scholarly journals ROLE OF CELLS OF INNATE IMMUNITY IN THE DEVELOPMENT OF MALIGNANT TUMORS OF THE BRAIN

2019 ◽  
pp. 4-12
Author(s):  
Mykola Lysіаniy ◽  
Lyudmila Belskaya ◽  
Irina Gnіdkova ◽  
Nastya Palamaryova
Keyword(s):  
Innate Immunity ◽  
Tumor Growth ◽  
Immune Cells ◽  
Tumor Antigens ◽  
Malignant Tumors ◽  
High Density ◽  
Low Density ◽  
Arginase 1 ◽  
Innate Immunity Cells ◽  
Cells Of The Microenvironment

This review presents data on changes in the activity of cells of innate and acquired immunity, namely leukocytes, neutrophils, platelets and lymphocytes in various malignant human tumors, including brain tumors. It was shown that against the background of immunosuppression of specific immunity, especially antitumor reactions, which are caused by factors such as prostaglandin E2, TGF-β, indolamine-2,3-dioxigenase (IDO) and interleukin (IL) -10, which leads to a decrease the sensitivity of T cells to proinflammatory signals and the ineffectiveness of the presentation of tumor antigens to immune cells, activation and polarization of innate immunity cells, namely neutrophils, macrophages and platelets, occurs. Macrophages are important immune cells of the microenvironment in a tumor site that change their phenotype from M1 cells with antitumor activity to M2, which enhance tumor growth. The release of metalloprotheasis from platelet α -granules destroys the components of the extracellular matrix, increases the ability of cancer cells to pass through the endothelial barrier, penetrate the parenchyma and create metastatic tissue damage. Previously, neutrophils were mainly considered as cells of the body’s first line of defense, mainly with antimicrobial functions, but now they are regarded as cells with tumor-stimulating, “protumorogenic” activity, since in many types of cancer an increased level of neutron is determined with a reduced content of lymphocytes in the peripheral blood and this is associated with a poor prognosis of the disease. The review analyzes the hypothesis that there are three subpopulations of neutrophils in cancer: normal high density neutrophils, immature low density neutrophils (G-MDSC) and large mature low density neutrophils. These types of cells have different functions, for example, neutrophils with high density are antitumor, and with low density - cells that can stimulate tumor growth. ]. Neutrophils realize their activity through molecules such as neutrophilic elastase (NE), cathepsin, arginase 1 (ARG1), matrix metalloproteinase-9 (MMP-9). Multidirectional changes in the parts of the immune system depend on the histogenesis and degree of malignancy of the tumors and indicate differentiated use immunotropic drugs in cancer patients, some should suppress the activity of innate immunity cells, others stimulate the acquired immune response.

scholarly journals Uncoupled biological and chronological aging of neutrophils in cancer promotes tumor progression

2021 ◽  
Vol 9 (12) ◽  
pp. e003495
Author(s):  
Laura A Mittmann ◽  
Florian Haring ◽  
Johanna B Schaubächer ◽  
Roman Hennel ◽  
Bojan Smiljanov ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Immune Cells ◽  
Malignant Tumors ◽  
Ex Vivo ◽  
Biological Aging ◽  
Malignant Neoplasms ◽  
Chronological Aging ◽  
Functional Changes

BackgroundBeyond their fundamental role in homeostasis and host defense, neutrophilic granulocytes (neutrophils) are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, aging of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their homeostatic and anti-infectious functional properties. The role of neutrophil aging in cancer remains largely obscure.MethodsEmploying advanced in vivo microscopy techniques in different animal models of cancer as well as utilizing pulse-labeling and cell transfer approaches, various ex vivo/in vitro assays, and human data, we sought to define the functional relevance of neutrophil aging in cancer.ResultsHere, we show that signals released during early tumor growth accelerate biological aging of circulating neutrophils, hence uncoupling biological from chronological aging of these immune cells. This facilitates the accumulation of highly reactive neutrophils in malignant lesions and endows them with potent protumorigenic functions, thus promoting tumor progression. Counteracting uncoupled biological aging of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth.ConclusionsOur data uncover a self-sustaining mechanism of malignant neoplasms in fostering protumorigenic phenotypic and functional changes in circulating neutrophils. Interference with this aberrant process might therefore provide a novel, already pharmacologically targetable strategy for cancer immunotherapy.

