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Pan Y, Zhang X, Diao C, Zhang J, Lin Y, Sun X, Li M, Gao F. [ 68Ga]Ga-NOTA-C-IPB-AIT: A novel radiotracer for in vivo detection of TREM-1 expression. Bioorg Chem 2025; 162:108611. [PMID: 40403496 DOI: 10.1016/j.bioorg.2025.108611] [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: 04/20/2025] [Revised: 05/05/2025] [Accepted: 05/16/2025] [Indexed: 05/24/2025]
Abstract
Triggering receptor expressed on myeloid cells 1 (TREM-1) plays a critical role in the initiation and advancement of cancer. The noninvasive and rapid detection of TREM-1 expression provides a significant value for oncologic diagnosis, tumor evaluation and the guide of TREM-1-targeted therapy. In this study, we developed three peptide-based TREM-1 targeted radiotracers and evaluated their radiochemical and biological properties, in order to identify the candidate for the detection of TREM-1 expression on tumors. Among three radiotracers, [68Ga]Ga-NOTA-C-IPB-AIT showed a high radiochemical purity (> 98 %), excellent stability and hydrophilicity, favorable binding affinity, remarkable tumor uptake, ideal tumor-to-muscle ratio, and prolonged tumor retention, indicating that it is promising for potential use in TREM-1 expression detection.
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Affiliation(s)
- Yuan Pan
- Key Laboratory for Experimental Teratology of the Ministry of Education and Research Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Xiaoli Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Research Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China; Department of Radiation Oncology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
| | - Can Diao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Research Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Jinglin Zhang
- Key Laboratory for Experimental Teratology of the Ministry of Education and Research Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Yixiang Lin
- Key Laboratory for Experimental Teratology of the Ministry of Education and Research Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
| | - Xiangyang Sun
- Department of Radiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
| | - Min Li
- Department of Nuclear Medicine, 960th Hospital of PLA, Jinan, Shandong, China.
| | - Feng Gao
- Key Laboratory for Experimental Teratology of the Ministry of Education and Research Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
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Yi F, Wu H, Zhao HK. Role of triggering receptor expressed on myeloid cells 1/2 in secondary injury after cerebral hemorrhage. World J Clin Cases 2025; 13:100312. [PMID: 40144485 PMCID: PMC11670023 DOI: 10.12998/wjcc.v13.i9.100312] [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: 08/13/2024] [Revised: 10/26/2024] [Accepted: 11/27/2024] [Indexed: 12/12/2024] Open
Abstract
Intracerebral hemorrhage (ICH) is a common severe emergency in neurosurgery, causing tremendous economic pressure on families and society and devastating effects on patients both physically and psychologically, especially among patients with poor functional outcomes. ICH is often accompanied by decreased consciousness and limb dysfunction. This seriously affects patients' ability to live independently. Although rapid advances in neurosurgery have greatly improved patient survival, there remains insufficient evidence that surgical treatment significantly improves long-term outcomes. With in-depth pathophysiological studies after ICH, increasing evidence has shown that secondary injury after ICH is related to long-term prognosis and that the key to secondary injury is various immune-mediated neuroinflammatory reactions after ICH. In basic and clinical studies of various systemic inflammatory diseases, triggering receptor expressed on myeloid cells 1/2 (TREM-1/2), and the TREM receptor family is closely related to the inflammatory response. Various inflammatory diseases can be upregulated and downregulated through receptor intervention. How the TREM receptor functions after ICH, the types of results from intervention, and whether the outcomes can improve secondary brain injury and the long-term prognosis of patients are unknown. An analysis of relevant research results from basic and clinical trials revealed that the inhibition of TREM-1 and the activation of TREM-2 can alleviate the neuroinflammatory immune response, significantly improve the long-term prognosis of neurological function in patients with cerebral hemorrhage, and thus improve the ability of patients to live independently.
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Affiliation(s)
- Fan Yi
- Xi’an Medical University, Xi’an 710021, Shaanxi Province, China
| | - Hao Wu
- Xi’an Medical University, Xi’an 710021, Shaanxi Province, China
- Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Medical University, Xi’an 710038, Shaanxi Province, China
| | - Hai-Kang Zhao
- Department of Neurosurgery, The Second Affiliated Hospital of Xi’an Medical University, Xi’an 710038, Shaanxi Province, China
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Ramatchandirin B, Balamurugan MA, Desiraju S, Chung Y, Wojczyk BS, MohanKumar K. Stored RBC transfusions leads to the systemic inflammatory response syndrome in anemic murine neonates. Inflamm Res 2024; 73:1859-1873. [PMID: 39235608 PMCID: PMC11540732 DOI: 10.1007/s00011-024-01936-y] [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] [Revised: 07/29/2024] [Accepted: 08/16/2024] [Indexed: 09/06/2024] Open
Abstract
OBJECTIVE RBC transfusions (RBCT) are life-saving treatment for premature and critically ill infants. However, the procedure has been associated with the development of systemic inflammatory response syndrome (SIRS) and potentially multiple organ dysfunction syndrome (MODS) in neonates. The present study aimed to investigate the mechanisms of RBCT-related SIRS in severely anemic murine neonates. METHODS C57BL/6 (WT), TLR4-/- and myeloid-specific triggered myeloid receptor-1 (trem1)-/- mouse pups were studied in 4 groups (n = 6 each): (1) naïve controls, (2) transfused control, (3) anemic (hematocrit 20-24%) and (4) anemic with RBC transfused using our established murine model of phlebotomy-induced anemia (PIA) and RBC transfusion. Plasma was measured for quantifying inflammatory cytokines (IFN-γ, IL-1β, TNF-α, IL-6, MIP-1α, MIP-1β, MIP2 and LIX) using a Luminex assay. In vitro studies included (i) sensitization by exposing the cells to a low level of lipopolysaccharide (LPS; 500 ng/ml) and (ii) trem1-siRNA transfection with/without plasma supernatant from stored RBC to assess the acute inflammatory response through trem1 by qRT-PCR and immunoblotting. RESULTS Anemic murine pups developed cytokine storm within 2 h of receiving stored RBCs, which increased until 6 h post-transfusion, as compared to non-anemic mice receiving stored RBCTs ("transfusion controls"), in a TLR4-independent fashion. Nonetheless, severely anemic pups had elevated circulating endotoxin levels, thereby sensitizing circulating monocytes to presynthesize proinflammatory cytokines (IFN-γ, IL-1β, TNF-α, IL-6, MIP-1α, MIP-1β, MIP2, LIX) and express trem1. Silencing trem1 expression in Raw264.7 cells mitigated both endotoxin-associated presynthesis of proinflammatory cytokines and the RBCT-induced release of inflammatory cytokines. Indeed, myeloid-specific trem1-/- murine pups had significantly reduced evidence of SIRS following RBCTs. CONCLUSION Severe anemia-associated low-grade inflammation sensitizes monocytes to enhance the synthesis of proinflammatory cytokines and trem1. In this setting, RBCTs further activate these monocytes, thereby inducing SIRS. Inhibiting trem1 in myeloid cells, including monocytes, alleviates the inflammatory response associated with the combined effects of anemia and RBCTs in murine neonates.
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Affiliation(s)
- Balamurugan Ramatchandirin
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Marie Amalie Balamurugan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Suneetha Desiraju
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Yerin Chung
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA
| | - Boguslaw S Wojczyk
- Department of Pathology and Cell Biology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, 10032, USA
| | - Krishnan MohanKumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
- Child Health Research Institute, Omaha, NE, 68198, USA.
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Zhang B, Liu J, Mo Y, Zhang K, Huang B, Shang D. CD8 + T cell exhaustion and its regulatory mechanisms in the tumor microenvironment: key to the success of immunotherapy. Front Immunol 2024; 15:1476904. [PMID: 39372416 PMCID: PMC11452849 DOI: 10.3389/fimmu.2024.1476904] [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: 08/06/2024] [Accepted: 09/04/2024] [Indexed: 10/08/2024] Open
Abstract
A steady dysfunctional state caused by chronic antigen stimulation in the tumor microenvironment (TME) is known as CD8+ T cell exhaustion. Exhausted-like CD8+ T cells (CD8+ Tex) displayed decreased effector and proliferative capabilities, elevated co-inhibitory receptor generation, decreased cytotoxicity, and changes in metabolism and transcription. TME induces T cell exhaustion through long-term antigen stimulation, upregulation of immune checkpoints, recruitment of immunosuppressive cells, and secretion of immunosuppressive cytokines. CD8+ Tex may be both the reflection of cancer progression and the reason for poor cancer control. The successful outcome of the current cancer immunotherapies, which include immune checkpoint blockade and adoptive cell treatment, depends on CD8+ Tex. In this review, we are interested in the intercellular signaling network of immune cells interacting with CD8+ Tex. These findings provide a unique and detailed perspective, which is helpful in changing this completely unpopular state of hypofunction and intensifying the effect of immunotherapy.
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Affiliation(s)
- Biao Zhang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jinming Liu
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yuying Mo
- Department of Oncology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Kexin Zhang
- Central Laboratory, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Bingqian Huang
- Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Department of Clinical Pharmacy, Affiliated Hangzhou First People’s Hospital, Westlake University, Hangzhou, China
| | - Dong Shang
- Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
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Ren L, Qiao GL, Zhang SX, Zhang ZM, Lv SX. Pharmacological Inhibition or Silencing of TREM1 Restrains HCC Cell Metastasis by Inactivating TLR/PI3K/AKT Signaling. Cell Biochem Biophys 2024; 82:2673-2685. [PMID: 38954352 DOI: 10.1007/s12013-024-01377-8] [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: 05/11/2024] [Accepted: 06/18/2024] [Indexed: 07/04/2024]
Abstract
Hepatocellular carcinoma (HCC), a widely prevalent malignancy strongly linked to inflammation, remains a significant public health concern. Triggering receptor expressed on myeloid cells 1 (TREM1), a modulator of inflammatory responses identified in recent years, has emerged as a crucial facilitator in cancer progression. Despite its significance, the precise regulatory mechanism of TREM1 in HCC metastasis remains unanswered. In the present investigation, we observed aberrant upregulation of TREM1 in HCC tissues, which was significantly linked to poorer overall survival. Inhibition of TREM1 expression resulted in a significant reduction in HCC Huh-7 and MHCC-97H cell proliferation, invasion, and epithelial-mesenchymal transition (EMT) process. Furthermore, inhibiting TREM1 decreased protein expressions of toll-like receptor 2/4 (TLR2/4) and major myeloid differentiation response gene 88 (MyD88), leading to the inactivation of phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT) in HCC cells. Notably, these effects were reversed by treatment with TLR2-specific agonist (CU-T12-9), indicating a potential crosstalk between TREM1 and TLR2/4. Mechanistic studies revealed a direct interaction between TREM1 and both TLR2 and TLR4. In vivo studies demonstrated that inhibition of TREM1 suppressed the growth of HCC cells in the orthotopic implant model and its metastatic potential in the experimental lung metastasis model. Overall, our findings underscore the role of TREM1 inhibition in regulating EMT and metastasis of HCC cells by inactivating the TLR/PI3K/AKT signaling pathway, thereby providing deeper mechanistic insights into how TREM1 regulates metastasis during HCC progression.
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Affiliation(s)
- Ling Ren
- Department of Gastroenterology, The Affifiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
- Department of Gastroenterology, The Affiliated Hospital of Kangda College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Guang-Lei Qiao
- Department of Oncology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shu-Xian Zhang
- Department of Gastroenterology, The Affifiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
- Department of Gastroenterology, The Affiliated Hospital of Kangda College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Zhi-Mei Zhang
- Department of Gastroenterology, The Affifiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
- Department of Gastroenterology, The Affiliated Hospital of Kangda College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China
| | - Sheng-Xiang Lv
- Department of Gastroenterology, The Affifiliated Lianyungang Hospital of Xuzhou Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China.
- Department of Gastroenterology, The Affiliated Hospital of Kangda College of Nanjing Medical University, The First People's Hospital of Lianyungang, Lianyungang, Jiangsu, China.
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Fan Y, Xu Y, Huo Z, Zhang H, Peng L, Jiang X, Thomson AW, Dai H. Role of triggering receptor expressed on myeloid cells-1 in kidney diseases: A biomarker and potential therapeutic target. Chin Med J (Engl) 2024; 137:1663-1673. [PMID: 38809056 PMCID: PMC11268828 DOI: 10.1097/cm9.0000000000003197] [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: 02/05/2024] [Indexed: 05/30/2024] Open
Abstract
ABSTRACT Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of the immunoglobulin superfamily. As an amplifier of the inflammatory response, TREM-1 is mainly involved in the production of inflammatory mediators and the regulation of cell survival. TREM-1 has been studied in infectious diseases and more recently in non-infectious disorders. More and more studies have shown that TREM-1 plays an important pathogenic role in kidney diseases. There is evidence that TREM-1 can not only be used as a biomarker for diagnosis of disease but also as a potential therapeutic target to guide the development of novel therapeutic agents for kidney disease. This review summarized molecular biology of TREM-1 and its signaling pathways as well as immune response in the progress of acute kidney injury, renal fibrosis, diabetic nephropathy, immune nephropathy, and renal cell carcinoma.
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Affiliation(s)
- Yuxi Fan
- Department of Immunology, School of Basic Medical Science, Central South University, Changsha, Hunan 410013, China
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Ye Xu
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
- Medical College of Guangxi University, Nanning, Guangxi 530004, China
| | - Zhi Huo
- Department of Immunology, School of Basic Medical Science, Central South University, Changsha, Hunan 410013, China
| | - Hedong Zhang
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Longkai Peng
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
| | - Xin Jiang
- Department of Organ Transplantation, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People’s Hospital), Zhengzhou, Henan 450000, China
| | - Angus W. Thomson
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Helong Dai
- Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China
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Guimarães GR, Maklouf GR, Teixeira CE, de Oliveira Santos L, Tessarollo NG, de Toledo NE, Serain AF, de Lanna CA, Pretti MA, da Cruz JGV, Falchetti M, Dimas MM, Filgueiras IS, Cabral-Marques O, Ramos RN, de Macedo FC, Rodrigues FR, Bastos NC, da Silva JL, Lummertz da Rocha E, Chaves CBP, de Melo AC, Moraes-Vieira PMM, Mori MA, Boroni M. Single-cell resolution characterization of myeloid-derived cell states with implication in cancer outcome. Nat Commun 2024; 15:5694. [PMID: 38972873 PMCID: PMC11228020 DOI: 10.1038/s41467-024-49916-4] [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: 07/31/2023] [Accepted: 06/19/2024] [Indexed: 07/09/2024] Open
Abstract
Tumor-associated myeloid-derived cells (MDCs) significantly impact cancer prognosis and treatment responses due to their remarkable plasticity and tumorigenic behaviors. Here, we integrate single-cell RNA-sequencing data from different cancer types, identifying 29 MDC subpopulations within the tumor microenvironment. Our analysis reveals abnormally expanded MDC subpopulations across various tumors and distinguishes cell states that have often been grouped together, such as TREM2+ and FOLR2+ subpopulations. Using deconvolution approaches, we identify five subpopulations as independent prognostic markers, including states co-expressing TREM2 and PD-1, and FOLR2 and PDL-2. Additionally, TREM2 alone does not reliably predict cancer prognosis, as other TREM2+ macrophages show varied associations with prognosis depending on local cues. Validation in independent cohorts confirms that FOLR2-expressing macrophages correlate with poor clinical outcomes in ovarian and triple-negative breast cancers. This comprehensive MDC atlas offers valuable insights and a foundation for futher analyses, advancing strategies for treating solid cancers.
