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 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 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.

Effect of therapeutic vaccine on CTLA4 and tumor debulking response in recurrent and metastatic HNSCC.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 115-115
Author(s):  
Somjin Chindavijak ◽  
Michael Har-Noy ◽  
Wirote Lausoontornsiri
Keyword(s):  
Immune Cell ◽  
Ex Vivo ◽  
Therapeutic Vaccine ◽  
Tumor Burden ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Memory Cells ◽  
Tumor Biopsy ◽  
Effector Cells ◽  
Tumor Debulking

115 Background: Head and Neck Squamous Cell Carcinoma (HNSCC) is associated with multiple immune suppression and avoidance mechanisms . Blocking the PD-1 signal axis in second line provides a significant survival advantage compared to chemotherapy. However, checkpoint blockade efficacy is limited to the subset of patients that present with tumors highly infiltrated with effector immune cells. We investigated a novel vaccine designed to increase the infiltration of tumor-specific effector cells and counter-regulate the suppressive tumor microenvironment. Methods: Pre-treated r/m HNSCC patients with externally visible tumors were accrued. Tumor biopsy samples were processed at baseline to purify endogenous chaperones with calreticulin, hsp70, hsp90 and gr94/gp96 (CRCL) as a source of tumor neoantigen. Ex-vivo differentiated, allogeneic Th1 memory cells with CD3/CD28-coated microbeads attached (aTh1) expressing CD40L and IFN-gamma served as adjuvant. Subjects were primed with 4 weekly aTh1 ID injections to increase allo-specific Th1 memory titer. Primed subjects were provided 3 weekly ID injections of CRCL + aTh1 to increase tumor-specific Th1 memory titer followed by intravenous aTh1 in the 4th week to activate circulating memory cells through CD40-CD40L, causing their extravasation and trafficking to tumor lesions. Allo-rejection response produces a sustained Type 1 cytokine release which dys-regulates suppressor circuits. The ID/IV cycle was then repeated. Results: 10 subjects with recurrent or metastatic disease were accrued. All with prior radiochemotherapy. 50% (5/10) had clinical response with visible reduction in tumor burden. Vaccine was well tolerated. Debulking response correlated with increased CD3+ immune cell infiltration and decreased CTLA-4 expression. Conclusions: This individualized vaccine caused increased immune cell infiltration in tumors, down-regulation of CTLA4 and visible tumor debulking in a heavily pre-treated, chemotherapy-refractory population. These results provide rationale for further evaluation of this vaccine in a first-line setting with and without PD1/L1 blockade. Clinical trial information: NCT01998542.

Distinct genomic and immune microenvironment between thymomas and thymic carcinomas.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13529-e13529
Author(s):  
Kaicheng Wang ◽  
Suxia Lin ◽  
Xue Hou ◽  
Yongdong Liu ◽  
Meichen Li ◽  
...  
Keyword(s):  
Immune Cell ◽  
Immune Escape ◽  
Nk Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Immune Microenvironment ◽  
Tissue Samples ◽  
Thymic Epithelial Tumors ◽  
Immune Infiltration ◽  
Thymic Carcinomas

e13529 Background: Thymomas and thymic carcinomas which uniformly known as thymic epithelial tumors (TETs) are rare intrathoracic malignancies and a limited studies have been reported addressing the molecular biology and immune discrepancy. The main purpose of this study was to depict the genomic and transcriptomic landscape of thymomas and thymic carcinomas, as well as elucidate the differentiated immune microenvironment. Methods: Totally 15 thymomas and 7 thymic carcinomas patients were enrolled from January 2014 to July 2018. Treatment-naïve tissue samples were collected, and we also obtained matched peripheral blood mononucleocytes as negative control. DNA and RNA were co-extracted and performed with whole exon and transcriptome sequencing. The immune cell infiltration scores were estimated using ssGSEA algorithm. Results: Exome sequencing revealed that GTF2I mutation occurred in all of type A thymomas but was absent in the aggressive subtypes. The median tumor mutation burden of thymomas was 0.12/Mb, significantly lower than thymic carcinomas (median: 1.02/Mb, p = 0.001). Copy number variation was more common in thymic carcinomas than thymomas (83.3% vs 9.1%, p = 0.005). Top mutational signatures enriched in both thymomas and thymic carcinomas included age and Aristolochic acid exposure, while the APOBEC signature was more common in thymomas than thymic carcinomas (81.8% vs 16.7%, p = 0.03). As a confirmed immune escape event, loss of heterozygosity of human leukocyte antigen was identified in 9.1% of thymomas and 50% of thymic carcinomas. Via unsupervised clustering of immune infiltration, all tissue samples were classified into high- and low-infiltration subgroups. Remarkably, up to 71.4% of samples from thymic carcinomas and only 6.7% of samples from thymomas were defined as low immune cell infiltration. In consideration of specific immune cell types, macrophage ( p = 0.01) and neutrophil ( p = 0.02) were enriched in thymic carcinomas while CD56+ NK cell ( p = 0.005) was enriched in thymomas, indicating the evidential discrepancy about immune cell infiltration between two subtypes of TETs. Conclusions: This study elucidated the molecular and immune microenvironment discrepancy between two subtypes of TETs. From molecular perspective, thymomas and thymic carcinomas are entirely different diseases with different etiology and characterized by distinct immune infiltration, and thus should be managed with disparate therapeutic strategies. Findings in this study may also be useful in future targets development and exploration of immunotherapies in TETs.