scholarly journals Hematopoiesis and innate immunity: an inseparable couple for good and bad times, bound together by an hormetic relationship

Leukemia ◽  
2021 ◽  
Author(s):  
Mariusz Z. Ratajczak ◽  
Magdalena Kucia
Keyword(s):  
Innate Immunity ◽  
Immune Cells ◽  
Biological Response ◽  
Cell Types ◽  
Surface Pattern ◽  
Hematopoietic Stem ◽  
Innate And Adaptive Immunity ◽  
Innate Immunity Cells ◽  
Low Exposure ◽  
Different Cell Types

AbstractHematopoietic and immune cells originate from a common hematopoietic/lymphopoietic stem cell what explains that these different cell types often share the same receptors and respond to similar factors. Moreover, the common goal of both lineages is to ensure tissue homeostasis under steady-state conditions, fight invading pathogens, and promote tissue repair. We will highlight accumulating evidence that innate and adaptive immunity modulate several aspects of hematopoiesis within the hormetic zone in which the biological response to low exposure to potential stressors generally is favorable and benefits hematopoietic stem/progenitor cells (HSPCs). Innate immunity impact on hematopoiesis is pleiotropic and involves both the cellular arm, comprised of innate immunity cells, and the soluble arm, whose major component is the complement cascade (ComC). In addition, several mediators released by innate immunity cells, including inflammatory cytokines and small antimicrobial cationic peptides, affect hematopoiesis. There are intriguing observations that HSPCs and immune cells share several cell-surface pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) and cytosol-expressed NOD, NOD-like, and RIG-I-like receptors and thus can be considered “pathogen sensors”. In addition, not only lymphocytes but also HSPCs express functional intracellular complement proteins, defined as complosome which poses challenging questions for further investigation of the intracellular ComC-mediated intracrine regulation of hematopoiesis.

scholarly journals P01.14 Excessive biological ageing of circulating neutrophils in cancer promotes tumor progression

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A15.1-A15
Author(s):  
CA Reichel ◽  
L Mittmann ◽  
J Schaubächer ◽  
R Hennel ◽  
G Zuchtriegel ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Tumor Progression ◽  
Cell Line ◽  
Immune Cells ◽  
Malignant Tumors ◽  
Biological Ageing ◽  
Functional Changes ◽  
Age Related

BackgroundBeyond their well-established role in host defense, neutrophils are increasingly recognized to contribute to the pathogenesis of malignant tumors. Recently, ageing of mature neutrophils in the systemic circulation has been identified to be critical for these immune cells to properly unfold their anti-infectious properties. The role of neutrophil ageing in cancer is still unknown.Material and MethodsEmploying syngeneic mouse models of head and neck squamous cell carcinoma (cell line SCC VII) and breast cancer (cell line 4T1), cytokine expression (by multiplex ELISA), neutrophil trafficking (by multi-channel in vivo microscopy and flow cytometry), and neutrophil function (in vitro assays) were analyzed.ResultsHere, we show that signals released during early tumor growth promote excessive biological ageing of circulating neutrophils as indicated by age-related changes in their molecular repertoire. These events facilitate the accumulation of these highly reactive immune cells in malignant lesions and endow them with potent pro-tumorigenic functions. In particular, excessively aged neutrophils release neutrophil elastase which, in turn, stimulates the proliferation of cancer cells. Counteracting accelerated biological ageing of circulating neutrophils by blocking the chemokine receptor CXCR2 effectively suppressed tumor growth.ConclusionsOur experimental data uncover a potent self-sustaining mechanism of malignant tumors in fostering pro-tumorigenic phenotypic and functional changes in circulating neutrophils, thus supporting tumor progression. Interference with this aberrant process might provide a novel, already pharmacologically targetable strategy for cancer therapy. This study was supported by Deutsche Forschungsgemeinschaft (DFG), Sonderforschungsbereich (SFB) 914.Disclosure InformationC.A. Reichel: None. L. Mittmann: None. J. Schaubächer: None. R. Hennel: None. G. Zuchtriegel: None. M. Canis: None. O. Gires: None. F. Krombach: None. L. Holdt: None. S. Brandau: None. T. Vogl: None. K. Lauber: None. B. Uhl: None.