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Affiliation(s)
- Gabriela Rapozo Guimarães
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Giovanna Resk Maklouf
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Cristiane Esteves Teixeira
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Leandro de Oliveira Santos
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Nayara Gusmão Tessarollo
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Nayara Evelin de Toledo
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Alessandra Freitas Serain
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Cristóvão Antunes de Lanna
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Marco Antônio Pretti
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Jéssica Gonçalves Vieira da Cruz
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Marcelo Falchetti
- Department of Microbiology, Immunology, and Parasitology, Federal University of Santa Catarina, Florianópolis, SC, Brazil
| | - Mylla M Dimas
- Department of Microbiology, Immunology, and Parasitology, Federal University of Santa Catarina, Florianópolis, SC, Brazil
| | - Igor Salerno Filgueiras
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo,(USP), São Paulo, Brazil
| | - Otavio Cabral-Marques
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo,(USP), São Paulo, Brazil
- Instituto D'Or de Ensino e Pesquisa, São Paulo, Brazil
- Department of Medicine, Division of Molecular Medicine, Laboratory of Medical Investigation 29, School of Medicine, University of São Paulo (USP), São Paulo, Brazil
| | - Rodrigo Nalio Ramos
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo,(USP), São Paulo, Brazil
- Instituto D'Or de Ensino e Pesquisa, São Paulo, Brazil
- Laboratory of Medical Investigation in Pathogenesis and Directed Therapy in Onco-Immuno-Hematology (LIM-31), Departament of Hematology and Cell Therapy, Hospital das Clínicas HCFMUSP, School of Medicine, University of São Paulo (USP), São Paulo, Brazil
| | | | | | - Nina Carrossini Bastos
- Division of Pathology, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Jesse Lopes da Silva
- Division of Clinical Research and Technological Development, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Edroaldo Lummertz da Rocha
- Department of Microbiology, Immunology, and Parasitology, Federal University of Santa Catarina, Florianópolis, SC, Brazil
| | - Cláudia Bessa Pereira Chaves
- Division of Clinical Research and Technological Development, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
- Gynecologic Oncology Section, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Andreia Cristina de Melo
- Division of Clinical Research and Technological Development, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil
| | - Pedro M M Moraes-Vieira
- Laboratory of Immunometabolism, Department of Genetics, Evolution, Microbiology, and Immunology, Institute of Biology, Universidade Estadual de Campinas, Campinas, SP, Brazil
- Obesity and Comorbidities Research Center (OCRC), Universidade Estadual de Campinas, Campinas, SP, Brazil
- Experimental Medicine Research Cluster (EMRC), Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Marcelo A Mori
- Obesity and Comorbidities Research Center (OCRC), Universidade Estadual de Campinas, Campinas, SP, Brazil
- Experimental Medicine Research Cluster (EMRC), Universidade Estadual de Campinas, Campinas, SP, Brazil
- Laboratory of Aging Biology, Department of Biochemistry and Tissue Biology, Universidade Estadual de Campinas, Campinas, SP, Brazil
| | - Mariana Boroni
- Laboratory of Bioinformatics and Computational Biology, Division of Experimental and Translational Research, Brazilian National Cancer Institute (INCA), Rio de Janeiro, RJ, Brazil.
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Ruskin P, Pandi C, Kannan B, Pandi A, A S SG, Jayaseelan VP, Arumugam P. Triggering Receptor Expression on Myeloid Cells-1 (TREM1) Promoter Hypomethylation and Its Overexpression Associated With Poor Survival of Cancer Patients: A Pan-Cancer Analysis. Cureus 2024; 16:e64640. [PMID: 39149674 PMCID: PMC11326766 DOI: 10.7759/cureus.64640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 07/13/2024] [Indexed: 08/17/2024] Open
Abstract
Background Triggering receptor expression on myeloid cells-1 (TREM1) belongs to the immunoglobulin superfamily and is implicated in various conditions, including infectious and non-infectious diseases, autoimmune disorders, and cancer. Notably, TREM1 is significantly dysregulated in numerous cancer types. However, the underlying mechanism driving TREM1 mRNA expression in cancers remains unclear. Objective This study aims to analyze the promoter methylation level of TREM1 and its overexpression with cancer. Methods This study utilized The Cancer Genome Atlas (TCGA) cohort to analyze the methylation and expression levels of TREM1 in cancers. The University of ALabama at Birmingham CANcer (UALCAN) database facilitated data analysis from the TCGA dataset. Additionally, survival analysis was conducted using the TCGA dataset via Kaplan-Meier (KM) plots to identify significant associations with prognosis. Results Promoter methylation analysis revealed that TREM1 is hypomethylated in cancers, resulting in significantly overexpressed mRNA across various cancer types. This methylation and expression showed a negative correlation. Furthermore, high TREM1 mRNA expression was linked to poor prognosis in several cancers. Conclusion TREM1 gene expression negatively correlates with promotor DNA methylation and is associated with poor survival. It may serve as a prognostic marker and biomarker for various cancers. Future research should focus on further validation and antitumor immunity to elucidate its oncogenic role in cancers.
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Affiliation(s)
- Pinky Ruskin
- Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Chandra Pandi
- Molecular Biology Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Balachander Kannan
- Molecular Biology Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Anitha Pandi
- Clinical Genetics Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Smiline Girija A S
- Microbiology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Vijayashree Priyadharsini Jayaseelan
- Clinical Genetics Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
| | - Paramasivam Arumugam
- Molecular Biology Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, IND
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9
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Li C, Cai C, Xu D, Chen X, Song J. TREM1: Activation, signaling, cancer and therapy. Pharmacol Res 2024; 204:107212. [PMID: 38749377 DOI: 10.1016/j.phrs.2024.107212] [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: 02/20/2024] [Revised: 04/12/2024] [Accepted: 05/09/2024] [Indexed: 06/01/2024]
Abstract
Triggering receptor expressed on myeloid cells 1 (TREM1) is a cell surface receptor expressed on neutrophils, monocytes and some tissue macrophages, where it functions as an immunoregulator that controls myeloid cell responses. The activation of TREM1 is suggested to be an upregulation-based, ligands-induced and structural multimerization-mediated process, in which damage- and pathogen-associated molecular patterns play important roles. Activated TREM1 initiates an array of downstream signaling pathways that ultimately result in the production of pro-inflammatory cytokines and chemokines, whereby it functions as an amplifier of inflammation and is implicated in the pathogenesis of many inflammation-associated diseases. Over the past decade, there has been growing evidence for the involvement of TREM1 overactivation in tumor stroma inflammation and cancer progression. Indeed, it was shown that TREM1 promotes tumor progression, immunosuppression, and resistance to therapy by activating tumor-infiltrating myeloid cells. TREM1-deficiency or blockade provide protection against tumors and reverse the resistance to anti-PD-1/PD-L1 therapy and arginine-deprivation therapy in preclinical models. Here, we first review the structure, activation modes and signaling pathways of TREM1 and emphasize the role of soluble TREM1 as a biomarker of infection and cancer. We then focus on the role of TREM1 in cancer and systematically summarize its expression patterns, upregulation mechanisms and functions in tumor development and progression. Lastly, we discuss the therapeutic prospects of TREM1 inhibition, via effective pharmacological inhibitors, in treating cancer and other diseases.
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Affiliation(s)
- Chenyang Li
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Clinical Medicine Research Centre for Hepatic Surgery of Hubei Province, Wuhan, Hubei 430030, China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei 430030, China
| | - Chujun Cai
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Key Laboratory of Cancer Invasion and Metastasis（Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China
| | - Dafeng Xu
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Clinical Medicine Research Centre for Hepatic Surgery of Hubei Province, Wuhan, Hubei 430030, China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei 430030, China
| | - Xiaoping Chen
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Clinical Medicine Research Centre for Hepatic Surgery of Hubei Province, Wuhan, Hubei 430030, China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei 430030, China; Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei 430030, China; Key Laboratory of Organ Transplantation, National Health Commission, Wuhan, Hubei 430030, China; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, Hubei 430030, China.
| | - Jia Song
- Hepatic Surgery Centre, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China; Clinical Medicine Research Centre for Hepatic Surgery of Hubei Province, Wuhan, Hubei 430030, China; Hubei Key Laboratory of Hepato-Pancreato-Biliary Diseases, Wuhan, Hubei 430030, China.
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10
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Kannan B, Pandi C, Pandi A, Jayaseelan VP, Arumugam P. Triggering receptor expressed in myeloid cells 1 (TREM1) as a potential prognostic biomarker and association with immune infiltration in oral squamous cell carcinoma. Arch Oral Biol 2024; 161:105926. [PMID: 38442472 DOI: 10.1016/j.archoralbio.2024.105926] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 02/13/2024] [Accepted: 02/19/2024] [Indexed: 03/07/2024]
Abstract
OBJECTIVE The objective of this study is to investigate the significance and impact of Triggering Receptor Expression on Myeloid Cells-1 (TREM-1) in the context of oral squamous cell carcinoma (OSCC). METHODS This study involved 51 OSCC patients, 21 oral epithelial dysplasia patients (OED), and the TCGA-HNSCC dataset. TREM1 expression was analyzed using quantitative reverse transcription PCR (RT-qPCR), and Western blot. Furthermore, we assessed TREM1 expression for clinicopathological, prognosis, and immune infiltration correlations utilizing publicly available TCGA-HNSCC datasets through UALCAN, Protein Atlas, Kaplan-Meier plot, TIMER2.0, and TISIDB. We also conducted bioinformatic analyses for functional enrichment employing publicly accessible datasets. RESULTS TREM1 was significantly upregulated in OSCC and OED when compared to normal tissues, confirmed through multiple methods. Analysis of clinicopathological features showed associations with disease stage, grade, nodal metastasis, HPV status, and TP53 mutation. High TREM1 expression correlated with poorer patient survival. TREM1 was linked to immune cell infiltration and immune-related pathways. CONCLUSION TREM1 is significantly upregulated in OSCC and is associated with poor clinicopathological features and survival. It may hold promise as a therapeutic target and prognostic marker in OSCC. Further research is needed to understand its functional role in OSCC.
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Affiliation(s)
- Balachander Kannan
- Molecular Biology Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600077, TN, India
| | - Chandra Pandi
- Molecular Biology Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600077, TN, India
| | - Anitha Pandi
- Clinical Genetics Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600077, TN, India
| | - Vijayashree Priyadharsini Jayaseelan
- Clinical Genetics Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600077, TN, India
| | - Paramasivam Arumugam
- Molecular Biology Lab, Centre for Cellular and Molecular Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai 600077, TN, India.
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11
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Zhang L, Qu X, Xu Y. Molecular and immunological features of TREM1 and its emergence as a prognostic indicator in glioma. Front Immunol 2024; 15:1324010. [PMID: 38370418 PMCID: PMC10869492 DOI: 10.3389/fimmu.2024.1324010] [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: 10/18/2023] [Accepted: 01/10/2024] [Indexed: 02/20/2024] Open
Abstract
Triggering receptor expressed on myeloid cells 1 (TREM1), which belongs to the Ig-like superfamily expressed on myeloid cells, is reportedly involved in various diseases but has rarely been studied in glioma. In this study, the prognostic value and functional roles of TREM2 in glioma were analyzed. TERM1 was observed to be significantly upregulated in GBM compared to in other grade gliomas and was associated with poor prognosis. Increased TREM1 accompanied distinct mutation and amplification of driver oncogenes. Moreover, gene ontology and KEGG analyses showed that TREM1 might play a role in immunologic biological processes in glioma. TREM1 was also found to be tightly correlated with immune checkpoint molecules. xCell research revealed a link between TREM1 expression and multiple immune cell types, especially monocytes and macrophages. Single-cell analysis and immunofluorescence results showed that macrophages expressed TREM1. In vitro, inhibition of TREM1 signaling could result in a decrease in tumor-promoting effects of monocytes/TAMs. In summary, TREM1 may be a potential independent prognostic factor and immune target, which might provide new avenues to improve the efficacy of immunotherapy in glioma patients.
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Affiliation(s)
- Lin Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Xun Qu
- Institute of Basic Medical Sciences, Qilu Hospital of Shandong University, Jinan, China
| | - Yangyang Xu
- Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China
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12
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Lu Q, Xie Y, Qi X, Yang S. TREM1 as a novel prognostic biomarker and tumor immune microenvironment evaluator in glioma. Medicine (Baltimore) 2023; 102:e36410. [PMID: 38050264 PMCID: PMC10695587 DOI: 10.1097/md.0000000000036410] [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: 07/06/2023] [Accepted: 11/10/2023] [Indexed: 12/06/2023] Open
Abstract
Glioma is the most malignant tumor in the central nervous system with a poor prognosis. The tumor immune microenvironment plays a crucial role in glioma formation and progress. TREM1, as a vital immune regulator, has not been investigated in glioma. This study aims to explore the role of TREM1 in prognosis and tumor immune microenvironment of glioma. The mRNA expression level of TREM1 was collected from TCGA and GEO databases. The correlations between the clinic-pathological features and TREM1 expression were analyzed using Cox regression analysis. Kaplan-Meier was used to evaluate the effect of TREM1 on OS. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes were performed to analyze the functional annotations and signaling pathways of the TREM1 coexpression genes. ESTIMATE and TIMER explored the correlations between TREM1 and immune cell infiltration. Spearman correlation analysis was conducted to examine the association between the TREM1 and immune checkpoint expression. The expression level of TREM1 was significantly increased in glioma. TREM1 overexpression was positively related to poor prognosis, higher World Health Organization grade, isocitrate dehydrogenase wildtype, and 1p/19q non-codeletion. TREM1 coexpression genes were mainly related to immunoregulation and inflammatory response. TREM1 participated in the initiation and progression of glioma by regulating immune cell infiltration and expression of immune checkpoints. TREM1 is an effective prognostic and diagnostic biomarker in glioma. It can be adopted as a novel predictor for clinical prognosis, pathological characteristics, and immune microenvironment in glioma patients.
