammatory signaling pathways in cancer and their possible therapeutic possibilities.
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Affiliation(s)
- Manisha Nigam
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Abhay Prakash Mishra
- Department of Pharmacology, Faculty of Health Science, University of Free State, 9300 Bloemfontein, South Africa.
| | - Vishal Kumar Deb
- Dietetics and Nutrition Technology Division, CSIR Institute of Himalayan Bioresource Technology, 176061 Palampur, Himanchal Pradesh, India
| | - Deen Bandhu Dimri
- Department of Biochemistry, Hemvati Nandan Bahuguna Garhwal University, 246174 Srinagar Garhwal, Uttarakhand, India
| | - Vinod Tiwari
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology BHU, Varanasi 221005, Uttar Pradesh, India
| | - Simona Gabriela Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania.
| | - Alexa Florina Bungau
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania
| | - Andrei-Flavius Radu
- Doctoral School of Biomedical Sciences, University of Oradea, 410087 Oradea, Romania; Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania
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Kharouf N, Flanagan TW, Hassan SY, Shalaby H, Khabaz M, Hassan SL, Megahed M, Haikel Y, Santourlidis S, Hassan M. Tumor Microenvironment as a Therapeutic Target in Melanoma Treatment. Cancers (Basel) 2023; 15:3147. [PMID: 37370757 DOI: 10.3390/cancers15123147] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 06/02/2023] [Accepted: 06/07/2023] [Indexed: 06/29/2023] Open
Abstract
The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma.
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Affiliation(s)
- Naji Kharouf
- Biomaterials and Bioengineering, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Unité Mixte de Recherche 1121, 67000 Strasbourg, France
- Department of Endodontics and Conservative Dentistry, Faculty of Dental Medicine, University of Strasbourg, 67000 Strasbourg, France
| | - Thomas W Flanagan
- Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, New Orleans, LA 70112, USA
| | - Sofie-Yasmin Hassan
- Department of Chemistry, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany
| | - Hosam Shalaby
- Department of Urology, School of Medicine, Tulane University, New Orleans, LA 70112, USA
| | - Marla Khabaz
- Department of Production, Beta Factory for Veterinary Pharmaceutical Industries, Damascus 0100, Syria
| | - Sarah-Lilly Hassan
- Department of Chemistry, Faculty of Science, Heinrich-Heine University Duesseldorf, 40225 Dusseldorf, Germany
| | - Mosaad Megahed
- Clinic of Dermatology, University Hospital of Aachen, 52074 Aachen, Germany
| | - Youssef Haikel
- Biomaterials and Bioengineering, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Unité Mixte de Recherche 1121, 67000 Strasbourg, France
- Department of Endodontics and Conservative Dentistry, Faculty of Dental Medicine, University of Strasbourg, 67000 Strasbourg, France
- Pôle de Médecine et Chirurgie Bucco-Dentaire, Hôpital Civil, Hôpitaux Universitaire de Strasbourg, 67000 Strasbourg, France
| | - Simeon Santourlidis
- Epigenetics Core Laboratory, Institute of Transplantation Diagnostics and Cell Therapeutics, Medical Faculty, Heinrich-Heine University Duesseldorf, 40225 Duesseldorf, Germany
| | - Mohamed Hassan
- Biomaterials and Bioengineering, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, Unité Mixte de Recherche 1121, 67000 Strasbourg, France
- Department of Endodontics and Conservative Dentistry, Faculty of Dental Medicine, University of Strasbourg, 67000 Strasbourg, France
- Research Laboratory of Surgery-Oncology, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA
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Xie L, Liu G, Huang Z, Zhu Z, Yang K, Liang Y, Xu Y, Zhang L, Du Z. Tremella fuciformis Polysaccharide Induces Apoptosis of B16 Melanoma Cells via Promoting the M1 Polarization of Macrophages. Molecules 2023; 28:molecules28104018. [PMID: 37241759 DOI: 10.3390/molecules28104018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/03/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Anti-tumor activity of Tremella fuciformis polysaccharides (TFPS) has been widely reported, but its mechanism remains poorly understood. In this study, we established an in vitro co-culture system (B16 melanoma cells and RAW 264.7 macrophage-like cells) to explore the potential anti-tumor mechanism of TFPS. Based on our results, TFPS exhibited no inhibition on the cell viability of B16 cells. However, significant apoptosis was observed when B16 cells were co-cultured with TFPS-treated RAW 264.7 cells. We further found that mRNA levels of M1 macrophage markers including iNOS and CD80 were significantly upregulated in TFPS-treated RAW 264.7 cells, while M2 macrophage markers such as Arg-1 and CD 206 remained unchanged. Besides, the migration, phagocytosis, production of inflammatory mediators (NO, IL-6 and TNF-α), and protein expression of iNOS and COX-2 were markedly enhanced in TFPS-treated RAW 264.7 cells. Network pharmacology analysis indicated that MAPK and NF-κB signaling pathways may be involved in M1 polarization of macrophages, and this hypothesis was verified by Western blot. In conclusion, our research demonstrated that TFPS induced apoptosis of melanoma cells by promoting M1 polarization of macrophages, and suggested TFPS may be applied as an immunomodulatory for cancer therapy.
