scholarly journals Systematic Multiomic Analysis of Ly75 Gene Expression and Its Prognostic Value through the Infiltration of Natural Killer (NK) Cells in Skin Cutaneous Melanoma

2020 ◽  
Vol 9 (5) ◽  
pp. 1383
Author(s):  
Minchan Gil ◽  
Kyung Eun Kim
Keyword(s):  
Gene Expression ◽  
Mrna Expression ◽  
Natural Killer ◽  
Immune Cells ◽  
Cutaneous Melanoma ◽  
Cell Activation ◽  
Immune Cell ◽  
Patient Survival ◽  
Nk Cell ◽  
Cell Infiltration

Ly75 (also known as DEC-205 or CD205) is expressed in immune cells and cancers and involved in tumor immunity. However, clinical relevance of Ly75 expression in skin cutaneous melanoma (SKCM) have not been comprehensively studied. This study analyzed the correlation between Ly75 mRNA expression and patient survival using systematic multiomic analysis tools. Ly75 mRNA expression level was significantly lower in SKCM tissues than in normal tissues. Survival analysis showed that Ly75 expression significantly correlated with good patient survival. To determine possible mechanisms, the association between Ly75 expression and immune cell infiltration was analyzed. Ly75 expression was positively correlated with various infiltrated immune cells, particularly with natural killer (NK) cell infiltration and activation in SKCM. Moreover, analysis of Ly75-co-altered gene expression revealed that Ptprc (CD45) was most significantly correlated with Ly75. Gene ontology analysis of Ly75-co-altered genes indicated the relation to lymphocyte activation, including NK cell activation. Overall, our study provides the first clinical evidence that Ly75 expression is significantly associated with melanoma patient survival and NK cell infiltration, suggesting that Ly75 could be a useful prognostic factor.

scholarly journals Interleukin-18 Is a Prognostic Biomarker Correlated with CD8+ T Cell and Natural Killer Cell Infiltration in Skin Cutaneous Melanoma

2019 ◽  
Vol 8 (11) ◽  
pp. 1993 ◽  
Author(s):  
Minchan Gil ◽  
Kyung Eun Kim
Keyword(s):  
Natural Killer ◽  
Immune Cell ◽  
Patient Survival ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Interleukin 18 ◽  
Effector Cells ◽  
Normal Tissues

Interleukin-18 (IL-18) is a cytokine that enhances innate and adaptive immune responses. Although there are conflicting reports about the roles of IL-18 in melanoma progression, the clinical relevance of IL-18 expression has not been comprehensively studied. In this study, we investigated IL-18 expression and its correlation with patient survival and immune cell infiltration in melanoma using cancer gene expression data publicly available through various databases. IL18 mRNA expression was found to be significantly lower in melanoma tissues than normal tissues. Kaplan–Meier survival analysis showed that IL18 expression was positively correlated with patient survival. To investigate the possible mechanisms by which IL18 expression increased patient survival, we then assessed the correlation between IL18 expression and immune cell infiltration levels. Infiltration of various immune cells, especially CD8+ T and natural killer (NK) cells, which are cytolytic effector cells, was significantly increased by IL18 expression. Additionally, the expression levels of two cytolytic molecules including perforin and granzyme B were significantly positively correlated with IL18 expression. Collectively, this study provides the first evidence that IL18 expression has prognostic value for melanoma patient survival and is strongly correlated with CD8+ T and NK cell infiltration, suggesting the role of IL-18 as a biomarker for predicting melanoma prognosis.

scholarly journals 789 Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule to enhance targeted tumor cytotoxicity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A824-A824
Author(s):  
Fay Dufort ◽  
Christopher Leitheiser ◽  
Gemma Mudd ◽  
Julia Kristensson ◽  
Alexandra Rezvaya ◽  
...  
Keyword(s):  
Phage Display ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Antigen ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
High Affinity ◽  
Tumor Cytotoxicity ◽  
Immune Oncology