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Affiliation(s)
- Qin Lu
- Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China
| | - Yonglin Xie
- Department of Emergency, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China
| | - Xuchen Qi
- Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China
| | - Shuxu Yang
- Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China
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Manfredi GF, Celsa C, John C, Jones C, Acuti N, Scheiner B, Fulgenzi CAM, Korolewicz J, Pinter M, Gennari A, Mauri FA, Pirisi M, Minisini R, Vincenzi F, Burlone M, Rigamonti C, Donadon M, Cabibbo G, D’Alessio A, Pinato DJ. Mechanisms of Resistance to Immunotherapy in Hepatocellular Carcinoma. J Hepatocell Carcinoma 2023; 10:1955-1971. [PMID: 37941812 PMCID: PMC10629523 DOI: 10.2147/jhc.s291553] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 10/24/2023] [Indexed: 11/10/2023] Open
Abstract
Systemic treatment for advanced hepatocellular carcinoma (HCC) has been revolutionized over the last few years following the approval of immune checkpoint inhibitors (ICI). Despite the promising survival extension seen with ICI combination regimens, responses are not universally seen and the optimal partner for programmed cell death 1 pathway inhibitors remains to be identified. Even fewer encouraging results have been demonstrated with ICI used for monotherapy. Several mechanisms of resistance have been described so far, involving characteristics of cancer cells (intrinsic mechanisms) and of the surrounding tumor microenvironment (extrinsic mechanisms). Factors related to therapy may also contribute to the development of resistance. Increasing research efforts are being dedicated to the discovery of novel approaches and targets to overcome resistance, some of which may be introduced into clinic in the future. Herein we describe a selection of resistance mechanisms that have been involved in impairing response to ICI and propose potential therapeutic approaches to overcome resistance.
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Affiliation(s)
- Giulia Francesca Manfredi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Translational Medicine, Università Del Piemonte Orientale, Novara, Italy
| | - Ciro Celsa
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
- Department of Surgical, Oncological and Oral Sciences (Di.chir.on.s.), University of Palermo, Palermo, Italy
| | - Chloe John
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Charlotte Jones
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Nicole Acuti
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Claudia Angela Maria Fulgenzi
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Department of Medical Oncology, University Campus Bio-Medico of Rome, Rome, Italy
| | - James Korolewicz
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alessandra Gennari
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - Francesco A Mauri
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
| | - Mario Pirisi
- Department of Translational Medicine, Università Del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università Del Piemonte Orientale, Novara, Italy
| | - Federica Vincenzi
- Department of Translational Medicine, Università Del Piemonte Orientale, Novara, Italy
| | - Michela Burlone
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Cristina Rigamonti
- Department of Translational Medicine, Università Del Piemonte Orientale, Novara, Italy
- Division of Internal Medicine, AOU Maggiore della Carità, Novara, Italy
| | - Matteo Donadon
- Department of Health Science, Università Del Piemonte Orientale, Novara, Italy
- Department of Surgery, University Maggiore Hospital della Carità, Novara, Italy
| | - Giuseppe Cabibbo
- Section of Gastroenterology & Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, Palermo, Italy
| | - Antonio D’Alessio
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
| | - David James Pinato
- Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, London, UK
- Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
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Ajith A, Mamouni K, Horuzsko DD, Musa A, Dzutsev AK, Fang JR, Chadli A, Zhu X, Lebedyeva I, Trinchieri G, Horuzsko A. Targeting TREM1 augments antitumor T cell immunity by inhibiting myeloid-derived suppressor cells and restraining anti-PD-1 resistance. J Clin Invest 2023; 133:e167951. [PMID: 37651197 PMCID: PMC10617775 DOI: 10.1172/jci167951] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 08/29/2023] [Indexed: 09/02/2023] Open
Abstract
The triggering receptor expressed on myeloid cell 1 (TREM1) plays a critical role in development of chronic inflammatory disorders and the inflamed tumor microenvironment (TME) associated with most solid tumors. We examined whether loss of TREM1 signaling can abrogate the immunosuppressive TME and enhance cancer immunity. To investigate the therapeutic potential of TREM1 in cancer, we used mice deficient in Trem1 and developed a novel small molecule TREM1 inhibitor, VJDT. We demonstrated that genetic or pharmacological TREM1 silencing significantly delayed tumor growth in murine melanoma (B16F10) and fibrosarcoma (MCA205) models. Single-cell RNA-Seq combined with functional assays during TREM1 deficiency revealed decreased immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs) accompanied by expansion in cytotoxic CD8+ T cells and increased PD-1 expression. Furthermore, TREM1 inhibition enhanced the antitumorigenic effect of anti-PD-1 treatment, in part, by limiting MDSC frequency and abrogating T cell exhaustion. In patient-derived melanoma xenograft tumors, treatment with VJDT downregulated key oncogenic signaling pathways involved in cell proliferation, migration, and survival. Our work highlights the role of TREM1 in cancer progression, both intrinsically expressed in cancer cells and extrinsically in the TME. Thus, targeting TREM1 to modify an immunosuppressive TME and improve efficacy of immune checkpoint therapy represents what we believe to be a promising therapeutic approach to cancer.
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Affiliation(s)
- Ashwin Ajith
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Kenza Mamouni
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Daniel D. Horuzsko
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Abu Musa
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Amiran K. Dzutsev
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Jennifer R. Fang
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Ahmed Chadli
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Xingguo Zhu
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
| | - Iryna Lebedyeva
- Department of Chemistry and Physics, Augusta University, Augusta, Georgia, USA
| | - Giorgio Trinchieri
- Laboratory of Integrative Cancer Immunology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Anatolij Horuzsko
- Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
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Silbereisen A, Lira-Junior R, Åkerman S, Klinge B, Boström EA, Bostanci N. Association of salivary TREM-1 and PGLYRP1 inflammatory markers with non-communicable diseases. J Clin Periodontol 2023; 50:1467-1475. [PMID: 37524498 DOI: 10.1111/jcpe.13858] [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: 03/25/2023] [Revised: 06/26/2023] [Accepted: 07/18/2023] [Indexed: 08/02/2023]
Abstract
AIM Triggering receptor expressed on myeloid cells 1 (TREM-1) and peptidoglycan recognition protein 1 (PGLYRP1) are elevated in biofluids in the presence of various inflammatory conditions. This cross-sectional study aimed to evaluate the effect of age, sex, smoking and different oral and systemic non-communicable diseases on the levels of TREM-1 and PGLYRP1 in saliva. MATERIALS AND METHODS In total, 445 individuals (mean age 48.7 ± 16.9 years, female:male 51%:49%) were included. All provided self-reported information on smoking and systemic diseases and whole stimulated saliva. Periodontal and cariological parameters were recorded. Salivary levels of TREM-1, PGLYRP1 and total protein were measured using commercially available assays. RESULTS Salivary TREM-1 levels were significantly higher in stages III-IV periodontitis compared to other periodontal diagnoses (p < .05). Smoking, bleeding on probing (BOP), percentage of pockets ≥4 mm and the number of manifest caries were associated with TREM-1 (p < .05), while sex, BOP, number of manifest caries and muscle and joint diseases were associated with PGLYRP1 (p < .05). CONCLUSIONS Salivary TREM-1 is associated with periodontitis and caries, while PGLYRP1 is associated with gingival inflammation and caries. Additionally, TREM-1 levels are modified by smoking, while PGLYRP1 is modified by sex and muscle and joint diseases. TREM-1 and PGLYRP1 in saliva could serve as potential biomarkers for detecting and monitoring non-communicable diseases.
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Affiliation(s)
- Angelika Silbereisen
- Section of Periodontology and Dental Prevention, Division of Oral Diseases, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Ronaldo Lira-Junior
- Section of Oral Diagnostics and Surgery, Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Sigvard Åkerman
- Department of Orofacial Pain and Jaw Function, Faculty of Odontology, Malmö University, Malmö, Sweden
| | - Björn Klinge
- Section of Periodontology and Dental Prevention, Division of Oral Diseases, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of Periodontology, Faculty of Odontology, Malmö University, Malmö, Sweden
| | - Elisabeth A Boström
- Section of Oral Diagnostics and Surgery, Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Nagihan Bostanci
- Section of Periodontology and Dental Prevention, Division of Oral Diseases, Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden
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Abstract
Triggering receptors expressed on myeloid cells (TREMs) encompass a family of cell-surface receptors chiefly expressed by granulocytes, monocytes and tissue macrophages. These receptors have been implicated in inflammation, neurodegenerative diseases, bone remodelling, metabolic syndrome, atherosclerosis and cancer. Here, I review the structure, ligands, signalling modes and functions of TREMs in humans and mice and discuss the challenges that remain in understanding TREM biology.
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Affiliation(s)
- Marco Colonna
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
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Ma K, Guo Q, Zhang X, Li Y. High Expression of Triggering Receptor Expressed on Myeloid Cells 1 Predicts Poor Prognosis in Glioblastoma. Onco Targets Ther 2023; 16:331-345. [PMID: 37274309 PMCID: PMC10238274 DOI: 10.2147/ott.s407892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 05/23/2023] [Indexed: 06/06/2023] Open
Abstract
Background Glioblastoma (GBM) is a highly malignant tumor with poor prognosis, and new treatment strategies are urgently needed. Currently, the role of triggering receptor expressed on myeloid cells 1 (TREM-1) in tumors has been studied, but the role of TREM-1 in GBM remains unclear. Methods Immunohistochemical staining for TREM-1 was performed in 91 patients diagnosed with GBM. Clinicopathological characteristics and survival times were recorded. TREM-1 expression and its effect on prognosis were analyzed using online Gene Expression Profiling Interactive Analysis (GEPIA), The Cancer Genome Atlas (TCGA), and Chinese Glioma Genome Atlas (CGGA) databases. The expression profile of TCGA-GBM cohort was used to perform functional enrichment analysis. The CIBERSORT method and Tumor Immune Estimation Resource (TIMER) database were used to estimate the tumor-infiltrating immune cells (TIICs). The ESTIMATE algorithm was used to estimate the immune-stromal scores. Finally, the relationships of TREM-1 with TIICs, immune-stromal score, and immune checkpoint genes (ICGs) were analyzed. Results The expression of TREM-1 was upregulated in GBM, and high TREM-1 expression predicted a poor prognosis. TREM-1, surgical resection, postoperative radiotherapy, and temozolomide (TMZ) chemotherapy were associated with the survival time of patients with GBM, but only surgical resection and TREM-1 expression were independent prognostic factors. GBM with high TREM-1 expression exhibited increased neutrophil and macrophage infiltration. TREM-1 was positively associated with the immune-stromal score and multiple ICGs, and most of which were involved in immunosuppressive responses. Conclusion The present study revealed that high expression of TREM-1 in GBM is an independent poor prognosis factor and that TREM-1 is associated with the immunosuppressive microenvironment. Thus, blocking TREM-1 may be a strategy for enhancing the GBM immune response.
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Affiliation(s)
- Ke Ma
- Department of Medical Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China
| | - Qianqian Guo
- Department of Medical Oncology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China
| | - Xianwei Zhang
- Department of Pathology, Henan Provincial People’s Hospital; People’s Hospital of Zhengzhou University; People’s Hospital of Henan University, Zhengzhou, Henan, 450003, People’s Republic of China
| | - Yanxin Li
- Department of Neurosurgery, Henan Provincial People’s Hospital; People’s Hospital of Zhengzhou University; People’s Hospital of Henan University, Zhengzhou, Henan, 450003, People’s Republic of China
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Yi B, Cheng Y, Chang R, Zhou W, Tang H, Gao Y, Zhang C. Prognostic significance of tumor-associated macrophages polarization markers in lung cancer: a pooled analysis of 5105 patients. Biosci Rep 2023; 43:BSR20221659. [PMID: 36633963 PMCID: PMC9902841 DOI: 10.1042/bsr20221659] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 12/01/2022] [Accepted: 01/11/2023] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND The prognostic significance of tumor-associated macrophages (TAMs) in patients with lung cancer (LCa) remains controversial. We therefore conducted the present study to systematically evaluate the role of different TAMs markers and histologic locations on the prognosis of LCa. METHODS Searches of Web of Science, PubMed, and EMBASE databases were performed up to 28 February 2022. The pooled analysis was conducted in random-effect or fixed-effects model with hazard risk (HR) and 95% confidence interval (CI) for survival data including overall survival (OS), and disease-free survival (DFS) from raw or adjusted measures, according to different TAMs markers and histologic locations. RESULTS Including a total of 5105 patients from 30 eligible studies, the results indicated that the total count of CD68+ TAMs was negatively associated with OS and DFS, which was also observed in the relationship of CD68+ or CD204+ TAMs in tumor stroma (TS) with OS and DFS (all P<0.05). Conversely, higher CD68+ TAMs density in tumor nest (TN) or TN/TS ratio of CD68+ TAMs predicted better OS (all P<0.05). Similarly, higher HLA-DR+ TAMs density was correlated with better OS in TN and TS (all P<0.05). Besides, neither nest CD163+ TAM density nor stromal CD163+ TAM density was a prognostic factor in LCa patients (all P>0.05). CONCLUSION Our study indicated that different TAMs markers and histologic locations could bring about different prognostic effects in LCa patients. Great understanding of the infiltration modes of TAMs may contribute to improve outcomes of LCa patients.
