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1.
Front Immunol ; 14: 1180209, 2023.
Article in English | MEDLINE | ID: mdl-37404831

ABSTRACT

CD169+ resident macrophages in lymph nodes of breast cancer patients are for unknown reasons associated with a beneficial prognosis. This contrasts CD169+ macrophages present in primary breast tumors (CD169+ TAMs), that correlate with a worse prognosis. We recently showed that these CD169+ TAMs were associated with tertiary lymphoid structures (TLSs) and Tregs in breast cancer. Here, we show that CD169+ TAMs can be monocyte-derived and express a unique mediator profile characterized by type I IFNs, CXCL10, PGE2 and inhibitory co-receptor expression pattern. The CD169+ monocyte-derived macrophages (CD169+ Mo-M) possessed an immunosuppressive function in vitro inhibiting NK, T and B cell proliferation, but enhanced antibody and IL6 secretion in activated B cells. Our findings indicate that CD169+ Mo-M in the primary breast tumor microenvironment are linked to both immunosuppression and TLS functions, with implications for future targeted Mo-M therapy.


Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/pathology , Macrophages , Monocytes , Prognosis , Lymph Nodes , Tumor Microenvironment
2.
Commun Biol ; 2: 176, 2019.
Article in English | MEDLINE | ID: mdl-31098409

ABSTRACT

Innate immune responses are rapid, dynamic and highly regulated to avoid overt reactions. This regulation is executed by innate immune tolerance mechanisms that remain obscure. Wnt5a is a signalling protein mainly involved in developmental processes and cancer. The effect of Wnt5a on inflammatory myeloid cells is controversial. Here, we combine primary cell cultures, in vitro binding studies, mass spectrometry and Drosophila protein modelling to show that Wnt5a is a direct ligand of toll-like receptor (TLR) 2 and 4. The binding promotes a MyD88-non-canonical nuclear factor of kappa B (NFκB) and AP-1 signalling cascade, with contradictory profiles in mouse (pro-inflammatory) and human (anti-inflammatory) myeloid immune cells. These data reveal that the true nature of Wnt5a in inflammatory cells, is to regulate TLR signals, and in human myeloid cells it acts as an endogenous, tolerance-associated molecular pattern (TAMP), inducing IL-10 and innate immune tolerance.


Subject(s)
Myeloid Cells/immunology , Toll-Like Receptor 2/immunology , Toll-Like Receptor 4/immunology , Wnt-5a Protein/immunology , Animals , Cells, Cultured , Cytokines/biosynthesis , Drosophila Proteins/chemistry , Drosophila Proteins/metabolism , Humans , Immune Tolerance , Immunity, Innate , Interleukin-10/biosynthesis , Interleukin-10/genetics , Intracellular Signaling Peptides and Proteins/chemistry , Intracellular Signaling Peptides and Proteins/metabolism , Ligands , Mice , Models, Immunological , Models, Molecular , Myeloid Cells/metabolism , NF-kappa B/metabolism , Signal Transduction/immunology , Toll-Like Receptor 2/metabolism , Toll-Like Receptor 4/metabolism , Toll-Like Receptors/chemistry , Toll-Like Receptors/metabolism , Transcription, Genetic , Wnt-5a Protein/metabolism
3.
Exp Cell Res ; 362(2): 525-531, 2018 01 15.
Article in English | MEDLINE | ID: mdl-29269075

ABSTRACT

The taxanes Docetaxel and Paclitaxel are two of the standard chemotherapies for patients with metastatic breast cancer. The functional effect of Docetaxel and Paclitaxel on human innate immune cells of the myeloid lineage is not well established, nor is the effects these agents have on differentiation of monocytes into macrophages and dendritic cells. Therefore, the aim with this project was to determine the effects of Docetaxel and Paclitaxel on primary human monocyte differentiation, activation and function. For this purpose, primary human monocytes were isolated from healthy donors and cultured with or without Docetaxel and Paclitaxel. We found that Docetaxel promoted the differentiation of primary human monocytes into pro-inflammatory macrophages with an M1 phenotype and an ability to present antigens to T cells. Monocytes treated with Docetaxel also displayed an elevated secretion of IL-8 and IL-1ß, but did not promote generation of monocytic myeloid-derived suppressor cells. In conclusion, Docetaxel appears to have an immune stimulatory effect that would be beneficial for an anti-tumorigenic type of immune response, whereas Paclitaxel seems to have less effect on myeloid cells.