scholarly journals A natural killer cell gene signature predicts melanoma patient survival

2018 ◽  
Author(s):  
Joseph Cursons ◽  
Fernando Souza-Fonseca-Guimaraes ◽  
Ashley Anderson ◽  
Momeneh Foroutan ◽  
Soroor Hediyeh-Zadeh ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Immune Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Activity ◽  
Human Tumors ◽  
The Cancer Genome Atlas ◽  
Cell Gene

AbstractAnimal models have demonstrated that natural killer (NK) cells can limit the metastatic dissemination of tumors, however their ability to combat established human tumors has been difficult to investigate.A number of computational methods have been developed for the deconvolution of immune cell types within solid tumors. We have taken the NK cell gene signatures from several tools, then curated and expanded this list using recent reports from the literature. Using a gene set scoring method to investigate RNA-seq data from The Cancer Genome Atlas (TCGA) we show that patients with metastatic cutaneous melanoma have an improved survival rate if their tumor shows evidence of greater NK cell infiltration. Furthermore, these survival effects are enhanced in tumors which have a higher expression of NK cell stimuli such as IL-15, suggesting NK cells are part of a coordinated immune response within these patients. Using this signature we then examine transcriptomic data to identify tumor and stromal components which may influence the penetrance of NK cells into solid tumors.These data support a role for NK cells in the regulation of human tumors and highlight potential survival effects associated with increased NK cell activity. Furthermore, our computational analysis identifies a number of potential targets which may help to unleash the anti-tumor potential of NK cells as we enter the age of immunotherapy.

scholarly journals Dynamic metabolic change of cancer cells induced by natural killer cells at single-cell level studied by label-free mass cytometry

2022 ◽  
Author(s):  
Zizheng Shen ◽  
Hansen Zhao ◽  
Huan Yao ◽  
Xingyu Pan ◽  
Jinlei Yang ◽  
...  
Keyword(s):  
Natural Killer Cell ◽  
Natural Killer ◽  
Immune Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Single Cell Level ◽  
Label Free ◽  
Mass Cytometry ◽  
Cell Level ◽  
Nk Cytotoxicity

Natural killer cell（NK cell）is an important immune cell which attracts increasing attention in cancer immunotherapy. Due to the heterogeneity of cells, individual cancer cell shows different resistance to NK cytotoxicity,...

scholarly journals Follistatin-like 1 (FSTL1) is a Prognostic Biomarker and Correlated with Immune Cell Infiltration in Gastric Cancer

2020 ◽  
Author(s):  
Li Li ◽  
Shanshan Huang ◽  
Yangyang Yao ◽  
Jun Chen ◽  
Junhe Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Immunity ◽  
Survival Data ◽  
Immune Cell ◽  
Bioinformatic Analysis ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Western Blot Assay ◽  
Immune Infiltration ◽  
Normal Tissues