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Affiliation(s)
- Bin Yi
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008 Hunan, P. R. China
| | - Yuanda Cheng
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008 Hunan, P. R. China
| | - Ruimin Chang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008 Hunan, P. R. China
| | - Wolong Zhou
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008 Hunan, P. R. China
| | - Huili Tang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008 Hunan, P. R. China
| | - Yang Gao
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008 Hunan, P. R. China
| | - Chunfang Zhang
- Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008 Hunan, P. R. China
- National Clinical Research Center for Geriatric Disorders, Changsha, 410008 Hunan, P. R. China
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Brustolin B, Touly N, Maillefer M, Parisot L, Di Pillo E, Derive M, Gibot S. Triggering receptor expressed on myeloid cells-1 deletion in mice attenuates high-fat diet-induced obesity. Front Endocrinol (Lausanne) 2023; 13:983827. [PMID: 36699032 PMCID: PMC9869264 DOI: 10.3389/fendo.2022.983827] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 12/05/2022] [Indexed: 01/12/2023] Open
Abstract
Introduction The low-grade inflammatory state present in obesity leads to the development and perpetuation of comorbidities associated with obesity. Our laboratory has been working for several years on an amplification loop of the inflammatory response mediated by TREM-1 (Triggering Receptor of Expressed on Myeloid Cells-1). It is implicated in many acute (septic shock) and chronic (IBD) inflammatory diseases. Previously, TREM-1 has been shown to be overexpressed in adipose and liver tissue in obese and diabetic patients, but its impact has never been characterized in these pathologies. Methods Our hypothesis is that TREM-1 plays a major role in the generation and perpetuation of inflammation during obesity and its associated complication (Insulin resistance and cardiac dysfunction). We assessed TREM-1 protein expression by western blot and immunofluorescence in omental and subcutaneous (pre-)adipocyte. Moreover, we submitted mice to a high-fat diet and investigated the effects of the genetic Trem1 deletion (trem1 KO mice). Results We showed, for the first time, that TREM-1 is expressed and is functional in subcutaneous and omental (pre-)adipocytes. In the mouse model of high-fat diet-induced obesity, we found that Trem1 suppression limited weight gain, insulin resistance and inflammation in white adipose tissue and liver. Discussion/conclusion Our results reveal the trem1 KO model can be viewed as a preventive model and that TREM-1 seems to play an important role in the development of obesity and its associated complication. It could therefore be a new therapeutic target in this context.
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Affiliation(s)
- Benjamin Brustolin
- Inserm Unité Mixte de Recherche (UMR) S1116, Faculté de Médecine de Nancy, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | - Nina Touly
- Inserm Unité Mixte de Recherche (UMR) S1116, Faculté de Médecine de Nancy, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | | | | | - Elisa Di Pillo
- Inserm Unité Mixte de Recherche (UMR) S1116, Faculté de Médecine de Nancy, Université de Lorraine, Vandœuvre-lès-Nancy, France
| | - Marc Derive
- INOTREM, University of Lorraine, Nancy, France
| | - Sébastien Gibot
- Inserm Unité Mixte de Recherche (UMR) S1116, Faculté de Médecine de Nancy, Université de Lorraine, Vandœuvre-lès-Nancy, France
- Service de Médecine Intensive Réanimation, Hôpital Central, Nancy, France
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Muller M, Haghnejad V, Lopez A, Tiotiu A, Renaud S, Derive M, Bronowicki JP. Triggering Receptors Expressed on Myeloid Cells 1 : Our New Partner in Human Oncology? Front Oncol 2022; 12:927440. [PMID: 35875168 PMCID: PMC9304869 DOI: 10.3389/fonc.2022.927440] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/01/2022] [Indexed: 11/14/2022] Open
Abstract
Inflammation is recognized as one of the hallmarks of cancer. Indeed, strong evidence indicates that chronic inflammation plays a major role in oncogenesis, promoting genome instability, epigenetic alterations, proliferation and dissemination of cancer cells. Mononuclear phagocytes (MPs) have been identified as key contributors of the inflammatory infiltrate in several solid human neoplasia, promoting angiogenesis and cancer progression. One of the most described amplifiers of MPs pro-inflammatory innate immune response is the triggering receptors expressed on myeloid cells 1 (TREM-1). Growing evidence suggests TREM-1 involvement in oncogenesis through cancer related inflammation and the surrounding tumor microenvironment. In human oncology, high levels of TREM-1 and/or its soluble form have been associated with poorer survival data in several solid malignancies, especially in hepatocellular carcinoma and lung cancer. TREM-1 should be considered as a potential biomarker in human oncology and could be used as a new therapeutic target of interest in human oncology (TREM-1 inhibitors, TREM-1 agonists). More clinical studies are urgently needed to confirm TREM-1 (and TREM family) roles in the prognosis and the treatment of human solid cancers.
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Affiliation(s)
- Marie Muller
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Vincent Haghnejad
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Anthony Lopez
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Angelica Tiotiu
- Department of Pulmonology, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Stéphane Renaud
- Department of Thoracic Surgery, Nancy University Hospital, University of Lorraine, Nancy, France
| | - Marc Derive
- INOTREM, University of Lorraine, Nancy, France
| | - Jean-Pierre Bronowicki
- Department of Gastroenterology, Nancy University Hospital, University of Lorraine, Nancy, France
- Inserm U1256 « Nutrition – Genetics and exposure to environmental risks - NGERE », Nancy, France
- *Correspondence: Jean-Pierre Bronowicki,
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Lu L, Liu X, Fu J, Liang J, Hou Y, Dou H. sTREM-1 promotes the phagocytic function of microglia to induce hippocampus damage via the PI3K-AKT signaling pathway. Sci Rep 2022; 12:7047. [PMID: 35487953 PMCID: PMC9054830 DOI: 10.1038/s41598-022-10973-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 04/15/2022] [Indexed: 12/18/2022] Open
Abstract
Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is a soluble form of TREM-1 released during inflammation. Elevated sTREM-1 levels have been found in neuropsychiatric systemic lupus erythematosus (NPSLE) patients; yet, the exact mechanisms remain unclear. This study investigated the role of sTREM-1 in brain damage and its underlying mechanism. The sTREM-1 recombinant protein (2.5 μg/3 μL) was injected into the lateral ventricle of C57BL/6 female mice. After intracerebroventricular (ICV) injection, the damage in hippocampal neurons increased, and the loss of neuronal synapses and activation of microglia increased compared to the control mice (treated with saline). In vitro. after sTREM-1 stimulation, the apoptosis of BV2 cells decreased, the polarization of BV2 cells shifted to the M1 phenotype, the phagocytic function of BV2 cells significantly improved, while the PI3K-AKT signal pathway was activated in vivo and in vitro. PI3K-AKT pathway inhibitor LY294002 reversed the excessive activation and phagocytosis of microglia caused by sTREM-1 in vivo and in vitro, which in turn improved the hippocampus damage. These results indicated that sTREM-1 activated the microglial by the PI3K-AKT signal pathway, and promoted its excessive phagocytosis of the neuronal synapse, thus inducing hippocampal damage. sTREM-1 might be a potential target for inducing brain lesions.
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Affiliation(s)
- Li Lu
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, People's Republic of China
| | - Xuan Liu
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, People's Republic of China
| | - Juanhua Fu
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.,Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, People's Republic of China
| | - Jun Liang
- Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, People's Republic of China.
| | - Yayi Hou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China. .,Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, People's Republic of China.
| | - Huan Dou
- The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China. .,Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, People's Republic of China.
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Iftikhar R, Penrose HM, King AN, Kim Y, Ruiz E, Kandil E, Machado HL, Savkovic SD. FOXO3 Expression in Macrophages Is Lowered by a High-Fat Diet and Regulates Colonic Inflammation and Tumorigenesis. Metabolites 2022; 12:250. [PMID: 35323693 PMCID: PMC8949544 DOI: 10.3390/metabo12030250] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 02/23/2022] [Accepted: 02/24/2022] [Indexed: 12/12/2022] Open
Abstract
Obesity, characterized by augmented inflammation and tumorigenesis, is linked to genetic predispositions, such as FOXO3 polymorphisms. As obesity is associated with aberrant macrophages infiltrating different tissues, including the colon, we aimed to identify FOXO3-dependent transcriptomic changes in macrophages that drive obesity-mediated colonic inflammation and tumorigenesis. We found that in mouse colon, high-fat-diet-(HFD)-related obesity led to diminished FOXO3 levels and increased macrophages. Transcriptomic analysis of mouse peritoneal FOXO3-deficient macrophages showed significant differentially expressed genes (DEGs; FDR < 0.05) similar to HFD obese colons. These DEG-related pathways, linked to mouse colonic inflammation and tumorigenesis, were similar to those in inflammatory bowel disease (IBD) and human colon cancer. Additionally, we identified a specific transcriptional signature for the macrophage-FOXO3 axis (MAC-FOXO382), which separated the transcriptome of affected tissue from control in both IBD (p = 5.2 × 10−8 and colon cancer (p = 1.9 × 10−11), revealing its significance in human colonic pathobiologies. Further, we identified (heatmap) and validated (qPCR) DEGs specific to FOXO3-deficient macrophages with established roles both in IBD and colon cancer (IL-1B, CXCR2, S100A8, S100A9, and TREM1) and those with unexamined roles in these colonic pathobiologies (STRA6, SERPINH1, LAMB1, NFE2L3, OLR1, DNAJC28 and VSIG10). These findings establish an important understanding of how HFD obesity and related metabolites promote colonic pathobiologies.
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Affiliation(s)
- Rida Iftikhar
- Department of Pathology and Laboratory Medicine, School of Medicine, Tulane University, New Orleans, LA 70012, USA; (R.I.); (H.M.P.); (A.N.K.); (Y.K.)
| | - Harrison M. Penrose
- Department of Pathology and Laboratory Medicine, School of Medicine, Tulane University, New Orleans, LA 70012, USA; (R.I.); (H.M.P.); (A.N.K.); (Y.K.)
| | - Angelle N. King
- Department of Pathology and Laboratory Medicine, School of Medicine, Tulane University, New Orleans, LA 70012, USA; (R.I.); (H.M.P.); (A.N.K.); (Y.K.)
| | - Yunah Kim
- Department of Pathology and Laboratory Medicine, School of Medicine, Tulane University, New Orleans, LA 70012, USA; (R.I.); (H.M.P.); (A.N.K.); (Y.K.)
| | - Emmanuelle Ruiz
- Division of Endocrine and Oncologic Surgery, Department of Surgery, Tulane University, New Orleans, LA 70012, USA; (E.R.); (E.K.)
| | - Emad Kandil
- Division of Endocrine and Oncologic Surgery, Department of Surgery, Tulane University, New Orleans, LA 70012, USA; (E.R.); (E.K.)
| | - Heather L. Machado
- Department of Biochemistry and Molecular Biology, School of Medicine, Tulane University, New Orleans, LA 70012, USA;
| | - Suzana D. Savkovic
- Department of Pathology and Laboratory Medicine, School of Medicine, Tulane University, New Orleans, LA 70012, USA; (R.I.); (H.M.P.); (A.N.K.); (Y.K.)
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Pullikuth AK, Routh ED, Zimmerman KD, Chifman J, Chou JW, Soike MH, Jin G, Su J, Song Q, Black MA, Print C, Bedognetti D, Howard-McNatt M, O’Neill SS, Thomas A, Langefeld CD, Sigalov AB, Lu Y, Miller LD. Bulk and Single-Cell Profiling of Breast Tumors Identifies TREM-1 as a Dominant Immune Suppressive Marker Associated With Poor Outcomes. Front Oncol 2021; 11:734959. [PMID: 34956864 PMCID: PMC8692779 DOI: 10.3389/fonc.2021.734959] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 11/15/2021] [Indexed: 11/13/2022] Open
Abstract
BackgroundTriggering receptor expressed on myeloid cells (TREM)-1 is a key mediator of innate immunity previously associated with the severity of inflammatory disorders, and more recently, the inferior survival of lung and liver cancer patients. Here, we investigated the prognostic impact and immunological correlates of TREM1 expression in breast tumors.MethodsBreast tumor microarray and RNAseq expression profiles (n=4,364 tumors) were analyzed for associations between gene expression, tumor immune subtypes, distant metastasis-free survival (DMFS) and clinical response to neoadjuvant chemotherapy (NAC). Single-cell (sc)RNAseq was performed using the 10X Genomics platform. Statistical associations were assessed by logistic regression, Cox regression, Kaplan-Meier analysis, Spearman correlation, Student’s t-test and Chi-square test.ResultsIn pre-treatment biopsies, TREM1 and known TREM-1 inducible cytokines (IL1B, IL8) were discovered by a statistical ranking procedure as top genes for which high expression was associated with reduced response to NAC, but only in the context of immunologically “hot” tumors otherwise associated with a high NAC response rate. In surgical specimens, TREM1 expression varied among tumor molecular subtypes, with highest expression in the more aggressive subtypes (Basal-like, HER2-E). High TREM1 significantly and reproducibly associated with inferior distant metastasis-free survival (DMFS), independent of conventional prognostic markers. Notably, the association between high TREM1 and inferior DMFS was most prominent in the subset of immunogenic tumors that exhibited the immunologically hot phenotype and otherwise associated with superior DMFS. Further observations from bulk and single-cell RNAseq analyses indicated that TREM1 expression was significantly enriched in polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and M2-like macrophages, and correlated with downstream transcriptional targets of TREM-1 (IL8, IL-1B, IL6, MCP-1, SPP1, IL1RN, INHBA) which have been previously associated with pro-tumorigenic and immunosuppressive functions.ConclusionsTogether, these findings indicate that increased TREM1 expression is prognostic of inferior breast cancer outcomes and may contribute to myeloid-mediated breast cancer progression and immune suppression.