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Affiliation(s)
- Lingna Xie
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Guangrong Liu
- Infinitus Company Ltd., 11 Sicheng Road, Tianhe District, Guangzhou 510000, China
| | - Zebin Huang
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Zhenyuan Zhu
- State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science and Technology, Tianjin 300457, China
- College of Food Science and Engineering, Tianjin University of Science and Technology, Tianjin 300457, China
| | - Kaiye Yang
- Infinitus Company Ltd., 11 Sicheng Road, Tianhe District, Guangzhou 510000, China
| | - Yiheng Liang
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Yani Xu
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
| | - Lanyue Zhang
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
- Guangdong Provincial Key Laboratory of Plant Resources Biorefinery, Guangdong University of Technology, Guangzhou 510006, China
| | - Zhiyun Du
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
- Guangdong Provincial Key Laboratory of Plant Resources Biorefinery, Guangdong University of Technology, Guangzhou 510006, China
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Fan YN, Zhao G, Zhang Y, Ye QN, Sun YQ, Shen S, Liu Y, Xu CF, Wang J. Progress in nanoparticle-based regulation of immune cells. MEDICAL REVIEW (2021) 2023; 3:152-179. [PMID: 37724086 PMCID: PMC10471115 DOI: 10.1515/mr-2022-0047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 03/03/2023] [Indexed: 09/20/2023]
Abstract
Immune cells are indispensable defenders of the human body, clearing exogenous pathogens and toxicities or endogenous malignant and aging cells. Immune cell dysfunction can cause an inability to recognize, react, and remove these hazards, resulting in cancers, inflammatory diseases, autoimmune diseases, and infections. Immune cells regulation has shown great promise in treating disease, and immune agonists are usually used to treat cancers and infections caused by immune suppression. In contrast, immunosuppressants are used to treat inflammatory and autoimmune diseases. However, the key to maintaining health is to restore balance to the immune system, as excessive activation or inhibition of immune cells is a common complication of immunotherapy. Nanoparticles are efficient drug delivery systems widely used to deliver small molecule inhibitors, nucleic acid, and proteins. Using nanoparticles for the targeted delivery of drugs to immune cells provides opportunities to regulate immune cell function. In this review, we summarize the current progress of nanoparticle-based strategies for regulating immune function and discuss the prospects of future nanoparticle design to improve immunotherapy.