Subject(s)
Carcinogenesis/drug effects , Cell Differentiation/drug effects , Immunity, Innate/drug effects , Monocytes/drug effects , Antineoplastic Agents/pharmacology , Dendritic Cells/drug effects , Docetaxel , Female , Humans , Macrophages/drug effects , Monocytes/pathology , Myeloid Cells/drug effects , Neoplasms/drug therapy , Neoplasms/pathology , Paclitaxel/pharmacology , T-Lymphocytes/drug effects , Taxoids/pharmacology
4.
Int J Cancer ; 140(11): 2557-2567, 2017 06 01.
Article in English | MEDLINE | ID: mdl-28247912

ABSTRACT

The concept of functional neutrophil subsets is new and their clinical significance in malignancies is unknown. Our study investigated the role of CD16dim CD62Lhigh , CD16high CD62Lhigh and CD16high CD62Ldim neutrophil subsets in head and neck squamous cell carcinoma (HNSCC) patients. These neutrophil subsets may play different roles in immune-related activity in cancer, based on their profile, activation state and migration ability within a tumor site, which may be important in predicting cancer prognoses. Tumor biopsies and blood were obtained from newly diagnosed untreated HNSCC patients and healthy controls. Neutrophil subsets and their phenotype were characterized using flow cytometry. Isolated granulocytes were assessed for anti-tumor immune functions. Compared to controls HNSCC patients exhibited increased CD16high CD62Ldim neutrophils in blood; this subset displayed a distinct phenotypes with high expression of CD11b and CD18. This subset was prone to migrate into the tumor facilitated by tumor-derived IL-8. Furthermore, IL-8 was also found to activate neutrophils and thereby promoting subset transition. Various assays demonstrated that activated CD16high CD62Ldim neutrophils inhibited migration, proliferation and induced apoptosis of FaDu cancer cells. Neutrophil elastase detected in activated CD16high CD62Ldim neutrophils and tumor biopsies suggested that CD16high CD62Ldim neutrophils impart anti-tumoral activity via neutrophil extracellular traps. Furthermore, increased fraction of CD16high CD62Ldim neutrophils was shown to correlate with an increased survival rate. Our study demonstrates the clinical relevance of the CD16high CD62Ldim neutrophil subset, providing evidence for its increased migration capacity, its anti-tumor activity including increased NET formation and finally its correlation with increased survival in HNSCC patients.


Subject(s)
Carcinoma, Squamous Cell/pathology , Cell Movement/physiology , Head and Neck Neoplasms/pathology , L-Selectin/metabolism , Neutrophils/pathology , Receptors, IgG/metabolism , Aged , Aged, 80 and over , Apoptosis/physiology , Carcinoma, Squamous Cell/metabolism , Cell Proliferation/physiology , Female , GPI-Linked Proteins/metabolism , Granulocytes/metabolism , Granulocytes/pathology , Head and Neck Neoplasms/metabolism , Humans , Interleukin-8/metabolism , Male , Middle Aged , Neutrophils/metabolism , Squamous Cell Carcinoma of Head and Neck , Survival Rate
5.
Oncotarget ; 8(2): 3649-3665, 2017 Jan 10.
Article in English | MEDLINE | ID: mdl-27690299

ABSTRACT

Myeloid-derived suppressor cells (MDSCs) have a strong immunosuppressive character that allows them to regulate immune responses and hinder overt inflammatory responses. In cancer, this leads to tumor immune evasion and disease progression. MDSCs come in at least two forms: monocytic (Mo-MDSCs) and granulocytic (G-MDSCs). The classical definition of MDSCs as immature myeloid cells blocked from differentiating has been challenged by recent studies suggesting that Mo-MDSCs and G-MDSCs may represent monocytes and granulocytes that have acquired immunosuppressive properties. The molecular mechanism behind their generation and their true origins are now widely debated. In this review we discuss the different proposed mechanisms of the generation of both types of MDSCs, with a special focus on human MDSCs in cancer.


Subject(s)
Myeloid-Derived Suppressor Cells/cytology , Myeloid-Derived Suppressor Cells/physiology , Animals , Cell Differentiation , Cellular Reprogramming/genetics , Cellular Reprogramming/immunology , Colony-Stimulating Factors/metabolism , Gene Expression Regulation , Granulocytes/cytology , Granulocytes/immunology , Granulocytes/metabolism , Hematopoiesis, Extramedullary/genetics , Hematopoiesis, Extramedullary/immunology , Humans , Immunomodulation , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , Myeloid Cells/cytology , Myeloid Cells/immunology , Myeloid Cells/metabolism , Myelopoiesis , Neutrophil Activation/genetics , Neutrophil Activation/immunology , Neutrophils/cytology , Neutrophils/immunology , Neutrophils/metabolism , Phenotype , Signal Transduction
6.
PLoS One ; 9(6): e98239, 2014.
Article in English | MEDLINE | ID: mdl-24886842