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Affiliation(s)
- Ashok K. Pullikuth
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Eric D. Routh
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, United States
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kip D. Zimmerman
- Center for Precision Medicine, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Julia Chifman
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, United States
- Department of Mathematics and Statistics, American University, Washington, DC, United States
| | - Jeff W. Chou
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston Salem, NC, United States
- The Comprehensive Cancer Center of Wake Forest University, Winston Salem, NC, United States
| | - Michael H. Soike
- Department of Radiation Oncology, University of Alabama-Birmingham, Birmingham, AL, United States
| | - Guangxu Jin
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, United States
- The Comprehensive Cancer Center of Wake Forest University, Winston Salem, NC, United States
| | - Jing Su
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston Salem, NC, United States
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Qianqian Song
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, United States
- Center for Cancer Genomics and Precision Oncology, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Michael A. Black
- Department of Biochemistry, Otago School of Medical Sciences, University of Otago, Dunedin, New Zealand
| | - Cristin Print
- Department of Molecular Medicine and Pathology and Maurice Wilkins Institute, Faculty of Medical and Health Sciences, The University of Auckland, Auckland, New Zealand
| | - Davide Bedognetti
- Cancer Program, Sidra Medicine, Doha, Qatar & Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy
| | - Marissa Howard-McNatt
- Surgical Oncology Service, Department of Surgery, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Stacey S. O’Neill
- The Comprehensive Cancer Center of Wake Forest University, Winston Salem, NC, United States
- Department of Pathology, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Alexandra Thomas
- The Comprehensive Cancer Center of Wake Forest University, Winston Salem, NC, United States
- Section of Hematology and Oncology, Department of Internal Medicine, Wake Forest Baptist Medical Center, Winston Salem, NC, United States
| | - Carl D. Langefeld
- Department of Biostatistics and Data Science, Wake Forest School of Medicine, Winston Salem, NC, United States
- The Comprehensive Cancer Center of Wake Forest University, Winston Salem, NC, United States
| | | | - Yong Lu
- The Comprehensive Cancer Center of Wake Forest University, Winston Salem, NC, United States
- Department of Microbiology & Immunology, Wake Forest School of Medicine, Winston Salem, NC, United States
| | - Lance D. Miller
- Department of Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, United States
- The Comprehensive Cancer Center of Wake Forest University, Winston Salem, NC, United States
- *Correspondence: Lance D. Miller,
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NRAS expression is associated with prognosis and tumor immune microenvironment in lung adenocarcinoma. J Cancer Res Clin Oncol 2021; 148:565-575. [PMID: 34746975 DOI: 10.1007/s00432-021-03842-w] [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: 08/30/2021] [Accepted: 10/19/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE NRAS plays a pivotal role in progression of various kinds of somatic malignancies; however, the correlation between NRAS and lung adenocarcinoma is less known. We aim to analyze the prognostic value of NRAS expression in lung adenocarcinoma, and explore the relationship between NRAS and tumor immune microenvironment. METHODS We obtained the transcriptome profiles and clinical data of LUAD from The Cancer Genome Atlas database and three Genome Expression Omnibus datasets. Specimens from 325 patients with completely resected lung adenocarcinoma were collected for immunohistochemical assays of NRAS, PD-L1, PD-1 and TIM-3. Then, we performed gene set enrichment analysis to investigate cancer-related and immune-related signaling pathways. TIMER algorithms were performed to evaluate tumor immune infiltrating cells and immune-related biomarkers. RESULTS Compared with adjacent non-tumor tissue, NRAS expression was significantly upregulated in LUAD tissue. NRAS expression was significantly correlated with more advanced stage and positive lymph nodes. Kaplan-Meier curves and Cox analysis suggested that high NRAS expression led to a poor prognosis, and could be an independent prognostic factor in LUAD patients. Besides, NRAS expression was positively correlated with CD8+ T cells, macrophages, and neutrophils, and negatively correlated with B cells and CD4+ T cells. The expression level of NRAS was positively correlated with PD-L1, PD-1, and TIM-3 both at RNA and protein level. CONCLUSIONS To conclude, we found NRAS is a novel prognostic biomarker in LUAD. Besides, the expression level of NRAS may influence the prognosis of LUAD via various kinds of cancer-related pathways and remodeling TIM.
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Xie Y, Li X, Lv D, He M, Sun Y, Lin X, Fan Y, Yang M, Xu H, Zhang X, Zhang Y, Beejadhursing R, Li F, Deng D. TREM-1 amplifies trophoblastic inflammation via activating NF-κB pathway during preeclampsia. Placenta 2021; 115:97-105. [PMID: 34598084 DOI: 10.1016/j.placenta.2021.09.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 09/12/2021] [Accepted: 09/22/2021] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Excessive activation of maternal systemic inflammation is one of the underlying causes of pathology during the disease course of preeclampsia (PE). The triggering receptor expressed on myeloid cells-1 (TREM-1) participates in the development and persistence of inflammation. We hypothesized that dysregulated TREM-1 may be involved in the pathogenesis of PE by promoting the secretion of trophoblastic pro-inflammatory cytokines that augment inflammation. METHODS The localization of TREM-1 in placenta and the extravillous trophoblast cell line (TEV-1) was determined by immunohistochemical staining. The expression level of TREM-1 and pro-inflammatory cytokines in placentas were compared between normal pregnancies and PE. We used lipopolysaccharide (LPS) to simulate trophoblastic inflammation. TEV-1 cells were transfected with TREM-1 plasmid and si-TREM-1 respectively, and then were incubated with LPS. The expression levels of pro-inflammatory cytokines and key molecules featured in nuclear transcription factor-kappaB (NF-κB) pathway were detected. Transwell assays were used to detect the effects of TREM-1 on cell migration and invasion. RESULTS TREM-1 was localized on both villous trophoblasts (VTs) and extravillous trophoblasts (EVTs). TREM-1 and pro-inflammatory cytokines were up-regulated in preeclamptic placenta. Overexpression of TREM-1 promoted the activation of NF-κB pathway and the release of pro-inflammatory factors induced by LPS, and enhanced migration and invasion of TEV-1 cells. Inhibition of TREM-1 significantly attenuated LPS-induced effects and suppressed migration and invasion. DISCUSSION This study suggested that TREM-1 was up-regulated in PE, and may promote the production of downstream inflammatory factors by activating NF-κB pathway in trophoblastic cells, thus exerting pro-inflammatory effects in the pathogenesis of PE.
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Affiliation(s)
- Yin Xie
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xuanxuan Li
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Dan Lv
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Mengzhou He
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Yanan Sun
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xingguang Lin
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Yao Fan
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Meitao Yang
- Department of Gynecology and Obstetrics, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China
| | - Heze Xu
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Xiaolei Zhang
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Yanling Zhang
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Rajluxmee Beejadhursing
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Fanfan Li
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
| | - Dongrui Deng
- Department of Gynecology and Obstetrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
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Soluble Triggering Receptor on Myeloid Cell-1 and its Predictive Factors in Patients With End-Stage Kidney Disease on Hemodialysis. ASAIO J 2021; 68:605-609. [PMID: 34352818 DOI: 10.1097/mat.0000000000001541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Triggering receptor expressed on myeloid cells (TREM)-1 is a potent and early amplifier of the inflammatory response expressed on neutrophils and monocytes/macrophages. TREM-1, and its soluble form (sTREM-1), are increased in sepsis and other noninfectious inflammatory conditions. However, virtually no data are available in kidney disease. To determine serum sTREM-1 and its associated variables in patients on hemodialysis (HD), cross-sectional study including 264 HD patients and 148 controls. sTREM-1 was measured by quantitative sandwich enzyme immunoassay; soluble tumor necrosis factor receptor-1 (sTNF-R1), interleukin-6 (IL-6), and C-reactive protein (CRP) were also measured. All inflammation markers were significantly higher in HD patients than controls. Median (IQR) sTREM-1 was 1,006 (613-1,650) pg/mL but undetectable in controls. Considering only HD patients, sTREM-1 was positively correlated with IL-6 (r = 0.19, p = 0.008), and its levels were significantly higher in patients with arteriovenous fistula than in those with temporary catheter (1,226 vs. 743 pg/mL), in patients with 3 HD sessions/week than in those with 2 sessions/week (1,150 vs. 646 pg/mL), and in patients with >1 year on HD than in those with ≤1 year (1,100 vs. 948 pg/mL), whereas they were not different regarding age or presence of infection. Serum sTREM-1, sTNF-R1, IL-6, and CRP were higher in HD patients compared to controls. In HD patients, sTREM-1 displayed higher levels in individuals with arteriovenous fistula, 3 sessions/week and longer vintage, but not in those with infection or older age; in multivariate analysis, only the first two variables significantly predicted higher sTREM-1 levels.
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Hornburg M, Desbois M, Lu S, Guan Y, Lo AA, Kaufman S, Elrod A, Lotstein A, DesRochers TM, Munoz-Rodriguez JL, Wang X, Giltnane J, Mayba O, Turley SJ, Bourgon R, Daemen A, Wang Y. Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer. Cancer Cell 2021; 39:928-944.e6. [PMID: 33961783 DOI: 10.1016/j.ccell.2021.04.004] [Citation(s) in RCA: 191] [Impact Index Per Article: 47.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 11/12/2020] [Accepted: 04/06/2021] [Indexed: 01/06/2023]
Abstract
Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.
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Affiliation(s)
- Milena Hornburg
- Department of Bioinformatics & Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Mélanie Desbois
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Shan Lu
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Yinghui Guan
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Amy A Lo
- Department of Research Pathology, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Susan Kaufman
- Department of Biochemical Cellular Pharmacology, Genentech, Inc., South San Francisco, CA 94080, USA
| | | | | | | | | | - Xingwei Wang
- Department of Digital Pathology, Roche Tissue Diagnostics, Santa Clara, CA 95050, USA
| | - Jennifer Giltnane
- Department of Research Pathology, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Oleg Mayba
- Department of Bioinformatics & Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Shannon J Turley
- Department of Cancer Immunology, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Richard Bourgon
- Department of Bioinformatics & Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Anneleen Daemen
- Department of Bioinformatics & Computational Biology, Genentech, Inc., South San Francisco, CA 94080, USA
| | - Yulei Wang
- Department of Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA 94080, USA.
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28
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Regulation of TREM1-Mediated Inflammation in Hepatocellular Carcinoma Cells. REPORTS 2021. [DOI: 10.3390/reports4020017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC), accounting for more than 90% of cases of primary liver cancer, is the third most common cause of cancer-related death worldwide. Chronic inflammation precedes the development of cirrhosis and HCC. TREM (triggering receptor expressed on myeloid cell)-1 is an inflammatory marker and amplifier of inflammation that signals through PI3K and ERK1/2 to activate transcription factors, resulting in increased secretion of pro-inflammatory cytokines, causing chronic inflammation and predisposing the liver to carcinogenesis. Thus, targeting TREM-1 in HCC might be a potential therapeutic target. A low level of vitamin D has been associated with chronic inflammation and poor prognosis in HCC. Thus, we evaluated the effect of vitamin D on TREM-1 expression in the HCC cell line. Additionally, the effects of high mobility group box-1, lipopolysaccharide, and transcription factor PU.1 on the expression of TREM-1 in normal liver cells and HCC cells have been investigated in the presence and absence of vitamin D. The results showed increased expression of TREM-1 in HCC cells and with IL-6, TNF-α, LPS, and rHMGB-1 and decreased expression with calcitriol. Calcitriol also attenuated the effect of IL-6, TNF-α, LPS, and rHMGB-1 on TREM-1. Calcitriol treatment attenuated the proliferation, migration, and invasion of HCC cells. These results (in vitro) provide molecular and biochemical evidence that calcitriol significantly attenuates the expression of mediators of inflammation, and thus might be used therapeutically together with conventional treatment to delay the progression of HCC. Additionally, the negative regulation of TREM-1 by PU.1 suggests PU.1 as a potential therapeutic target.
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29
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Ghafarpour V, Khansari M, Banaei-Moghaddam AM, Najafi A, Masoudi-Nejad A. DNA methylation association with stage progression of head and neck squamous cell carcinoma. Comput Biol Med 2021; 134:104473. [PMID: 34034219 DOI: 10.1016/j.compbiomed.2021.104473] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/27/2021] [Accepted: 05/02/2021] [Indexed: 01/13/2023]
Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide, which accounts for approximately 6% of all cases and is responsible for an estimated 2% of all cancer deaths. Despite progress in the treatment of squamous cell carcinomas, survival rates remain low. It is a fact that epigenetic modifications have numerous associations with biological processes and complex diseases such as cancer. Hence, a more systematic approach is needed to provide potential screening targets and have an effective therapy method. This study developed a workflow to analyze HM450 methylation arrays with mRNA expression profiles that identified novel signatures of epigenetic regulators for tumor progression. We identified differentially expressed genes and differentially methylated regions and the correlation between associated genes to identify epigenetic modifications underlying regulation roles. We have taken the differentiation direction of expressions into account during the integration of gene expression and DNA methylation modification to detect epigenetic regulators of core genes of tumor-stage progression. Enrichment analysis of selected key genes provides better insight into their functionality. Thus, we have investigated gene copy number alteration and mutations to filter differentially expressed genes, including some members of the fibroblast growth factor family and cyclin-dependent kinase inhibitor family with other potential known regulators. Our analysis has revealed the list of 61 commercial methylation probes positively correlated with 31 differentially expressed genes, which can be associated with HNSC metastasis stages. Most of these genes have already reported potential epigenetic regulators, and their role in cancer progression was studied. We suggest these selected probes of DNA methylation as potential targets of the epigenetic regulators in revealed genes that have displayed significant genetic and epigenetic modification behavior during cancer stage progression and tumor metastasis.
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Affiliation(s)
- Vahid Ghafarpour
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Mohammad Khansari
- Faculty of New Sciences and Technologies, University of Tehran, Tehran, Iran
| | - Ali M Banaei-Moghaddam
- Laboratory of Genomics and Epigenomics (LGE), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Ali Najafi
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Tehran, Iran
| | - Ali Masoudi-Nejad
- Laboratory of Systems Biology and Bioinformatics (LBB), Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran. http://lbb.ut.ac.ir/
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30
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Hossian AKMN, Zahra FT, Poudel S, Abshire CF, Polk P, Garai J, Zabaleta J, Mikelis CM, Mattheolabakis G. Advanced bioinformatic analysis and pathway prediction of NSCLC cells upon cisplatin resistance. Sci Rep 2021; 11:6520. [PMID: 33753779 PMCID: PMC7985311 DOI: 10.1038/s41598-021-85930-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 03/05/2021] [Indexed: 11/08/2022] Open
Abstract
This study aims to identify pathway involvement in the development of cisplatin (cis-diamminedichloroplatinum (II); CDDP) resistance in A549 lung cancer (LC) cells by utilizing advanced bioinformatics software. We developed CDDP-resistant A549 (A549/DDP) cells through prolonged incubation with the drug and performed RNA-seq on RNA extracts to determine differential mRNA and miRNA expression between A549/DDP and A549 cells. We analyzed the gene dysregulation with Ingenuity Pathway Analysis (IPA; QIAGEN) software. In contrast to prior research, which relied on the clustering of dysregulated genes to pathways as an indication of pathway activity, we utilized the IPA software for the dynamic evaluation of pathway activity depending on the gene dysregulation levels. We predicted 15 pathways significantly contributing to the chemoresistance, with several of them to have not been previously reported or analyzed in detail. Among them, the PKR signaling, cholesterol biosynthesis, and TEC signaling pathways are included, as well as genes, such as PIK3R3, miR-34c-5p, and MDM2, among others. We also provide a preliminary analysis of SNPs and indels, present exclusively in A549/DDP cells. This study's results provide novel potential mechanisms and molecular targets that can be explored in future studies and assist in improving the understanding of the chemoresistance phenotype.
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Affiliation(s)
- A K M Nawshad Hossian
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, USA
| | - Fatema Tuz Zahra
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Sagun Poudel
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, USA
| | - Camille F Abshire
- Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Paula Polk
- Louisiana State University Health Sciences Center, Shreveport, LA, USA
| | - Jone Garai
- Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Jovanny Zabaleta
- Department of Pediatrics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA
| | - Constantinos M Mikelis
- Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - George Mattheolabakis
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana Monroe, Monroe, LA, USA.