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Affiliation(s)
- Ya-Nan Fan
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong Province, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong Province, China
| | - Gui Zhao
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong Province, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong Province, China
| | - Yue Zhang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong Province, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong Province, China
| | - Qian-Ni Ye
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong Province, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, Guangdong Province, China
| | - Yi-Qun Sun
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong Province, China
- Key Laboratory of Biomedical Materials and Engineering of the Ministry of Education, South China University of Technology, Guangzhou, Guangdong Province, China
| | - Song Shen
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong Province, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong Province, China
| | - Yang Liu
- Department of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Cong-Fei Xu
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong Province, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong Province, China
| | - Jun Wang
- School of Biomedical Sciences and Engineering, South China University of Technology, Guangzhou International Campus, Guangzhou, Guangdong Province, China
- National Engineering Research Center for Tissue Restoration and Reconstruction, South China University of Technology, Guangzhou, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Biomedical Engineering, South China University of Technology, Guangzhou, Guangdong Province, China
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Zhang Y, Li H, Lv L, Lu K, Li H, Zhang W, Cui T. Autophagy: Dual roles and perspective for clinical treatment of colorectal cancer. Biochimie 2023; 206:49-60. [PMID: 36244578 DOI: 10.1016/j.biochi.2022.10.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 09/29/2022] [Accepted: 10/09/2022] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) raises concerns to people because of its high recurrence and metastasis rate, diagnosis challenges, and poor prognosis. Various studies have shown the association of altered autophagy with tumorigenesis, tumor-stroma interactions, and resistance to cancer therapy in CRC. Autophagy is a highly conserved cytosolic catabolic process in eukaryotes that plays distinct roles in CRC occurrence and progression. In early tumorigenesis, autophagy may inhibit tumor growth through diverse mechanisms, whereas it exhibits a tumor promoting function in CRC progression. This different functions of autophagy in CRC occurrence and progression make developing therapies targeting autophagy complicated. In this review, we discuss the classification and process of autophagy as well as its dual roles in CRC, functions in the tumor microenvironment, cross-talk with apoptosis, and potential usefulness as a CRC therapeutic target.
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Affiliation(s)
- Yabin Zhang
- West China Second University Hospital, State Key Laboratory of Biotherapy, Laboratory of Metabolomics and Gynecological Disease Research and Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 610041, Chengdu, China
| | - Haiyan Li
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Liang Lv
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Kefeng Lu
- Department of Neurosurgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Huihui Li
- West China Second University Hospital, State Key Laboratory of Biotherapy, Laboratory of Metabolomics and Gynecological Disease Research and Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 610041, Chengdu, China
| | - Wenli Zhang
- Department of Orthopedics, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Tao Cui
- West China Second University Hospital, State Key Laboratory of Biotherapy, Laboratory of Metabolomics and Gynecological Disease Research and Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 610041, Chengdu, China.
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de Miguel-Perez D, Russo A, Gunasekaran M, Buemi F, Hester L, Fan X, Carter-Cooper BA, Lapidus RG, Peleg A, Arroyo-Hernández M, Cardona AF, Naing A, Hirsch FR, Mack PC, Kaushal S, Serrano MJ, Adamo V, Arrieta O, Rolfo C. Baseline extracellular vesicle TGF-β is a predictive biomarker for response to immune checkpoint inhibitors and survival in non-small cell lung cancer. Cancer 2023; 129:521-530. [PMID: 36484171 DOI: 10.1002/cncr.34576] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Revised: 10/09/2022] [Accepted: 10/24/2022] [Indexed: 12/14/2022]
Abstract
BACKGROUND Immune-checkpoint inhibitors (ICIs) are an effective therapeutic strategy, improving the survival of patients with lung cancer compared with conventional treatments. However, novel predictive biomarkers are needed to stratify which patients derive clinical benefit because the currently used and highly heterogenic histological PD-L1 has shown low accuracy. Liquid biopsy is the analysis of biomarkers in body fluids and represents a minimally invasive tool that can be used to monitor tumor evolution and treatment effects, potentially reducing biases associated with tumor heterogeneity associated with tissue biopsies. In this context, cytokines, such as transforming growth factor-β (TGF-β), can be found free in circulation in the blood and packaged into extracellular vesicles (EVs), which have a specific delivery tropism and can affect in tumor/immune system interaction. TGF-β is an immunosuppressive cytokine that plays a crucial role in tumor immune escape, treatment resistance, and metastasis. Thus, we