BackgroundNatural killer (NK) cells are immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Tumor specific activation of NK cells is thus an area of active investigation in immune oncology, but to date has relied on complex biologic modalities (e.g., antibodies, fusion proteins, or cell therapies), each of which has inherent disadvantages in this application. Thus, alternative approaches are warranted. Bicycle® are small (ca. 1.5 kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have now applied this technology to identify Bicycles that bind specifically to the key activating receptors, NKp46 and CD16a. When chemically coupled to tumor antigen binding Bicycles this results in highly potent, antigen-dependent receptor activation and NK cell activation. We term this new class of fully synthetic molecules Bicycle® natural killer- tumor-targeted immune cell agonists (NK-TICAs™) and we will describe their discovery and evaluation in this presentation.MethodsUsing our unique phage display screening platform, we have identified high affinity, selective binders to NKp46 and CD16a. By conjugating the Bicycle® NK cell-engaging binders to a model tumor antigen EphA2-binding Bicycle®, we have developed a bifunctional Bicycle NK-TICA™ molecule. In in vitro functional assays, we evaluated the ability of the Bicycle NK-TICAs™ to induce NK cell activation as well as cell-mediated cytotoxicity and cytokine production in NK-tumor co-culture assays.ResultsWe have developed a novel modular compound with high affinity and selectivity to NK cell receptors with specific tumor targeting capability. We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function. With Bicycle's novel NK-TICA™ compound, we demonstrate engagement of NK cells, specific activation and function of NK cells, and enhanced EphA2-expressing tumor cytotoxicity, in a dose dependent manner.ConclusionsBicycle NK-TICAs™ are novel therapeutic agents capable of enhancing the landscape of immune oncology. We hypothesize that utilization of Bicycle NK-TICA™ as a multifunctional immune cell engager will promote modulation of NK cells, and infiltration and anti-tumor activity of NK cells in solid tumors. The data presented here provide initial proof of concept for application of the Bicycle technology to drive NK cell-mediated tumor immunity.

scholarly journals NT5E/CD73 as Correlative Factor of Patient Survival and Natural Killer Cell Infiltration in Glioblastoma

2019 ◽  
Vol 8 (10) ◽  
pp. 1526 ◽  
Author(s):  
Jiao Wang ◽  
Sandro Matosevic
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Patient Survival ◽  
Nk Cell ◽  
Killer Cell ◽  
Surface Protein ◽  
The Cancer Genome Atlas ◽  
Negative Prognostic Factor ◽  
A Cell

CD73, a cell-surface protein encoded by the gene NT5E, is overexpressed in glioblastoma (GBM), where it contributes to the tumor’s pathophysiology via the generation of immunosuppressive adenosine. Adenosinergic signaling, in turn, drives immunosuppression of natural killer (NK) cells through metabolic and functional reprogramming. The correlation of CD73 with patient survival in relation to GBM pathology and the intratumoral infiltration of NK cells has not been comprehensively studied before. Here, we present an analysis of the prognostic relevance of CD73 in GBM based on transcriptional gene expression from patient data from The Cancer Genome Atlas (TCGA) database. Utilizing bioinformatics data mining tools, we explore the relationship between GBM prognosis, NT5E expression, and intratumoral presence of NK cells. Our analysis demonstrates that CD73 is a negative prognostic factor for GBM and that presence of NK cells may associate with improved prognosis. Moreover, the interplay between expression of NT5E and specific NK genes hints to potential functional effects of CD73 on NK cell activation.

The application of the natural killer cells, macrophages and dendritic cells in treating various types of cancer

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Anna Helmin-Basa ◽  
Lidia Gackowska ◽  
Sara Balcerowska ◽  
Marcelina Ornawka ◽  
Natalia Naruszewicz ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Natural Killer ◽  
Immune Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Adoptive Cell Transfer ◽  
Pharmacological Agents ◽  
Immune Cell Migration ◽  
And Function ◽  
Anti Tumor Activity

AbstractInnate immune cells such as natural killer (NK) cells, macrophages and dendritic cells (DCs) are involved in the surveillance and clearance of tumor. Intensive research has exposed the mechanisms of recognition and elimination of tumor cells by these immune cells as well as how cancers evade immune response. Hence, harnessing the immune cells has proven to be an effective therapy in treating a variety of cancers. Strategies aimed to harness and augment effector function of these cells for cancer therapy have been the subject of intense researches over the decades. Different immunotherapeutic possibilities are currently being investigated for anti-tumor activity. Pharmacological agents known to influence immune cell migration and function include therapeutic antibodies, modified antibody molecules, toll-like receptor agonists, nucleic acids, chemokine inhibitors, fusion proteins, immunomodulatory drugs, vaccines, adoptive cell transfer and oncolytic virus–based therapy. In this review, we will focus on the preclinical and clinical applications of NK cell, macrophage and DC immunotherapy in cancer treatment.