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31
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Xie Z, Li X, He Y, Wu S, Wang S, Sun J, He Y, Lun Y, Xin S, Zhang J. Analysis of the Prognostic Value and Potential Molecular Mechanisms of TREM-1 Overexpression in Papillary Thyroid Cancer via Bioinformatics Methods. Front Endocrinol (Lausanne) 2021; 12:646793. [PMID: 34122331 PMCID: PMC8190971 DOI: 10.3389/fendo.2021.646793] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 05/03/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Triggering receptor expressed on myeloid cells-1 (TREM-1) has been reported as a biomarker in many cancers. However, the biological function of TREM-1 in papillary thyroid carcinoma (PTC) remains unknown. METHODS We obtained TREM-1 expression data from The Cancer Genome Atlas (TCGA) database. Enrichment analysis of coexpressed genes and TREM-1 methylation analysis were performed via LinkedOmics. The correlations between TREM-1 and immune infiltrates were investigated via ESTIMATE, TIMER and TISIDB. We analyzed the association of TREM-1 expression with pan-cancer overall survival via Gene Expression Profiling Interactive Analysis (GEPIA). RESULTS TREM-1 has lower methylation levels and higher expression levels in PTC tissues compared to normal tissues. TREM-1 expression is significantly associated with poor prognosis, advanced T classification, advanced N classification, and an increased incidence of BRCA2 and BRAF mutations. Genes coexpressed with TREM-1 primarily participate in immune-related pathways. TREM-1 expression is positively correlated with immune infiltration, tumor progression and poor overall survival across cancers. CONCLUSIONS TREM-1 is a good prognostic and diagnostic biomarker in PTC. TREM-1 may promote thyroid cancer progression through immune-related pathways. Methylation may act as an upstream regulator of TREM-1 expression and biological function. Additionally, TREM-1 has broad prognostic value in a pan-cancer cohort.
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32
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Aslam N, Abusharieh E, Abuarqoub D, Ali D, Al-Hattab D, Wehaibi S, Al-Kurdi B, Jamali F, Alshaer W, Jafar H, Awidi AS. Anti-oncogenic activities exhibited by paracrine factors of MSCs can be mediated by modulation of KITLG and DKK1 genes in glioma SCs in vitro. MOLECULAR THERAPY-ONCOLYTICS 2020; 20:147-165. [PMID: 33575478 PMCID: PMC7851499 DOI: 10.1016/j.omto.2020.11.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022]
Abstract
Cancer stem cells (CSCs) use their stemness properties to perpetuate their lineage and survive chemotherapy. Currently cell-based and cell-free therapies are under investigation to develop novel anti-cancer treatment modalities. We designed this study to investigate how cell extracts of mesenchymal stem cells affect the growth of glioma stem cells in vitro. Gliospheres were generated from the U87MG cell line and treated with conditioned media of Wharton’s jelly and bone marrow mesenchymal stem cells. The effects were investigated at the functional and molecular levels. Our results showed that conditioned media from both types of mesenchymal stem cells changed the morphology of spheres and inhibited the proliferation, invasion, and self-renewal ability of glioma stem cells. At the molecular level, metabolism interruption at oxidative phosphorylation, cell cycle arrest, cell differentiation, and upregulation of the immune response were observed. Furthermore, this effect was mediated by the upregulation of the DKK1 gene inhibiting the Wnt pathway mediated by growth factor activity and downregulation of the KITLG gene activated by growth factor and cytokine activity, inhibiting multiple pathways. We conclude that different types of mesenchymal stem cells possess antitumor properties and their paracrine factors, in combination with anti-immune modalities, can provide practical therapeutic targets for glioblastoma treatment.
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Affiliation(s)
- Nazneen Aslam
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Elham Abusharieh
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Faculty of Pharmacy, The University of Jordan, Amman 11942, Jordan
| | - Duaa Abuarqoub
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Department of Pharmacology and Biomedical Sciences, Faculty of Pharmacy and Medical Sciences, University of Petra, Amman 11196, Jordan
| | - Dema Ali
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Dana Al-Hattab
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Laboratory for Nanomedicine, Division of Biological & Environmental Science & Engineering (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal 23955-6900, Saudi Arabia
| | - Suha Wehaibi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Ban Al-Kurdi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Fatima Jamali
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Walhan Alshaer
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan
| | - Hanan Jafar
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Department of Anatomy and Histology, School of Medicine, The University of Jordan, Amman 11942, Jordan
| | - Abdalla S Awidi
- Cell Therapy Center, The University of Jordan, Amman 11942, Jordan.,Department of Medicine, School of Medicine, The University of Jordan, Amman 11942, Jordan.,Department of Hematology and Oncology, Jordan University Hospital, The University of Jordan, Amman 11942, Jordan
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33
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An Integrating Immune-Related Signature to Improve Prognosis of Hepatocellular Carcinoma. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2020; 2020:8872329. [PMID: 33204302 PMCID: PMC7655255 DOI: 10.1155/2020/8872329] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 09/26/2020] [Accepted: 10/15/2020] [Indexed: 01/27/2023]
Abstract
Growing evidence suggests that the superiority of long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) could act as biomarkers for cancer prognosis. However, the prognostic marker for hepatocellular carcinoma with high accuracy and sensitivity is still lacking. In this research, a retrospective, cohort-based study of genome-wide RNA-seq data of patients with hepatocellular carcinoma was carried out, and two protein-coding genes (GTPBP4, TREM-1) and one lncRNA (LINC00426) were sorted out to construct an integrative signature to predict the prognosis of patients. The results show that both the AUC and the C-index of this model perform well in TCGA validation dataset, cross-platform GEO validation dataset, and different subsets divided by gender, stage, and grade. The expression pattern and functional analysis show that all three genes contained in the model are associated with immune infiltration, cell proliferation, invasion, and metastasis, providing further confirmation of this model. In summary, the proposed model can effectively distinguish the high- and low-risk groups of hepatocellular carcinoma patients and is expected to shed light on the treatment of hepatocellular carcinoma and greatly improve the patients' prognosis.
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34
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Larionova I, Tuguzbaeva G, Ponomaryova A, Stakheyeva M, Cherdyntseva N, Pavlov V, Choinzonov E, Kzhyshkowska J. Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers. Front Oncol 2020; 10:566511. [PMID: 33194645 PMCID: PMC7642726 DOI: 10.3389/fonc.2020.566511] [Citation(s) in RCA: 259] [Impact Index Per Article: 51.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Accepted: 09/21/2020] [Indexed: 12/11/2022] Open
Abstract
Tumor-associated macrophages (TAMs) are major innate immune cells that constitute up to 50% of the cell mass of human tumors. TAMs are highly heterogeneous cells that originate from resident tissue-specific macrophages and from newly recruited monocytes. TAMs' variability strongly depends on cancer type, stage, and intratumor heterogeneity. Majority of TAMs are programmed by tumor microenvironment to support primary tumor growth and metastatic spread. However, TAMs can also restrict tumor growth and metastasis. In this review, we summarized the knowledge about the role of TAMs in tumor growth, metastasis and in the response to cancer therapy in patients with five aggressive types of cancer: breast, colorectal, lung, ovarian, and prostate cancers that are frequently metastasize into distant organs resulting in high mortality of the patients. Two major TAM parameters are applied for the evaluation of TAM correlation with the cancer progression: total amount of TAMs and specific phenotype of TAMs identified by functional biomarkers. We summarized the data generated in the wide range of international patient cohorts on the correlation of TAMs with clinical and pathological parameters of tumor progression including lymphatic and hematogenous metastasis, recurrence, survival, therapy efficiency. We described currently available biomarkers for TAMs that can be measured in patients' samples (tumor tissue and blood). CD68 is the major biomarker for the quantification of total TAM amounts, while transmembrane receptors (stabilin-1, CD163, CD206, CD204, MARCO) and secreted chitinase-like proteins (YKL-39, YKL-40) are used as biomarkers for the functional TAM polarization. We also considered that specific role of TAMs in tumor progression can depend on the localization in the intratumoral compartments. We have made the conclusion for the role of TAMs in primary tumor growth, metastasis, and therapy sensitivity for breast, colorectal, lung, ovarian, and prostate cancers. In contrast to other cancer types, majority of clinical studies indicate that TAMs in colorectal cancer have protective role for the patient and interfere with primary tumor growth and metastasis. The accumulated data are essential for using TAMs as biomarkers and therapeutic targets to develop cancer-specific immunotherapy and to design efficient combinations of traditional therapy and new immunomodulatory approaches.
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Affiliation(s)
- Irina Larionova
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Gulnara Tuguzbaeva
- Department of Pathophysiology, Bashkir State Medical University, Ufa, Russia
| | - Anastasia Ponomaryova
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Marina Stakheyeva
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Nadezhda Cherdyntseva
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Valentin Pavlov
- Department of Urology, Bashkir State Medical University, Ufa, Russia
| | - Evgeniy Choinzonov
- Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia
| | - Julia Kzhyshkowska
- Laboratory of Translational Cellular and Molecular Biomedicine, National Research Tomsk State University, Tomsk, Russia
- Institute of Transfusion Medicine and Immunology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
- German Red Cross Blood Service Baden-Württemberg—Hessen, Mannheim, Germany
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35
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Qin S, Jiang J, Lu Y, Nice EC, Huang C, Zhang J, He W. Emerging role of tumor cell plasticity in modifying therapeutic response. Signal Transduct Target Ther 2020; 5:228. [PMID: 33028808 PMCID: PMC7541492 DOI: 10.1038/s41392-020-00313-5] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 08/25/2020] [Accepted: 08/30/2020] [Indexed: 02/07/2023] Open
Abstract
Resistance to cancer therapy is a major barrier to cancer management. Conventional views have proposed that acquisition of resistance may result from genetic mutations. However, accumulating evidence implicates a key role of non-mutational resistance mechanisms underlying drug tolerance, the latter of which is the focus that will be discussed here. Such non-mutational processes are largely driven by tumor cell plasticity, which renders tumor cells insusceptible to the drug-targeted pathway, thereby facilitating the tumor cell survival and growth. The concept of tumor cell plasticity highlights the significance of re-activation of developmental programs that are closely correlated with epithelial-mesenchymal transition, acquisition properties of cancer stem cells, and trans-differentiation potential during drug exposure. From observations in various cancers, this concept provides an opportunity for investigating the nature of anticancer drug resistance. Over the years, our understanding of the emerging role of phenotype switching in modifying therapeutic response has considerably increased. This expanded knowledge of tumor cell plasticity contributes to developing novel therapeutic strategies or combination therapy regimens using available anticancer drugs, which are likely to improve patient outcomes in clinical practice.
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Affiliation(s)
- Siyuan Qin
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People's Republic of China
| | - Jingwen Jiang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People's Republic of China
| | - Yi Lu
- School of Medicine, Southern University of Science and Technology Shenzhen, Shenzhen, Guangdong, 518055, People's Republic of China
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, Guangdong, People's Republic of China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, People's Republic of China.
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Road, 611137, Chengdu, People's Republic of China.
| | - Jian Zhang
- School of Medicine, Southern University of Science and Technology Shenzhen, Shenzhen, Guangdong, 518055, People's Republic of China.
- Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen, Guangdong, People's Republic of China.
| | - Weifeng He
- State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People's Republic of China.
- Chongqing Key Laboratory for Disease Proteomics, Chongqing, People's Republic of China.
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36
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Cioni B, Zaalberg A, van Beijnum JR, Melis MHM, van Burgsteden J, Muraro MJ, Hooijberg E, Peters D, Hofland I, Lubeck Y, de Jong J, Sanders J, Vivié J, van der Poel HG, de Boer JP, Griffioen AW, Zwart W, Bergman AM. Androgen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion. Nat Commun 2020; 11:4498. [PMID: 32908142 PMCID: PMC7481219 DOI: 10.1038/s41467-020-18313-y] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Accepted: 06/29/2020] [Indexed: 12/14/2022] Open
Abstract
The androgen receptor (AR) is the master regulator of prostate cancer (PCa) development, and inhibition of AR signalling is the most effective PCa treatment. AR is expressed in PCa cells and also in the PCa-associated stroma, including infiltrating macrophages. Macrophages have a decisive function in PCa initiation and progression, but the role of AR in macrophages remains largely unexplored. Here, we show that AR signalling in the macrophage-like THP-1 cell line supports PCa cell line migration and invasion in culture via increased Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) signalling and expression of its downstream cytokines. Moreover, AR signalling in THP-1 and monocyte-derived macrophages upregulates IL-10 and markers of tissue residency. In conclusion, our data suggest that AR signalling in macrophages may support PCa invasiveness, and blocking this process may constitute one mechanism of anti-androgen therapy. Anti-androgen therapy inhibits prostate cancer (PC) progression, and is thought to act directly on cancer cells. Here the authors show that androgen receptor is expressed on normal and PC-associated macrophages, and its stimulation alters macrophage secretome to promote migration of cultured PC cell lines.
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Affiliation(s)
- Bianca Cioni
- Divisions of Oncogenomics, The Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Anniek Zaalberg
- Divisions of Oncogenomics, The Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Judy R van Beijnum
- Angiogenesis laboratory, Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Monique H M Melis
- Molecular Genetics, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | | | - Mauro J Muraro
- Hubrecht Institute - KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT, Utrecht, The Netherlands
| | - Erik Hooijberg
- Division of Pathology, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Dennis Peters
- Core Facility Molecular Pathology, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Ingrid Hofland
- Core Facility Molecular Pathology, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Yoni Lubeck
- Division of Pathology, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Jeroen de Jong
- Division of Pathology, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Joyce Sanders
- Division of Pathology, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Judith Vivié
- Hubrecht Institute - KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584CT, Utrecht, The Netherlands
| | - Henk G van der Poel
- Urology and Medical Oncology, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Jan Paul de Boer
- Urology and Medical Oncology, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands
| | - Arjan W Griffioen
- Angiogenesis laboratory, Medical Oncology, Amsterdam UMC, Cancer Center Amsterdam, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands
| | - Wilbert Zwart
- Divisions of Oncogenomics, The Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. .,Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, 5600MB, Eindhoven, The Netherlands. .,, Oncode Institute, The Netherlands.
| | - Andries M Bergman
- Divisions of Oncogenomics, The Netherlands Cancer Institute (NKI), Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands. .,Urology and Medical Oncology, NKI, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands.