aimed to evaluate the predictive value of circulating and EV TGF-β in patients with non-small-cell lung cancer receiving ICIs. METHODS Plasma samples were collected in 33 patients with advanced non-small-cell lung cancer before and during treatment with ICIs. EV were isolated from plasma by serial ultracentrifugation methods and circulating and EV TGF-β expression levels were evaluated by enzyme-linked immunosorbent assay. RESULTS Baseline high expression of TGF-β in EVs was associated with nonresponse to ICIs as well as shorter progression-free survival and overall survival, outperforming circulating TGF-β levels and tissue PD-L1 as a predictive biomarker. CONCLUSION If validated, EV TGF-β could be used to improve patient stratification, increasing the effectiveness of treatment with ICIs and potentially informing combinatory treatments with TGF-β blockade. PLAIN LANGUAGE SUMMARY Treatment with immune-checkpoint inhibitors (ICIs) has improved the survival of some patients with lung cancer. However, the majority of patients do not benefit from this treatment, making it essential to develop more reliable biomarkers to identify patients most likely to benefit. In this pilot study, the expression of transforming growth factor-β (TGF-β) in blood circulation and in extracellular vesicles was analyzed. The levels of extracellular vesicle TGF-β before treatment were able to determine which patients would benefit from treatment with ICIs and have a longer survival with higher accuracy than circulating TGF-β and tissue PD-L1, which is the currently used biomarker in clinical practice.
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Affiliation(s)
- Diego de Miguel-Perez
- Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, Mount Sinai, New York, New York, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Alessandro Russo
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Medical Oncology Unit, A.O. Papardo & Department of Human Pathology, University of Messina, Messina, Italy
| | - Muthukumar Gunasekaran
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Departments of Surgery and Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Francesco Buemi
- Medical Oncology Unit, A.O. Papardo & Department of Human Pathology, University of Messina, Messina, Italy
| | - Lisa Hester
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Xiaoxuan Fan
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Brandon A Carter-Cooper
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Rena G Lapidus
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Ariel Peleg
- Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | | | - Andres F Cardona
- Luis Carlos Sarmiento Angulo Cancer Treatment and Research Center (CTIC)/Foundation for Clinical and Applied Cancer Research (FICMAC)/Molecular Oncology and Biology Systems Research Group (Fox-G), Universidad El Bosque, Bogota, Colombia
| | - Aung Naing
- Departments of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Fred R Hirsch
- Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Philip C Mack
- Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, Mount Sinai, New York, New York, USA
| | - Sunjay Kaushal
- Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.,Departments of Surgery and Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Maria Jose Serrano
- GENYO Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Granada, Spain
| | - Vincenzo Adamo
- Medical Oncology Unit, A.O. Papardo & Department of Human Pathology, University of Messina, Messina, Italy
| | - Oscar Arrieta
- Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - Christian Rolfo
- Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai Medical System & Icahn School of Medicine, Mount Sinai, New York, New York, USA.,Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Wang L, Qin X, Zhang Y, Xue S, Song X. The prognostic predictive value of systemic immune index and systemic inflammatory response index in nasopharyngeal carcinoma: A systematic review and meta-analysis. Front Oncol 2023; 13:1006233. [PMID: 36816962 PMCID: PMC9936064 DOI: 10.3389/fonc.2023.1006233] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Objective To study the predictive value of systemic immune index (SII) and systemic inflammatory response index (SIRI) in the prognosis of patients with nasopharyngeal carcinoma. Methods Two researchers independently searched PubMed, Cochrane, Embase, and Web of Science databases (until March 18, 2022) for all studies on SII, SIRI, and prognosis in patients with nasopharyngeal carcinoma. Quality assessment of included studies was assessed using the Newcastle-Ottawa Scale (NOS). In addition, a bivariate mixed-effects model was used to explore predictive value. Results A total of 9 studies that satisfied the requirements were included, involving, 3187 patients with nasopharyngeal carcinoma. The results of the meta-analysis showed that SII could be an independent predictor of OS (HR=1.78, 95%CI [1.44-2.20], Z=5.28, P<0.05), and SII could also be an independent predictor of PFS (HR=1.66, 95%CI [1.36-2.03], Z=4.94, P<0.05). In addition, SIRI could also serve as an independent predictor of OS (HR=2.88, 95%CI [1.97-4.19], Z=5.51, P<0.05). The ROC area was 0.63, the sensitivity was 0.68 (95%CI [0.55-0.78]), and the specificity was 0.55 (95%CI [0.47-0.62]), all of which indicated that SII had a certain predictive value for OS. Conclusion SII and SIRI can be used as independent predictors to predict the prognosis and survival status of patients with nasopharyngeal carcinoma and have certain predictive accuracy. Therefore, SII and SIRI should be considered in studies that update survival risk assessment systems. Systematic Review Registration https://www.ytyhdyy.com/, identifier PROSPERO (CRD42022319678).