scholarly journals Regulation of Immunity via Multipotent Mesenchymal Stromal Cells

Acta Naturae ◽  
2012 ◽  
Vol 4 (1) ◽  
pp. 23-31 ◽  
Author(s):  
Yu. P. Rubtsov ◽  
Yu. G. Suzdaltseva ◽  
K. V. Goryunov ◽  
N. I. Kalinina ◽  
V. Yu. Sysoeva ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Mesenchymal Stromal Cells ◽  
Immune Cells ◽  
Stromal Cells ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Multipotent Mesenchymal Stromal Cells

Immune cells responsible for inflammation development are involved in tissue damage caused by wounding and various pathologies. Control of immune cell activation could be of significant benefit for regenerative medicine and the treatment of patients with autoimmune and degenerative diseases. It is a proven fact that MCSs (multipotent mesenchymal stromal cells) are capable of suppressing immune responses via the inhibition of dendritic cell maturation and via the restraining of the T, B, and NK cell function in the course of autoimmune diseases and various forms of inflammation. MSCs can be isolated easily from almost every type of tissue or organ and subsequently expanded in vitro. These cells are self-renewable and can be differentiated into various cell types of mesenchymal lineage. The current review contains a collection and critical analysis of data regarding the molecular mechanisms responsible for cross-talk between immune cells and MSCs. Some of these mechanisms can be used for the development of new practical approaches for the treatment of autoimmune diseases.

scholarly journals Polysaccharide from Codium fragile Induces Anti-Cancer Immunity by Activating Natural Killer Cells

Marine Drugs ◽  
2020 ◽  
Vol 18 (12) ◽  
pp. 626
Author(s):  
Hae-Bin Park ◽  
Juyoung Hwang ◽  
Wei Zhang ◽  
Seulgi Go ◽  
Jihoe Kim ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Cell Infiltration ◽  
Codium Fragile ◽  
Cancer Immunity ◽  
Anti Cancer ◽  
Ifn Γ

Natural polysaccharides exhibit beneficial immune modulatory effects, including immune stimulatory and anti-cancer activities. In this study, we examined the effect of Codium fragile polysaccharide (CFP) on natural killer (NK) cell activation, and its effect on tumor-bearing mice. Intravenous CFP treatment of C57BL/6 mice resulted in the upregulation of CD69, which is a marker associated with NK cell activation. In addition, intracellular levels of interferon (IFN)-γ and the cytotoxic mediators perforin and granzyme B were markedly increased in response to the CFP treatment of splenic NK cells. IFN-γ production by NK cells was directly induced by CFP, whereas the upregulation of CD69 and cytotoxic mediators required IL-12. Finally, intraperitoneal treatment with CFP prevented CT-26 (murine carcinoma) tumor cell infiltration in the lungs, without significantly reducing the body weight. In addition, treatment with CFP prevented B16 melanoma cell infiltration in the lung of C57BL/6 mice. Moreover, the anti-tumor effect was diminished by the depletion of NK cells. Therefore, these data suggest that CFP may be used as an NK cell stimulator to produce a phenomenon that contributes to anti-cancer immunity.

scholarly journals Effect of Immune Cell Infiltration on Occurrence of Pulmonary Hypertension in Pulmonary Fibrosis Patients Based on Gene Expression Profiles

2021 ◽  
Vol 8 ◽  
Author(s):  
Feng Zhu ◽  
Lili Zuo ◽  
Rui Hu ◽  
Jin Wang ◽  
Zhihua Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Hypertension ◽  
Random Forest ◽  
Pulmonary Fibrosis ◽  
Immune Cells ◽  
Cross Validation ◽  
Immune Cell ◽  
Expression Profiles ◽  
Cell Infiltration ◽  
Immune Cell Infiltration