scholarly journals 765 The first-in-class small molecule TREX1 inhibitor CPI-381 demonstrates type I IFN induction and sensitization of tumors to immune checkpoint blockade

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A800-A800
Author(s):  
Costa Salojin ◽  
Anna Gardberg ◽  
Valerie Vivat ◽  
Lei Cui ◽  
Jeffrey Lauer ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Tumor Growth ◽  
Small Molecule ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Type I ◽  
Type I Ifn ◽  
Syngeneic Tumor

BackgroundTREX1 is an exonuclease that functions as a negative regulator of innate immunity. TREX1 controls dsDNA sensing in tumor and immune cells by preventing aberrant dsDNA buildup that triggers STING-mediated Type 1 Interferon (IFN) induction leading to priming of the adaptive immune system. Loss of function mutations in TREX1 and genetic ablation of trex1 in mice lead to induction of IFNbeta-driven autoimmunity. Thus, TREX1 is a promising target to elicit IFN-mediated anti-tumor immunity.MethodsTo characterize TREX1 inhibitors we developed cell-based assays utilizing human HCT116 carcinoma and THP-1 monocytic Dual reporter cell lines to monitor IRF activity. Activation of cGAS was assessed by measuring cGAMP levels in B16F10 melanoma cells. The potency of TREX1 inhibitors in primary human dendritic cells (DC)s was analyzed by measuring IFNbeta induction by exogenous dsDNA. Analysis of tumor growth inhibition following TREX1 inhibitor treatment was conducted in mouse syngeneic tumor models. TREX1 activity was assessed by measuring degradation of a custom dsDNA substrate.ResultsWe report here the development of a small molecule TREX1 inhibitor, CPI-381, with nanomolar cellular potency, which translated into a robust induction of IRF reporter activity. We observed a significant increase in cGAMP production in B16F10 cells transfected with DNA in the presence of CPI-381, suggesting that CPI-381-mediated inhibition of TREX1 leads to the activation of dsDNA sensors, such as cGAS. Treatment of THP-1 cells with CPI-381 induced the expression of several key ISG involved in innate immunity. Moreover, inhibition of TREX1 with CPI-381 phenocopied the effect of TREX1 genetic deletion in primary human DCs by upregulating IFNbeta. To evaluate whether TREX1 negatively regulates IFNbeta production in syngeneic tumor models, we knocked down trex1 in B16F10, MB49, MC38, and CT26 murine cells. Accumulation of cytosolic dsDNA resulted in a substantial increase in IFNbeta secretion by all four TREX1-KO cell lines.In vivo efficacy studies with CPI-381 demonstrated reduced tumor growth in the MC38 syngeneic tumor model either alone or in combination with anti-PD1. We observed a reduction of TREX1 activity in CPI-381 treated tumors, confirming an inverse relationship between TREX1 intra-tumor activity and tumor growth, and efficient target engagement after systemic (oral) delivery.ConclusionsWe have developed a first-in-class, potent TREX1 inhibitor demonstrating excellent in vitro and in vivo potency via enhancement of cytosolic dsDNA sensing and induction of IFNbeta in cancer and immune cells. CPI-381-induced tumor-intrinsic TREX1 inhibition elicits antitumor immunity as a single agent and increases response to immune checkpoint blockade via mechanisms downstream of TREX1 that activate type I IFN signaling.Ethics ApprovalAll animal work was approved and conducted under the oversight of the Charles River Accelerator and Development Lab (CRADL, Cambridge, MA) Institutional Animal Care and Use Committee (protocol # 2021-1258).