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Li N, Geng C, Hou S, Fan H, Gong Y. Damage-Associated Molecular Patterns and Their Signaling Pathways in Primary Blast Lung Injury: New Research Progress and Future Directions. Int J Mol Sci 2020; 21:ijms21176303. [PMID: 32878118 PMCID: PMC7504526 DOI: 10.3390/ijms21176303] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/20/2020] [Accepted: 08/20/2020] [Indexed: 12/13/2022] Open
Abstract
Primary blast lung injury (PBLI) is a common cause of casualties in wars, terrorist attacks, and explosions. It can exist in the absence of any other outward signs of trauma, and further develop into acute lung injury (ALI) or a more severe acute respiratory distress syndrome (ARDS). The pathogenesis of PBLI at the cellular and molecular level has not been clear. Damage-associated molecular pattern (DAMP) is a general term for endogenous danger signals released by the body after injury, including intracellular protein molecules (HMGB1, histones, s100s, heat shock proteins, eCIRP, etc.), secretory protein factors (IL-1β, IL-6, IL-10, TNF-α, VEGF, complements, etc.), purines and pyrimidines and their derived degradation products (nucleic acids, ATP, ADP, UDPG, uric acid, etc.), and extracellular matrix components (hyaluronic acid, fibronectin, heparin sulfate, biglycan, etc.). DAMPs can be detected by multiple receptors including pattern recognition receptors (PRRs). The study of DAMPs and their related signaling pathways, such as the mtDNA-triggered cGAS-YAP pathway, contributes to revealing the molecular mechanism of PBLI, and provides new therapeutic targets for controlling inflammatory diseases and alleviating their symptoms. In this review, we focus on the recent progress of research on DAMPs and their signaling pathways, as well as the potential therapeutic targets and future research directions in PBLI.
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Affiliation(s)
- Ning Li
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China; (N.L.); (C.G.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Chenhao Geng
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China; (N.L.); (C.G.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Shike Hou
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China; (N.L.); (C.G.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
| | - Haojun Fan
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China; (N.L.); (C.G.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
- Correspondence: (H.F.); (Y.G.)
| | - Yanhua Gong
- Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China; (N.L.); (C.G.); (S.H.)
- Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
- Correspondence: (H.F.); (Y.G.)
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Sigalov AB. SCHOOL of nature: ligand-independent immunomodulatory peptides. Drug Discov Today 2020; 25:1298-1306. [PMID: 32405248 PMCID: PMC7217646 DOI: 10.1016/j.drudis.2020.05.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 04/24/2020] [Accepted: 05/05/2020] [Indexed: 12/12/2022]
Abstract
Groundbreaking studies in protein biophysics have identified the mechanisms of transmembrane signaling at the level of druggable protein-protein interactions (PPIs). This resulted in the development of the signaling chain homooligomerization (SCHOOL) strategy to modulate cell responses using receptor-specific peptides. Inspired by nature, these short peptides use ligand-independent mechanisms of receptor inhibition and demonstrate potent efficacy in vitro and in vivo. The SCHOOL strategy is especially important when receptor ligands are unknown. An example is the triggering receptor expressed on myeloid cells-1 (TREM-1) receptor, an emerging therapeutic target involved in the pathogenesis of most inflammatory diseases. Here, I discuss advances in the field with a focus on TREM-1 inhibitory SCHOOL peptides that offer new hope for a 'magic bullet' cure for cancer, arthritis, sepsis, retinopathy, and other medical challenges.
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TREM-1 and TREM-2 Expression on Blood Monocytes Could Help Predict Survival in High-Grade Glioma Patients. Mediators Inflamm 2020; 2020:1798147. [PMID: 32684831 PMCID: PMC7350089 DOI: 10.1155/2020/1798147] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/27/2020] [Accepted: 05/25/2020] [Indexed: 12/16/2022] Open
Abstract
Objective In recent years, the role of the modern inflammatory markers TREM-1 (triggering receptors expressed on myeloid cells) and HMGB1 (high mobility group box 1 protein) in tumorigenesis has begun to be studied. Their role in gliomas is not clear. The aim of our study was to find the role of inflammation in gliomas. Patients and Methods. In 63 adult patients with gliomas and 31 healthy controls, the expressions of TREM-1 and TREM-2 on CD14+ blood cells (method: flow cytometry) and the levels of soluble sTREM-1, HMGB1, IL-6, and IL-10 (Elisa tests) were analyzed. Results Cox proportional hazard analysis showed that a TREM-1/TREM-2 ratio was associated with reduced overall survival (HR = 1.001, P = 0.023). Patients with a TREM-1/TREM-2 ratio above 125 survived significantly shorter than patients with a TREM-1/TREM-2 ratio below 125. The percentage of CD14+ TREM-1+ cells was strongly associated with a plasma IL-6/IL-10 ratio (positively) and with IL-10 (negatively). Conversely, we found a higher percentage of CD14+ TREM-2+ monocytes in better surviving patients; these cells could downregulate the exaggerated inflammation and potentiate the phagocytosis in the tumor. The serum levels of HMGB1 negatively correlated with the percentage of CD14+ TREM-1+ cells and with the TREM-1/TREM-2 ratio. The positive correlation between the serum levels of a late proinflammatory cytokine HMGB1 with the percentage of TREM2+ CD14+ monocytes can be explained as an effort for suppression of systemic inflammation by anti-inflammatory acting CD14+ TREM-2+ cells. Conclusion We showed that the TREM-1/TREM-2 ratio (expression on the surface of blood monocytes) could help predict prognosis in patients with gliomas, especially in high-grade gliomas, and that systemic inflammation has an impact on the patient's overall survival. This is the first study that showed that TREM expression on monocytes in peripheral blood could help predict prognosis in patients with gliomas.
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Raggi F, Bosco MC. Targeting Mononuclear Phagocyte Receptors in Cancer Immunotherapy: New Perspectives of the Triggering Receptor Expressed on Myeloid Cells (TREM-1). Cancers (Basel) 2020; 12:cancers12051337. [PMID: 32456204 PMCID: PMC7281211 DOI: 10.3390/cancers12051337] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/18/2020] [Accepted: 05/22/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory cells are major players in the onset of cancer. The degree of inflammation and type of inflammatory cells in the tumor microenvironment (TME) are responsible for tilting the balance between tumor progression and regression. Cancer-related inflammation has also been shown to influence the efficacy of conventional therapy. Mononuclear phagocytes (MPs) represent a major component of the inflammatory circuit that promotes tumor progression. Despite their potential to activate immunosurveillance and exert anti-tumor responses, MPs are subverted by the tumor to support its growth, immune evasion, and spread. MP responses in the TME are dictated by a network of stimuli integrated through the cross-talk between activatory and inhibitory receptors. Alterations in receptor expression/signaling can create excessive inflammation and, when chronic, promote tumorigenesis. Research advances have led to the development of new therapeutic strategies aimed at receptor targeting to induce a tumor-infiltrating MP switch from a cancer-supportive toward an anti-tumor phenotype, demonstrating efficacy in different human cancers. This review provides an overview of the role of MP receptors in inflammation-mediated carcinogenesis and discusses the most recent updates regarding their targeting for immunotherapeutic purposes. We focus in particular on the TREM-1 receptor, a major amplifier of MP inflammatory responses, highlighting its relevance in the development and progression of several types of inflammation-associated malignancies and the promises of its inhibition for cancer immunotherapy.
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Frafjord A, Skarshaug R, Hammarström C, Stankovic B, Dorg LT, Aamodt H, Woldbaek PR, Helland Å, Brustugun OT, Øynebråten I, Corthay A. Antibody combinations for optimized staining of macrophages in human lung tumours. Scand J Immunol 2020; 92:e12889. [PMID: 32299134 DOI: 10.1111/sji.12889] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 04/02/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022]
Abstract
The analysis of tumour-associated macrophages (TAMs) has a high potential to predict cancer recurrence and response to immunotherapy. However, the heterogeneity of TAMs poses a challenge for quantitative and qualitative measurements. Here, we critically evaluated by immunohistochemistry and flow cytometry two commonly used pan-macrophage markers (CD14 and CD68) as well as some suggested markers for tumour-promoting M2 macrophages (CD163, CD204, CD206 and CD209) in human non-small cell lung cancer (NSCLC). Tumour, non-cancerous lung tissue and blood were investigated. For immunohistochemistry, CD68 was confirmed to be a useful pan-macrophage marker although careful selection of antibody was found to be critical. The widely used anti-CD68 antibody clone KP-1 stains both macrophages and neutrophils, which is problematic for TAM quantification because lung tumours contain many neutrophils. For TAM counting in tumour sections, we recommend combined labelling of CD68 with a cell membrane marker such as CD14, CD163 or CD206. In flow cytometry, the commonly used combination of CD14 and HLA-DR was found to not be optimal because some TAMs do not express CD14. Instead, combined staining of CD68 and HLA-DR is preferable to gate all TAMs. Concerning macrophage phenotypic markers, the scavenger receptor CD163 was found to be expressed by a substantial fraction (50%-86%) of TAMs with a large patient-to-patient variation. Approximately 50% of TAMs were positive for CD206. Surprisingly, there was no clear overlap between CD163 and CD206 positivity, and three distinct TAM sub-populations were identified in NSCLC tumours: CD163+ CD206+ , CD163+ CD206- and CD163- CD206- . This work should help develop macrophage-based prognostic tools for cancer.
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Affiliation(s)
- Astri Frafjord
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Renate Skarshaug
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Clara Hammarström
- Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Branislava Stankovic
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Linda T Dorg
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway.,Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Henrik Aamodt
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway.,Department of Cardiothoracic Surgery, Ullevål Hospital, Oslo University Hospital, Oslo, Norway
| | - Per Reidar Woldbaek
- Department of Cardiothoracic Surgery, Ullevål Hospital, Oslo University Hospital, Oslo, Norway
| | - Åslaug Helland
- Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, University of Oslo, Oslo, Norway.,Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Odd Terje Brustugun
- Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Section of Oncology, Drammen Hospital, Vestre Viken Health Trust, Drammen, Norway
| | - Inger Øynebråten
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Alexandre Corthay
- Tumor Immunology Lab, Department of Pathology, Rikshospitalet, Oslo University Hospital and University of Oslo, Oslo, Norway.,Hybrid Technology Hub - Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
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Dantas PHDS, Matos ADO, da Silva Filho E, Silva-Sales M, Sales-Campos H. Triggering receptor expressed on myeloid cells-1 (TREM-1) as a therapeutic target in infectious and noninfectious disease: a critical review. Int Rev Immunol 2020; 39:188-202. [PMID: 32379561 DOI: 10.1080/08830185.2020.1762597] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
The triggering receptor expressed on myeloid cells-1 (TREM-1) is an innate immune receptor found in the surface of several immune and non-immune cells. Since its first description in 2000, this molecule and its soluble form (sTREM-1) have been implicated in many diseases with infectious and noninfectious origins. As an amplifier of inflammation, the membrane-associated TREM-1 (mTREM-1) isoform induces the production of pro-inflammatory mediators, thus contributing to the pathogenesis of diseases such as sepsis, arthritis, colitis and infections. In this context, many studies have used molecules capable of inhibiting TREM-1 activity as anti-inflammatory drugs. In this regard, a few peptides have been showing promising results in the amelioration of detrimental immune responses. Some commercially available drugs, including corticosteroids and antibiotics, with known anti-inflammatory effects, have also shown activity in TREM-1 signaling. Therefore, considering the potential of this receptor as a therapeutic target, the present review encompasses the main compounds explored so far in TREM-1 modulation, highlighting and critically discussing its effects and major drawbacks of such approaches.
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Affiliation(s)
| | - Amanda de Oliveira Matos
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
| | - Ernandes da Silva Filho
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
| | - Marcelle Silva-Sales
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
| | - Helioswilton Sales-Campos
- Institute of Tropical Pathology and Public Health, Federal University of Goias, Goiânia, Goiás, Brazil
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Lum LG, Thakur A, Elhakiem A, Alameer L, Dinning E, Huang M. Anti-CS1 × Anti-CD3 Bispecific Antibody (BiAb)-Armed Anti-CD3 Activated T Cells (CS1-BATs) Kill CS1 + Myeloma Cells and Release Type-1 Cytokines. Front Oncol 2020; 10:544. [PMID: 32432032 PMCID: PMC7214537 DOI: 10.3389/fonc.2020.00544] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 03/26/2020] [Indexed: 11/13/2022] Open
Abstract
Background: Multiple myeloma (MM) remains incurable despite significant advances in chemotherapy, targeted therapies, and immunotherapy. Bispecific antibody (BiAb)-armed activated T cells (BATs) have been developed for targeting and treatment of solid and hematologic malignancies. BATs are serial killers of tumor cells, secrete Th1 cytokines, and induce adaptive cellular and humoral immune responses in patients (pts). This study provides preclinical data using bispecific anti-CS1 (elotuzumab) × anti-CD3 (OKT3) antibody (CS1Bi)-armed activated T cells (CS1- BATs) that provide a strong rationale for applying CS1-BATs to pts with MM. Methods: CS1-BATs and unarmed activated T cells (ATC) were incubated with MM cell targets at various effector to target ratios (E:T) in a quantitative flow cytometry-based assay to determine the degree of cell loss relative to target cells incubated without ATC. ATC from up to 8 normal donors were armed with various concentrations of CS1 BiAb and tested against 5 myeloma cells lines for CS1-BATs-mediated killing and release of Th1 cytokines, chemokines and granzyme B. Results: CS1-BATs from normal donors killed each of 5 MM cell lines proportional to E:T ratios ranging between 1:1 and 10:1 and arming concentrations of 12.5 to 50 ng/million ATC, which was accompanied by release of Th1 cytokines, chemokines and granzyme B. CS1-BATs prepared from MM pts' peripheral blood mononuclear cells (PBMC) showed increasing cytotoxicity and T cell expansion over time against ARH77 MM cells. The optimal arming dose of CS1Bi is 50 ng/106 ATC. Conclusions: These data demonstrate the therapeutic potential of CS1-BATs-mediated cytotoxicity and Th1 cytokines release at low E:T and support advancing their clinical development in pts with MM.