Pulmonary hypertension (PH) is a frequent complication in patients with pulmonary fibrosis (PF), whereas the mechanism was not well-understood. This study aimed to explore the influence of immune cell infiltration on PH status based on the genomic expression profiles. Microarray data of GSE24988 were downloaded from the GEO database, including 116 lung tissue samples derived from PF patients with various PH status. Proportion of infiltrated immune cells was evaluated using CIBERSORT, a gene expression-based de-convolution algorithm. A random forest classifier was constructed and out of bag (OOB) cross-validation was carried out for PH prediction. The proportions of immune infiltration cells varied differently in PH samples except T regulatory cells (p-value = 0). Compared with non-PH samples, increased number of naive B cells and plasma cells were identified in PH samples, whereas activated dendritic cells and M2 macrophages were relatively lower (p < 0.05). In the random forest model, these four types of immune cells obtained a higher variable importance score than other cells, including mean decreased accuracy and mean decreased gini evaluation. We ran the OOB cross-validation in each sample of datasets (training set and testing set) and obtained 79 and 69% accuracy, respectively. Abnormal proportions of four types of immune cells were identified in PH samples compared with non-PH samples, suggesting their involvement in PH development. In summary, the immune cell infiltration in PF patients is associated with the PH status of patients, which deserves further investigation in the future.

scholarly journals Human Conjunctival Transcriptome Analysis Reveals the Prominence of Innate Defense in Chlamydia trachomatis Infection

2010 ◽  
Vol 78 (11) ◽  
pp. 4895-4911 ◽  
Author(s):  
Angels Natividad ◽  
Tom C. Freeman ◽  
David Jeffries ◽  
Matthew J. Burton ◽  
David C. W. Mabey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chlamydia Trachomatis ◽  
Host Response ◽  
Antigen Processing ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
Clinical Feature ◽  
Specific Gene ◽  
Innate Defense

ABSTRACT Trachoma is the leading infectious cause of blindness and is endemic in 52 countries. There is a critical need to further our understanding of the host response during disease and infection, as millions of individuals are still at risk of developing blinding sequelae. Infection of the conjunctival epithelial cells by the causative bacterium, Chlamydia trachomatis, stimulates an acute host response. The main clinical feature is a follicular conjunctivitis that is incompletely defined at the tissue-specific gene expression and molecular levels. To explore the features of disease and the response to infection, we measured host gene expression in conjunctival samples from Gambian children with active trachoma and healthy controls. Genome-wide expression and transcription network analysis identified signatures characteristic of the expected infiltrating immune cell populations, such as neutrophils and T/B lymphocytes. The expression signatures were also significantly enriched for genes in pathways which regulate NK cell activation and cytotoxicity, antigen processing and presentation, chemokines, cytokines, and cytokine receptors. The data suggest that in addition to polymorph and adaptive cellular responses, NK cells may contribute to a significant component of the conjunctival inflammatory response to chlamydial infection.

scholarly journals The Immune Cell Landscape in Renal Allografts

2021 ◽  
Vol 30 ◽  
pp. 096368972199545
Author(s):  
Jun Lu ◽  
Yi Zhang ◽  
Jingjing Sun ◽  
Shulin Huang ◽  
Weizhen Wu ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Infiltration ◽  
M1 Macrophages ◽  
Deconvolution Analysis ◽  
Renal Allografts ◽  
Antibody Mediated Rejection

Immune cell infiltration plays an important role in the pathophysiology of kidney grafts, but the composition of immune cells is ill-defined. Here, we aimed at evaluating the levels and composition of infiltrating immune cells in kidney grafts. We used CIBERSORT, an established algorithm, to estimate the proportions of 22 immune cell types based on gene expression profiles. We found that non-rejecting kidney grafts were characteristic with high rates of M2 macrophages and resting mast cells. The proportion of M1 macrophages and activated NK cells were increased in antibody-mediated rejection (ABMR). In T cell-mediated rejection (TCMR), a significant increase in CD8 T cell and γδT cell infiltration was observed. CD8 positive T cells were dramatically increased in mixed-ABMR/TCMR. Then, the function of ABMR and TCMR prognostic molecular biomarkers were identified. Finally, we described the gene expression of molecular markers for ABMR diagnosis was elevated and related to the ratio of monocytes and M1 macrophages in ABMR biopsies, while the expression of TCMR diagnosis markers was increased too and positively correlated with γδT cells and activated CD4 memory T cells in TCMR biopsies. Our data suggest that CIBERSORT’s deconvolution analysis of gene expression data provides valuable information on the composition of immune cells in renal allografts.

scholarly journals Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

2021 ◽  
Author(s):  
Leoni Rolfes ◽  
Tobias Ruck ◽  
Christina David ◽  
Stine Mencl ◽  
Stefanie Bock ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Subset ◽  
Neurological Deficits ◽  
In Vitro Assays ◽  
Experimental Stroke ◽  
Transfer Model

AbstractRag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

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