scholarly journals ID2006 Crosstalk between effector cells of adaptive immunity and mesenchymal stromal cells

2017 ◽  
Vol 4 (S) ◽  
pp. 38
Author(s):  
Aleksandra Gornostaeva
Keyword(s):  
Innate Immunity ◽  
Adaptive Immunity ◽  
Mesenchymal Stromal Cells ◽  
Immune Cells ◽  
Stromal Cells ◽  
Feedback Loop ◽  
Inflammatory Phenotype ◽  
Innate Immunity Cells ◽  
Immunomodulatory Properties ◽  
Anti Inflammatory

Multipotent mesenchymal stromal cells (MSCs) are a perspective tool for regenerative medicine due low immunogenicity and immunomodulation. The "feedback loop" exists in MSC/immune cells relationships, when "inflammatory" stimulation switches immunoregulaton by MSCs. Currently, the most studied effect of allogeneic MSCs on adaptive immunity cells, mainly on T lymphocytes. Studies of the interaction of MSCs and innate immunity cells are much less. "Reverse effects" (the effect of immune cells on MSCs) are virtually not investigated. Initiation of the inflammation occurs with activation of innate immunity cells, that "turns on" immunomodulatory properties. In this regard, the study of the interaction of MSCs and monocytes is particularly relevant. MSCs from human adipose tissue and CD14+monocytes (MNs) from peripheral blood of healthy volunteers were used. To stimulate monocytes conditioned medium (CM) after 72 hours of mixed lymphocyte reaction (MLR) was applied. This CM was enriched with IL-8, INF-gamma and TNF-a.  Optimization of MN activation procedure was performed prior to experiments. CD14+MNs were incubated with different concentration of MLR-CM for a different time. The activation and viability of MNs was evaluated every 24 hours. The overnight exposure of MNs to 3-day 50% CM-MLR was found to be optimum regime. We studied the of MSC/monocyte interaction paying special attention to "feedback loop".  In the presence of activated MNs, MSCs possessed unchanged viability (96%), transmembrane mitochondria potential, ROS level and twice reduced lysosome activity. The cytokine profile in coculture medium was changed significantly. IL-6 and MCP-1 were increased vs monocultures of both cell types. IL-8 was similar to MN monoculture. TNF alpha, MIG, IL-10 were detected as tracers. Elevation of IL-6 and MIG indicates on acquisition of anti-inflammatory phenotype by MSCs. After interaction with MSC, the share of CD69+ MNs (nonspecific marker of early activation) decreased, HLA-DR (MHC class II receptor) increased slightly. A threefold increase in both CD163+ MN’s share and MFI was detected, whereas CD86 antigen was not expressed. The changes in the cytokine profile and the expression of surface markers described above are characteristic of the anti-inflammatory phenotype of monocytes.  Thus, upon interaction MSC exhibited pronounced immunomodulatory properties and shifted the phenotype of monocytes towards the anti-inflammatory. These data indicate on the MSC potential to modulate early stages of inflammation, while retaining their functional state.