Abstract Background: Follistatin-like 1 (FSTL1) plays a central role in the progression of tumor and tumor immunity. However, the effect of FSTL1 on the prognosis and immune infiltration of gastric cancer (GC) remains to be elucidated.Method: The expression of FSTL1 data was analyzed in Oncomine and TIMER databases. Analyses of clinical parameters and survival data were conducted by Kaplan-Meier plotter and immunohistochemistry. Western blot assay and real‐time quantitative PCR (RT-qPCR) was using to analyzed protein and mRNA expression, respectively. The correlations between FSTL1 and cancer immune infiltrates was analyzed by Tumor Immune Estimation Resource (TIME), Gene Expression Profiling Interactive Analysis (GEPIA) and LinkedOmics database.Results: The expression of FSTL1 was significantly higher in GC tissues than in normal tissues, and bioinformatic analysis and Immunohistochemistry (IHC) indicated that high FSTL1 expression significantly correlated with poor prognosis in GC. Moreover, FSTL1 was predicted as an independent prognostic factor in GC patients. Bioinformatics analysis results suggested that FSTL1 mainly involved in tumor progression and tumor immunity. And significant correlations were found between FSTL1 expression and immune cell infiltration in GC.Conclusion: The study effectively revealed useful information about FSTL1 expression, prognostic values, potential functional networks and impact of tumor immune infiltration in GC. In summary, FSTL1 can be used as a biomarker for prognosis and evaluating immune cell infiltration in GC.

scholarly journals Proteome Analysis of Human Natural Killer Cell Derived Extracellular Vesicles for Identification of Anticancer Effectors

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5216
Author(s):  
Jung-Won Choi ◽  
Soyeon Lim ◽  
Jung Hwa Kang ◽  
Sung Hwan Hwang ◽  
Ki-Chul Hwang ◽  
...  
Keyword(s):  
Natural Killer ◽  
Extracellular Vesicles ◽  
Fas Ligand ◽  
Immune Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Proteome Analysis ◽  
Therapeutic Modality ◽  
Functional Study ◽  
Human Natural Killer Cell

Cancer immunotherapy is a clinically validated therapeutic modality for cancer and has been rapidly advancing in recent years. Adoptive transfer of immune cells such as T cells and natural killer (NK) cells has emerged as a viable method of controlling the immune system against cancer. Recent evidence indicates that even immune-cell-released vesicles such as NK-cell-derived exosomes also exert anticancer effect. Nevertheless, the underlying mechanisms remain elusive. In the present study, the anticancer potential of isolated extracellular vesicles (EVs) from expanded and activated NK-cell-enriched lymphocytes (NKLs) prepared by house-developed protocol was evaluated both in vitro and in vivo. Moreover, isolated EVs were characterized by using two-dimensional electrophoresis (2-DE)-based proteome and network analysis, and functional study using identified factors was performed. Our data indicated that the EVs from expanded and active NKLs had anticancer properties, and a number of molecules, such as Fas ligand, TRAIL, NKG2D, β-actin, and fibrinogen, were identified as effector candidates based on the proteome analysis and functional study. The results of the present study suggest the possibility of NK-cell-derived EVs as a viable immunotherapeutic strategy for cancer.

scholarly journals Metabolic but not transcriptional regulation by PKM2 is important for Natural Killer cell responses

2020 ◽  
Author(s):  
Jessica F. Walls ◽  
Jeff J. Subleski ◽  
Erika M. Palmieri ◽  
Marieli Gonzalez Cotto ◽  
Clair M. Gardiner ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Nk Cells ◽  
Natural Killer ◽  
Transcriptional Control ◽  
Immune Cell ◽  
Nk Cell ◽  
Killer Cell ◽  
Glycolytic Enzyme ◽  
Glycolytic Flux ◽  
Mcmv Infection

AbstractNatural Killer (NK) cells have an important role in immune responses to viruses and tumours. Integrating changes in signal transduction pathways and cellular metabolism is essential for effective NK cells responses. The PKM2 isoform of the glycolytic enzyme Pyruvate Kinase Muscle has described roles in regulating glycolytic flux and signal transduction, especially gene transcription. While PKM2 expression is robustly induced in activated NK cells, mice lacking PKM2 in NK cells showed no defect in NK cell metabolism or anti-viral responses to MCMV infection. This maintenance of function is explained by compensatory PKM1 expression in PKM2-null NK cell cells demonstrating that PKM2 is not a signalling molecule in this immune cell type. To further investigate the role of PKM2 we forced the tetramerization of the protein with TEPP-46, which increases its catalytic activity while inhibiting any signalling functions mediated by mono/dimeric conformations. NK cells activated with TEPP-46 had reduced effector function due to TEPP-46-induced increases in oxidative stress. Overall, PKM2-regulated glycolytic metabolism and redox status, not transcriptional control, facilitate optimal NK cells responses.

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