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Affiliation(s)
- Li Wang
- Otorhinolaryngology Head and Neck Surgery, Yantai Yuhuangding Hospital, Yantai Shandong, China,*Correspondence: Li Wang, ; Xicheng Song,
| | - Xianfei Qin
- School of Clinical Medicine, Binzhou Medical University, Yantai, China
| | - Yu Zhang
- Otorhinolaryngology Head and Neck Surgery, Yantai Yuhuangding Hospital, Yantai Shandong, China
| | - Shouyu Xue
- Otorhinolaryngology Head and Neck Surgery, Yantai Yuhuangding Hospital, Yantai Shandong, China
| | - Xicheng Song
- Otorhinolaryngology Head and Neck Surgery, Yantai Yuhuangding Hospital, Yantai Shandong, China,*Correspondence: Li Wang, ; Xicheng Song,
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49
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Zwager MC, Bense R, Waaijer S, Qiu SQ, Timmer-Bosscha H, de Vries EGE, Schröder CP, van der Vegt B. Assessing the role of tumour-associated macrophage subsets in breast cancer subtypes using digital image analysis. Breast Cancer Res Treat 2023; 198:11-22. [PMID: 36622544 PMCID: PMC9883348 DOI: 10.1007/s10549-022-06859-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 12/29/2022] [Indexed: 01/10/2023]
Abstract
PURPOSE The number of M1-like and M2-like tumour-associated macrophages (TAMs) and their ratio can play a role in breast cancer development and progression. Early clinical trials using macrophage targeting compounds are currently ongoing. However, the most optimal detection method of M1-like and M2-like macrophage subsets and their clinical relevance in breast cancer is still unclear. We aimed to optimize the assessment of TAM subsets in different breast cancer subtypes, and therefore related TAM subset numbers and ratio to clinicopathological characteristics and clinical outcome. METHODS Tissue microarrays of 347 consecutive primary Luminal-A, Luminal-B, HER2-positive and triple-negative tumours of patients with early-stage breast cancer were serially sectioned and immunohistochemically stained for the pan-macrophage marker CD68 and the M2-like macrophage markers CD163, CSF-1R and CD206. TAM numbers were quantified using a digital image analysis algorithm. M1-like macrophage numbers were calculated by subtracting M2-like TAM numbers from the total TAM number. RESULTS M2-like markers CD163 and CSF-1R showed a moderate positive association with each other and with CD68 (r ≥ 0.47), but only weakly with CD206 (r ≤ 0.06). CD68 + , CD163 + and CSF-1R + macrophages correlated with tumour grade in Luminal-B tumours (P < 0.001). Total or subset TAM numbers did not correlate with disease outcome in any breast cancer subtype. CONCLUSION In conclusion, macrophages and their subsets can be detected by means of a panel of TAM markers and are related to unfavourable clinicopathological characteristics in Luminal-B breast cancer. However, their impact on outcome remains unclear. Preferably, this should be determined in prospective series.