Quantitative defect studies in semiconductor TEM samples prepared by low angle ion milling

1995 ◽  
Vol 53 ◽  
pp. 512-513
Author(s):  
L. Mulestagno ◽  
J.C. Holzer ◽  
P. Fraundorf
Keyword(s):  
Sample Preparation ◽  
Milling Time ◽  
High Density ◽  
Low Density ◽  
Ion Milling ◽  
High Quality ◽  
Variable Angle ◽  
Major Disadvantage ◽  
Induced Defects

Due to the wealth of information, both analytical and structural that can be obtained from it TEM always has been a favorite tool for the analysis of process-induced defects in semiconductor wafers. The only major disadvantage has always been, that the volume under study in the TEM is relatively small, making it difficult to locate low density defects, and sample preparation is a somewhat lengthy procedure. This problem has been somewhat alleviated by the availability of efficient low angle milling.Using a PIPS® variable angle ion -mill, manufactured by Gatan, we have been consistently obtaining planar specimens with a high quality thin area in excess of 5 × 104 μm2 in about half an hour (milling time), which has made it possible to locate defects at lower densities, or, for defects of relatively high density, obtain information which is statistically more significant (table 1).

Scanning Electron Microscopic and Electrophoretic Observations on Barium Sulphate Used to Adsorb Clotting Factors

1975 ◽  
Vol 33 (02) ◽  
pp. 256-270
Author(s):  
R. M Howell ◽  
S. L. M Deacon
Keyword(s):  
Electron Microscopy ◽  
Factor Xa ◽  
Barium Sulphate ◽  
High Density ◽  
Low Density ◽  
Factor X ◽  
Clotting Factors ◽  
Electron Microscopic ◽  
Complementary Techniques ◽  
Scanning Electron

SummaryElectron microscopy and particle electrophoresis were found to be complementary techniques with which to complete the physical data from an earlier study on barium sulphates used to adsorb clotting factors from serum. The differences revealed by scanning electron microscopy (S. E. M.) in the physical shape of low and high density grades of barium sulphate particles appear to be of greater significance than charge as expressed by electrophoretic mobility, in determining whether or not precursor or preformed factor Xa is eluted.This conclusion was based on the finding that at pH values close to 7, where the adsorption from serum occurs, all samples with the exception of natural barytes were uncharged. However as the high-density, or soil-grade, was found by S. E. M. to consist of large solid crystals it was suggested that this shape might induce activation of factor X as a result of partial denaturation and consequent unfolding of the adsorbed protein. In contrast, uptake of protein into the centre of the porous aggregates revealed by S. E. M. pictures of low-density or X-ray grade barium sulphate may afford protection against denaturation and exposure of the enzyme site.The porous nature of particles of low-density barium sulphate compared with the solid crystalline forms of other grades accounts not only for its lower bulk density but also for its greater surface/gram ratio which is reflected by an ability to adsorb more protein from serum.Neither technique produced evidence from any of the samples to indicate the presence of stabilising agents sometimes used to coat particles in barium meals.

THE PROGNOSTIC VALUE OF PD-L1 EXPRESSION IN TUMOR AND IMMUNE CELLS IN SQUAMOUS CELL CARCINOMA OF THE ORAL MUCOSA

2017 ◽  
Vol 63 (5) ◽  
pp. 759-765
Author(s):  
Svetlana Kutukova ◽  
Natalya Belyak ◽  
Grigoriy Raskin ◽  
Marina Mukhina ◽  
Georgiy Manikhas ◽  
...  
Keyword(s):  
Oral Mucosa ◽  
Malignant Tumor ◽  
Immune Cells ◽  
Prognostic Value ◽  
Hard Palate ◽  
Malignant Tumors ◽  
Small Cell ◽  
Alveolar Process ◽  
Small Cell Lung ◽  
Lower Jaw

The most frequent of malignant tumor cites of the oral mucosa are tongue - 55 %, mucosa of the cheek - 12 %, the fundus of the oral cavity - 10 %, the alveolar process of the upper jaw and the hard palate - 9 %, the alveolar process of the lower jaw - 6 %, the soft palate - 2 %. Malignant tumor cells carry PD-L1 ligands on their surface and its expression level is often correlated with an unfavorable prognosis in particular for such tumors as melanoma, kidney cancer and non-small cell lung cancer. It is relevant to evaluate the correlation between overexpression of PD-L1 and overall survival in patients with malignant tumors of the oral mucosa.

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