ABSTRACT

BACKGROUND: The human nasal epithelium is an important physical barrier, and a part of the innate immune defense that protect against pathogens. The epithelial cells recognize microbial components by pattern-recognition receptors (PRRs), and thereby trigger an immune response. Even though TLR3, TLR7, TLR9, RIG-I and MDA-5 are all known to respond to viral stimulation, their potential role in chronic airway inflammation triggered by local cytokine release remains to be established. METHODS: mRNA and corresponding protein expression of TLR3, TLR7, TLR9, RIG-I and MDA-5 were analyzed in nasal biopsies and various upper airway epithelial cell lines using real-time reverse transcription PCR, immunohistochemistry and flow cytometry. Ligand induced, cytokine release, was evaluated with ELISA. RESULTS: Nasal biopsies were found to express TLR3, TLR7, TLR9, RIG-I and MDA-5, with the most abundant expression in the surface epithelium. These receptors were verified in primary human nasal epithelial cell (HNEC) as well as in the airway epithelial cell lines Detroit-562 and FaDu. Poly(I:C) (TLR3) and R-837 (TLR7) stimulation increased secretion of IL-6 and GM-CSF from the nasal mucosa and the epithelial cell lines. CpG (TLR9) stimulation caused release of IL-8 in the nasal mucosa and in FaDu. Poly(I:C)/LyoVec (RIG-I/MDA-5) stimulation activated the secretion of IFN-ß in the nasal mucosa. A corresponding release was also detected from HNEC and Detroit-562. CONCLUSION: The nasal epithelium has the ability to recognize viral intrusion through TLR and RLR receptors, and the subsequent response might have a role in exacerbation of inflammatory diseases like allergic rhinitis and chronic rhinosinusitis.


Subject(s)
DEAD-box RNA Helicases/metabolism , Epithelial Cells/metabolism , Nose/cytology , Toll-Like Receptors/metabolism , Adolescent , Adult , Cell Line , DEAD Box Protein 58 , DEAD-box RNA Helicases/genetics , Epithelium/metabolism , Female , Humans , Interferon-Induced Helicase, IFIH1 , Male , Nasal Mucosa/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Immunologic , Toll-Like Receptors/genetics , Young Adult
7.
Pathog Dis ; 72(1): 55-60, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24821514

ABSTRACT

In the upper airway, the production of antimicrobial peptides (AMPs) protects against bacteria, viruses and fungi. Previous investigations have revealed downregulated expression of AMPs in different manifestations of allergic disease. In this study, we examined the expression of LL-37, Ribonuclease7 (RNase7) and Liver-expressed antimicrobial peptide 2 (LEAP-2) in tonsillar tissue and studied a possible relation to seasonal allergic rhinitis (SAR). Tonsils, obtained from patients with SAR and nonallergic controls, were examined for the occurrence of LL-37, RNase7 and LEAP-2 with real-time RT-PCR and immunohistochemistry. Tonsillar mononuclear cells were cultured in presence or absence of LEAP-2 or LL-37 and analyzed for cytokine levels using ELISA. mRNA and protein for LL-37, RNase 7 and LEAP-2 were found in all tonsils. Immunohistochemistry revealed prominent staining for LL-37 and RNase7 in the tonsillar epithelium, whereas a moderate staining was seen with LEAP-2. Real-time RT-PCR showed a downregulation of RNase7 and LEAP-2 in the allergic as compared to the nonallergic group. Mononuclear cells cultured in presence of LEAP-2 or LL-37 demonstrated reduced levels of IL-10. The present study demonstrates the presence and function of LEAP-2, LL-37 and RNase7 in tonsils. Moreover, a downregulation of LEAP-2 and RNase7 is seen in SAR patients, indicating that allergic individuals may be more susceptible to respiratory tract infections due to an impaired antimicrobial defense.


Subject(s)
Antimicrobial Cationic Peptides/analysis , Blood Proteins/analysis , Down-Regulation , Palatine Tonsil/pathology , Rhinitis, Allergic, Seasonal/pathology , Ribonucleases/analysis , Adolescent , Adult , Cells, Cultured , Child , Child, Preschool , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Gene Expression Profiling , Humans , Immunohistochemistry , Leukocytes, Mononuclear/immunology , Male , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Young Adult , Cathelicidins
8.
PLoS One ; 9(1): e86796, 2014.
Article in English | MEDLINE | ID: mdl-24466243

ABSTRACT

Several epidemiological studies have investigated the relation between allergy and cancer with contradicting conclusions, and reports on immunological differences are scarce. By focusing on inflammation, the present study was designed to compare the immune response induced by allergic rhinitis (AR) and head and neck squamous cell carcinoma (HNSCC). Blood and serum was obtained from patients with symptomatic seasonal AR, and newly detected HNSCC, as well as healthy controls. Peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes (PMN) were isolated and cultured with or without the toll-like receptor ligands, Pam3CSK4, LPS, R837, and CpG. Cellular activation and cytokine release were assessed with ELISA, Luminex Multiplex Immunoassay, flow cytometry, and real-time RT-PCR. Sera from HNSCC patients showed elevated levels of innate immune cytokines, and exhibited a response profile consistent with an increased innate immune reaction. In contrast, sera and stimulated PBMC from AR patients displayed increased concentrations of T cell related cytokines, consistent with an adaptive immune response. The presented data demonstrate that AR and HNSCC induce two distinct immunological processes, indicating an inverse association between the immunological responses seen in patients with allergy and cancer of the upper airway.