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Affiliation(s)
- Lawrence G Lum
- Division of Hematology and Oncology, Bone Marrow Transplantation and Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, United States
| | - Archana Thakur
- Division of Hematology and Oncology, Bone Marrow Transplantation and Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, United States
| | - Abdalla Elhakiem
- Division of Hematology and Oncology, Bone Marrow Transplantation and Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, United States
| | - Lena Alameer
- Division of Hematology and Oncology, Bone Marrow Transplantation and Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, United States
| | - Emily Dinning
- Division of Hematology and Oncology, Bone Marrow Transplantation and Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, United States
| | - Manley Huang
- Division of Hematology and Oncology, Bone Marrow Transplantation and Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, United States
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Zhu M, Yang Z, Yu H, Zhu Q, Xu Y, Li Y, Li C, Zhao W, Liang Z, Chen L. The efficacy and safety of low-frequency rotating static magnetic field therapy combined with chemotherapy on advanced lung cancer patients: a randomized, double-blinded, controlled clinical trial. Int J Radiat Biol 2020; 96:943-950. [PMID: 32238091 DOI: 10.1080/09553002.2020.1748737] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Purpose: To evaluate the efficacy and safety of magnetic field (MF) therapy by a randomized, double-blinded, controlled clinical trial.Materials and methods: From February 2016 to August 2019, patients with advanced lung cancer who conformed to inclusion criteria were enrolled in this study. Patients were assigned into MF therapy group (MF group, receiving both MF therapy and chemotherapy) and control group (CON group, receiving sham MF therapy and chemotherapy) randomly. The treatment course was 21 days and 2 hours per day. Changes of life quality assessment scales, objective response rate (ORR) and disease control rate (DCR) were analyzed as primary end points. The secondary end points were progression-free survival (PFS), change of blood cytokine concentrations and safety. This study has been registered on Clinicaltrials.gov (ID: NCT02701231).Results: 77 patients were enrolled and 60 finished the study. Comparing to CON group, more patients in MF group (66.7% vs 25.9%) were experiencing life quality improvement on day 21. Besides, MF group patients had higher concentrations of IP-10 and GM-CSF, and lower concentration of sTREM-1 in plasma. However, the two groups were having similar ORR, DCR and PFS after treatment. Moreover, MF treatment did not increase adverse events in MF group.Conclusions: MF therapy could improve life quality and modulate blood cytokine concentration in advanced lung cancer patients. Hence, it might be applied as an adjuvant therapy along with chemotherapy.
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Affiliation(s)
- Minghui Zhu
- Department of Respiratory Diseases, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhen Yang
- Department of Respiratory Diseases, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Hang Yu
- Department of Respiratory Diseases, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Qiang Zhu
- Department of Respiratory Diseases, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yang Xu
- Department of Respiratory Diseases, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Yanran Li
- Department of Neurology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Chunyan Li
- Department of Respiratory Diseases, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Wei Zhao
- Department of Respiratory Diseases, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Zhixin Liang
- Department of Respiratory Diseases, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Liangan Chen
- Department of Respiratory Diseases, Chinese People's Liberation Army General Hospital, Beijing, China
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Rich AM, Hussaini HM, Seo B, Zain RB. Understanding the complex microenvironment in oral cancer: the contribution of the Faculty of Dentistry, University of Otago over the last 100 years. J R Soc N Z 2020. [DOI: 10.1080/03036758.2020.1736586] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Alison Mary Rich
- Faculty of Dentistry, Sir John Walsh Research Institute, University of Otago, Dunedin, New Zealand
| | - Haizal Mohd Hussaini
- Faculty of Dentistry, Sir John Walsh Research Institute, University of Otago, Dunedin, New Zealand
| | - Benedict Seo
- Faculty of Dentistry, Sir John Walsh Research Institute, University of Otago, Dunedin, New Zealand
| | - Rosnah Bt Zain
- Faculty of Dentistry, MAHSA University, Selangor, Malaysia
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Ruan X, Sun Y, Wang W, Ye J, Zhang D, Gong Z, Yang M. Multiplexed molecular profiling of lung cancer with malignant pleural effusion using next generation sequencing in Chinese patients. Oncol Lett 2020; 19:3495-3505. [PMID: 32269623 PMCID: PMC7115151 DOI: 10.3892/ol.2020.11446] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Accepted: 11/19/2019] [Indexed: 12/24/2022] Open
Abstract
Lung cancer is the most common type of cancer and the leading cause of cancer-associated death worldwide. Malignant pleural effusion (MPE), which is observed in ~50% of advanced non-small cell lung cancer (NSCLC) cases, and most frequently in lung adenocarcinoma, is a common complication of stage III-IV NSCLC, and it can be used to predict a poor prognosis. In the present study, multiple oncogene mutations were detected, including 17 genes closely associated with initiation of advanced lung cancer, in 108 MPE samples using next generation sequencing (NGS). The NGS data of the present study had broader coverage, deeper sequencing depth and higher capture efficiency compared with NGS findings of previous studies on MPE. In the present study, using NGS, it was demonstrated that 93 patients (86%) harbored EGFR mutations and 62 patients possessed mutations in EGFR exons 18-21, which are targets of available treatment agents. EGFR L858R and exon 19 indel mutations were the most frequently observed alterations, with frequencies of 31 and 25%, respectively. In 1 patient, an EGFR amplification was identified and 6 patients possessed a T790M mutation. ALK + EML4 gene fusions were identified in 6 patients, a ROS1 + CD74 gene fusion was detected in 1 patient and 10 patients possessed a BIM (also known as BCL2L11) 2,903-bp intron deletion. In 4 patients, significant KRAS mutations (G12D, G12S, G13C and A146T) were observed, which are associated with resistance to afatinib, icotinib, erlotinib and gefitinib. There were 83 patients with ERBB2 mutations, but only two of these mutations were targets of available treatments. The results of the present study indicate that MPE is a reliable specimen for NGS based detection of somatic mutations.
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Affiliation(s)
- Xingya Ruan
- Department of Pulmonary and Critical Care Medicine, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
| | - Yonghua Sun
- Shanghai YunYing Medical Technology Co., Ltd., Shanghai 201600, P.R. China
| | - Wei Wang
- Shanghai YunYing Medical Technology Co., Ltd., Shanghai 201600, P.R. China
| | - Jianwei Ye
- Shanghai YunYing Medical Technology Co., Ltd., Shanghai 201600, P.R. China
| | - Daoyun Zhang
- Shanghai YunYing Medical Technology Co., Ltd., Shanghai 201600, P.R. China
| | - Ziying Gong
- Shanghai YunYing Medical Technology Co., Ltd., Shanghai 201600, P.R. China
| | - Mingxia Yang
- Department of Pulmonary and Critical Care Medicine, The Affiliated Changzhou No. 2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213000, P.R. China
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Dou L, Shi X, He X, Gao Y. Macrophage Phenotype and Function in Liver Disorder. Front Immunol 2020; 10:3112. [PMID: 32047496 PMCID: PMC6997484 DOI: 10.3389/fimmu.2019.03112] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022] Open
Abstract
Hepatic macrophages are a remarkably heterogeneous population consisting of self-renewing tissue-resident phagocytes, termed Kupffer cells (KCs), and recruited macrophages derived from peritoneal cavity as well as the bone marrow. KCs are located in the liver sinusoid where they scavenge the microbe from the portal vein to maintain liver homeostasis. Liver injury may trigger hepatic recruitment of peritoneal macrophages and monocyte-derived macrophages. Studies describing macrophage accumulation have shown that hepatic macrophages are involved in the initiation and progression of various liver diseases. They act as tolerogenic antigen-presenting cells to inhibit T-cell activation by producing distinct sets of cytokines, chemokines, and mediators to maintain or resolve inflammation. Furthermore, by releasing regenerative growth factors, matrix metalloproteinase arginase, they promote tissue repair. Recent experiments found that KCs and recruited macrophages may play different roles in the development of liver disease. Given that hepatic macrophages are considerably plastic populations, their phenotypes and functions are likely switching along disease progression. In this review, we summarize current knowledge about the role of tissue-resident macrophages and recruited macrophages in pathogenesis of alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), viral hepatitis, and hepatocellular carcinoma (HCC).
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Affiliation(s)
- Lang Dou
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaomin Shi
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xiaoshun He
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yifang Gao
- Organ Transplantation Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol 2019; 20:95-112. [PMID: 31558839 DOI: 10.1038/s41577-019-0215-7] [Citation(s) in RCA: 1066] [Impact Index Per Article: 177.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/13/2019] [Indexed: 12/11/2022]
Abstract
The innate immune system has the capacity to detect 'non-self' molecules derived from pathogens, known as pathogen-associated molecular patterns, via pattern recognition receptors. In addition, an increasing number of endogenous host-derived molecules, termed damage-associated molecular patterns (DAMPs), have been found to be sensed by various innate immune receptors. The recognition of DAMPs, which are produced or released by damaged and dying cells, promotes sterile inflammation, which is important for tissue repair and regeneration, but can also lead to the development of numerous inflammatory diseases, such as metabolic disorders, neurodegenerative diseases, autoimmune diseases and cancer. Here we examine recent discoveries concerning the roles of DAMP-sensing receptors in sterile inflammation and in diseases resulting from dysregulated sterile inflammation, and then discuss insights into the cross-regulation of these receptors and their ligands.
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Wu Q, Zhou W, Yin S, Zhou Y, Chen T, Qian J, Su R, Hong L, Lu H, Zhang F, Xie H, Zhou L, Zheng S. Blocking Triggering Receptor Expressed on Myeloid Cells-1-Positive Tumor-Associated Macrophages Induced by Hypoxia Reverses Immunosuppression and Anti-Programmed Cell Death Ligand 1 Resistance in Liver Cancer. Hepatology 2019; 70:198-214. [PMID: 30810243 PMCID: PMC6618281 DOI: 10.1002/hep.30593] [Citation(s) in RCA: 198] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Accepted: 02/20/2019] [Indexed: 12/12/2022]
Abstract
Tumor-associated macrophages (TAMs) are recognized as antitumor suppressors, but how TAMs behave in the hypoxic environment of hepatocellular carcinoma (HCC) remains unclear. Here, we demonstrated that hypoxia inducible factor 1α induced increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in TAMs, resulting in immunosuppression. Specifically, TREM-1-positive (TREM-1+ ) TAMs abundant at advanced stages of HCC progression indirectly impaired the cytotoxic functions of CD8+ T cells and induced CD8+ T-cells apoptosis. Biological and functional assays showed that TREM-1+ TAMs had higher expression of programmed cell death ligand 1 (PD-L1) under hypoxic environment. However, TREM-1+ TAMs could abrogate spontaneous and PD-L1-blockade-mediated antitumor effects in vivo, suggesting that TREM-1+ TAM-induced immunosuppression was dependent on a pathway separate from PD-L1/programmed cell death 1 axis. Moreover, TREM-1+ TAM-associated regulatory T cells (Tregs) were crucial for HCC resistance to anti-PD-L1 therapy. Mechanistically, TREM-1+ TAMs elevated chemokine (C-C motif) ligand 20 expression through the extracellular signal-regulated kinase/NF-κβ pathway in response to hypoxia and tumor metabolites leading to CCR6+ Foxp3+ Treg accumulation. Blocking the TREM-1 pathway could significantly inhibit tumor progression, reduce CCR6+ Foxp3+ Treg recruitment, and improve the therapeutic efficacy of PD-L1 blockade. Thus, these data demonstrated that CCR6+ Foxp3+ Treg recruitment was crucial for TREM-1+ TAM-mediated anti-PD-L1 resistance and immunosuppression in hypoxic tumor environment. Conclusion: This study highlighted that the hypoxic environment initiated the onset of tumor immunosuppression through TREM-1+ TAMs attracting CCR6+ Foxp3+ Tregs, and TREM-1+ TAMs endowed HCC with anti-PD-L1 therapy resistance.
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Affiliation(s)
- Qinchuan Wu
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouChina,NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina
| | - Wuhua Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouChina,NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina,Department of Hepatobiliary and Pancreatic SurgeryTaihe Hospital, Hubei University of MedicineHubeiChina
| | - Shengyong Yin
- NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina
| | - Yuan Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouChina,NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina
| | - Tianchi Chen
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouChina,NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina
| | - Junjie Qian
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouChina,NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina
| | - Rong Su
- NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina
| | - Liangjie Hong
- NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina
| | - Haohao Lu
- NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina
| | - Feng Zhang
- NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina
| | - Haiyang Xie
- NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseasesHangzhouChina
| | - Lin Zhou
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouChina,NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseasesHangzhouChina
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of SurgeryThe First Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouChina,NHFPC Key Laboratory of Combined Multi‐organ TransplantationHangzhouChina,Key Laboratory of the Diagnosis and Treatment of Organ TransplantationCAMSHangzhouChina,Key Laboratory of Organ TransplantationZhejiang ProvinceHangzhouChina,Collaborative Innovation Center for Diagnosis Treatment of Infectious DiseasesHangzhouChina
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Lee YS, Yeo IJ, Kim KC, Han SB, Hong JT. Inhibition of Lung Tumor Development in ApoE Knockout Mice via Enhancement of TREM-1 Dependent NK Cell Cytotoxicity. Front Immunol 2019; 10:1379. [PMID: 31275318 PMCID: PMC6592261 DOI: 10.3389/fimmu.2019.01379] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Accepted: 05/31/2019] [Indexed: 01/06/2023] Open
Abstract
Apolipoprotein E (ApoE) is known to regulate lipid homeostasis and associated with atherosclerogenesis. Eventhough atherosclerogenesis is associated with tumor development, the role of ApoE in lung tumorigenesis and metastasis is not clear. Thus, the tumor growth and metastasis were compared in WT and ApoE knockout (KO) mice. Urethane-induced lung tumor incidence and B16F10 lung metastasis in ApoE knockout (KO) mice were significantly reduced in comparison to that in WT mice. Knockdown of ApoE expression in lung cancer cells and B16F10 cells also decreased cancer cell growth and metastasis. The inhibitory effect of ApoE KO on tumor development and metastasis was associated with increase of infiltration of NK cells. NK cells derived from ApoE KO mice showed much greater cytotoxicity than those from WT mice. These cytotoxic effect of NK cells derived from ApoE KO mice was associated with higher expression of Granzyme B, Fas Ligand, IFN-γ, TNF-α, NKG2D, NKp46, and DNAM-1 expression. Triggering receptor expressed on myeloid cell (TREM)-1 is a proinflammatory mediator expressed on NK cells, and is known to be associated with NK cell cytotoxicity. Thus, we investigated the role of TREM-1 on ApoE KO mice originated NK cell mediated cytotoxicity for cancer cells. Blockade of TREM-1 expression with a TREM-1 antagonist prevented NK cell-mediated cytotoxicity. TREM-1 antibody recovered cytotoxic effect of NK cells derived from KO mice of T-bet, which upregulating gene for TREM-1. These data indicate that ApoE KO suppressed lung tumor development and metastasis via increase of TREM-1-dependent anti-tumor activity of NK cells.
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Affiliation(s)
- Yong Sun Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
| | - In Jun Yeo
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
| | - Ki Cheon Kim
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
| | - Sang-Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, Cheongju, South Korea
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