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Affiliation(s)
- Mieke C. Zwager
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rico Bense
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Stijn Waaijer
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Si-Qi Qiu
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Diagnosis and Treatment Center of Breast Diseases, Clinical Research Center, Shantou Central Hospital, Shantou, China
- Guangdong Provincial Key Laboratory for Breast Cancer Diagnosis and Treatment, Shantou University Medical College, Shantou, China
| | - Hetty Timmer-Bosscha
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Elisabeth G. E. de Vries
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Carolien P. Schröder
- Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Medical Oncology, Dutch Cancer Institute, Amsterdam, Netherlands
| | - Bert van der Vegt
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands
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50
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Wang HK, Wei Q, Yang YL, Lu TY, Yan Y, Wang F. Clinical usefulness of the lymphocyte-to-monocyte ratio and aggregate index of systemic inflammation in patients with esophageal cancer: a retrospective cohort study. Cancer Cell Int 2023; 23:13. [PMID: 36707809 PMCID: PMC9881346 DOI: 10.1186/s12935-023-02856-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Accepted: 01/21/2023] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Multiple perioperative inflammatory markers are considered important factors affecting the long-term survival of esophageal cancer (EC) patients. Hematological parameters, whether single or combined, have high predictive value. AIM To investigate the inflammatory status of patients with preoperative EC using blood inflammatory markers, and to establish and validate competing risk nomogram prediction models for overall survival (OS) and progression-free survival (PFS) in EC patients. METHODS A total of 508 EC patients who received radical surgery (RS) treatment in The First Affiliated Hospital of Zhengzhou University from August 5, 2013, to May 1, 2019, were enrolled and randomly divided into a training cohort (356 cases) and a validation cohort (152 cases). We performed least absolute shrinkage and selection operator (LASSO)-univariate Cox- multivariate Cox regression analyses to establish nomogram models. The index of concordance (C-index), time-dependent receiver operating characteristic (ROC) curves, time-dependent area under curve (AUC) and calibration curves were used to evaluate the discrimination and calibration of the nomograms, and decision curve analysis (DCA) was used to evaluate the net benefit of the nomograms. The relative integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were calculated to evaluate the improvement in predictive accuracy of our new model compared with the AJCC staging system and another traditional model. Finally, the relationship between systemic inflammatory response markers and prognostic survival was explored according to risk plot, time-dependent AUC, Kaplan-Meier and restricted cubic spline (RCS). RESULTS Based on the multivariate analysis for overall survival (OS) in the training cohort, nomograms with 10 variables, including the aggregate index of systemic inflammation (AISI) and lymphocyte-to-monocyte ratio (LMR), were established. Time-dependent ROC, time-dependent AUC, calibration curves, and DCA showed that the 1-, 3-, and 5 year OS and PFS probabilities predicted by the nomograms were consistent with the actual observations. The C-index, NRI, and IDI of the nomograms showed better performance than the AJCC staging system and another prediction model. Moreover, risk plot, time-dependent AUC, and Kaplan-Meier showed that higher AISI scores and lower LMR were associated with poorer prognosis, and there was a nonlinear relationship between them and survival risk. CONCLUSION AISI and LMR are easy to obtain, reproducible and minimally invasive prognostic tools that can be used as markers to guide the clinical treatment and prognosis of patients with EC.
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Affiliation(s)
- Hui-Ke Wang
- grid.412633.10000 0004 1799 0733Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.50 Eastern Jianshe Road, Zhengzhou, 450052 Henan China
| | - Qian Wei
- grid.412633.10000 0004 1799 0733Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.50 Eastern Jianshe Road, Zhengzhou, 450052 Henan China
| | - Ya-Lan Yang
- grid.412633.10000 0004 1799 0733Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.50 Eastern Jianshe Road, Zhengzhou, 450052 Henan China
| | - Tai-Ying Lu
- grid.412633.10000 0004 1799 0733Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.50 Eastern Jianshe Road, Zhengzhou, 450052 Henan China
| | - Yan Yan
- grid.412633.10000 0004 1799 0733Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.50 Eastern Jianshe Road, Zhengzhou, 450052 Henan China
| | - Feng Wang
- grid.412633.10000 0004 1799 0733Department of Oncology, The First Affiliated Hospital of Zhengzhou University, No.50 Eastern Jianshe Road, Zhengzhou, 450052 Henan China
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