Subject(s)
Adaptive Immunity/immunology , Carcinoma, Squamous Cell/immunology , Head and Neck Neoplasms/immunology , Immunity, Innate/immunology , Rhinitis, Allergic, Seasonal/immunology , Adult , Aged , Carcinoma, Squamous Cell/blood , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Female , Flow Cytometry , Head and Neck Neoplasms/blood , Humans , Immunoassay , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Rhinitis, Allergic, Seasonal/blood , Squamous Cell Carcinoma of Head and Neck , Statistics, Nonparametric , Toll-Like Receptors/metabolism
9.
Acta Otolaryngol ; 133(12): 1333-44, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24053487

ABSTRACT

CONCLUSION: The capability of Nod1 to recognize bacteria along with its altered expression and ability to cause an immunological response in head and neck cancer suggest a novel pathway for bacteria to interfere with ongoing cancer inflammation. OBJECTIVE: Nucleotide oligomerization domain (Nod)-like receptors (NLRs) comprise a recently discovered family of pattern-recognition receptors. In addition to their protective function against infections, accumulating evidence suggests a role for these receptors in various diseases, including cancer. The present study was designed to explore the presence of NLRs in head and neck squamous cell carcinoma, and to determine if these cells have the ability to respond immunologically to ligand stimulation. METHODS: The pharyngeal squamous cell carcinoma cell lines Detroit-562 and FaDu were used as a model for head and neck cancer, and compared to healthy primary human nasal epithelial cells. Analyses were performed using immunohistochemistry, real-time RT-PCR, Luminex Multiplex Immunoassay, ELISA, and flow cytometry. RESULTS: The expression profile of NLRs in head and neck cancer cells differed from that seen in healthy epithelial cells. Further, Nod1 stimulation induced an immunological response in tumor cells that differed from the response in normal epithelial cells, especially regarding the expression of ß-defensin 2, granulocyte monocyte colony stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), intercellular adhesion molecule-1 (ICAM-1), and cell survival.


Subject(s)
Carcinoma, Squamous Cell/genetics , Gene Expression Regulation, Neoplastic , Head and Neck Neoplasms/genetics , Nod1 Signaling Adaptor Protein/genetics , RNA, Neoplasm/genetics , Apoptosis , Biomarkers, Tumor/biosynthesis , Biomarkers, Tumor/genetics , Carcinoma, Squamous Cell/metabolism , Carcinoma, Squamous Cell/pathology , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Humans , Immunohistochemistry , Nod1 Signaling Adaptor Protein/biosynthesis , Real-Time Polymerase Chain Reaction , Signal Transduction , Squamous Cell Carcinoma of Head and Neck , Tumor Cells, Cultured
10.
PLoS One ; 7(12): e51120, 2012.
Article in English | MEDLINE | ID: mdl-23251433

ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) is known to cause substantial immunosuppression. The present study was designed to characterize blood leukocyte activation in HNSCC and to investigate if the individual activation pattern could be related to tumor progress and survival. The leukocyte activation profile of HNSCC patients and healthy controls was assessed with flow cytometry. HNSCC patients displayed increased numbers of monocytes, neutrophils and total leukocytes as well as an enhanced neutrophil/lymphocyte ratio. In addition, patients had a higher percentage of CD69(+), CD71(+) and CD98(+) T cell subsets and NK cells, and a reduced expression of L-selectin in CD14(high)CD16(+) monocytes and neutrophils, when compared to controls. These changes could be correlated to both tumor burden and spread to lymph nodes. Among the cancer patients an increased neutrophil/lymphocyte ratio, a low neutrophil and CD14(high) CD16(+) monocyte activation state and an elevated CD4/CD8 ratio were related to poor survival. In contrast, a high percentage of CD98(+) Th cells appeared to be associated with a better outcome. Taken together, the present data indicate that HNSCC causes activation of blood leukocytes and that the individual activation pattern can be linked to prognosis.


Subject(s)
Carcinoma, Squamous Cell/blood , Head and Neck Neoplasms/blood , Leukocytes/immunology , Survival Analysis , Antigens, CD/immunology , Female , Flow Cytometry , Humans , Male
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