NT5E expression and the immune landscape of prostate cancer (PC): An analysis from The Cancer Genome Atlas database.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16591-e16591
Author(s):  
Abhishek Tripathi ◽  
Edwin Lin ◽  
Roberto Nussenzveig ◽  
Mark Yandell ◽  
Sumanta K. Pal ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
The Cancer Genome Atlas ◽  
Effector Memory ◽  
Marker Genes ◽  
Promote Tumor Growth ◽  
Tumor Phenotype ◽  
Tcga Dataset ◽  
Tumor Expression

e16591 Background: Immune checkpoint inhibitors targeting PD-1/L1 and CTLA-4 pathway have shown modest activity in patients with advanced PC. Additional immunosuppressive mechanisms in the PC tumor microenvironment need to be investigated. Increased CD73 (encoded by NT5E) expression results in generation of immunosuppressive adenosine in the tumor microenvironment and has been associated with metastasis and poor survival in PC. Utilizing the TCGA dataset, we investigated the association of NT5E expression with the immune landscape of PC. Methods: RNA-seq data for 331 PC tumor samples and 51 normal adjacent tissue (NAT) samples was downloaded and log2 transformed. Patients were split into low, intermediate, and high expression groups based on NT5E expression (≤ -1, -1 to 1 and ≥1 standard deviation from the overall mean) in tumor and NAT. A tumor inflammation signature (TIS) reflecting an inflamed tumor phenotype was calculated based on the averaged tumor expression of 18 previously validated genes (Ayers et al, 2017). Abundance of infiltrating immune cell subsets was estimated based on expression of previously identified 782 immune metagenes (Charoentong et al, 2017). Immune cell abundance scores and TIS were compared between NT5E expression groups using the Mann-Whitney U test and the Bonferroni correction was used to control for false discovery rate. Results: NT5E expression in NAT was not associated with the TIS or expression of immune cell marker genes. In contrast, NT5E expression in tumor tissue correlated positively with TIS (P < 0.001). Compared to tumors with low NT5E expression, those in high NT5E expression group had higher expression of central memory CD4+, effector memory CD8+, type 1 helper, NK and regulatory T (Treg) cell markers. Conclusions: In our analysis, NT5E expression correlated with markers of inflamed tumor phenotype in PC. Although NT5E expression was associated with higher CD8+and CD4+ T cells, concurrent increase in Tregs could inhibit the infiltrating lymphocytes and promote tumor growth. Our findings indicate a possible role for the adenosine pathway as a mediator of immunosuppression in PC and a potential therapeutic target. AT and EL: Equal contribution

Immune correlates of CD73 expression in patients with urothelial carcinoma (UC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4548-4548
Author(s):  
Edwin Lin ◽  
Roberto Nussenzveig ◽  
Andrew W Hahn ◽  
Mark Yandell ◽  
Lauren Christine Harshman ◽  
...  
Keyword(s):  
Nk Cells ◽  
Immune Evasion ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Statistical Significance ◽  
The Cancer Genome Atlas ◽  
Immune Checkpoints ◽  
Cancer Dataset ◽  
Immune Correlates ◽  
Tumor Phenotype

4548 Background: Checkpoint inhibitors have improved outcomes in UC. However, response rates are low and additional mechanisms of immune evasion need to be ascertained. CD73 (encoded by NT5E) converts extracellular AMP to adenosine, which exerts an immunosuppressive effect in the tumor microenvironment by inhibiting infiltrating T and NK cells. Utilizing The Cancer Genome Atlas (TCGA) bladder cancer dataset, we evaluated correlations between NT5E expression and the immune milieu in UC. Methods: RNA-seq data from 411 primary UC tumor samples were obtained from the TCGA. Patients were split into low, intermediate, and high NT5E expression groups (≤ -1, -1 to 1 and ≥1 standard deviation from the overall mean). A tumor inflammation signature (TIS) reflecting an inflamed tumor phenotype was calculated based on the averaged expression of 18 previously validated genes (Ayers et al, 2017). NT5E expression was compared between tumors with high and low TIS scores and among the TCGA molecular subtypes. Abundance of infiltrating immune cell subsets was estimated based on expression of previously identified 782 immune metagenes and compared between NT5E expression groups (Charoentong et al, 2017). The Mann-Whitney U test assessed statistical significance, and the Bonferroni correction was used to control for false discovery rate. Results: NT5E expression was significantly higher in tumors with a high TIS score compared to those with low TIS score (P<0.0001) and correlated with expression of other immune checkpoints such as PD-L1, IDO and LAG-3 (each P<0.01). Patients with basal/squamous subtype had the highest NT5E expression compared to luminal or neuronal subtypes. High NT5E expression was associated with increased infiltrating NK cells, neutrophils, Tregs and decreased Type 2 T helper cells. Conclusions: High expression of NT5E in UC patients with an inflamed tumor phenotype was associated with an increase in infiltrating Tregs, and the basal/squamous subtype. Our findings highlight a potential role of CD73-adenosine pathway as a mechanism of immune evasion and a novel therapeutic target in UC. Further studies to assess the clinical impact of NT5E expression on outcomes in UC patients treated with immunotherapy are needed. AT and NA: equal contribution.

scholarly journals Bioinformatics Analysis to Screen the Key Prognostic Genes in Tumor Microenvironment of Bladder Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Zhao Zhang ◽  
Dongshan Chen ◽  
Zeyan Li ◽  
Zhao Liu ◽  
Lei Yan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Cancer Genomics ◽  
The Cancer Genome Atlas ◽  
Functional Enrichment ◽  
Marker Genes ◽  
High Morbidity ◽  
Tumor Prognosis

Bladder cancer (BLCA) is the fifth most common cancer and has the features of low survival rate and high morbidity and mortality. The Cancer Genome Atlas (TCGA) is a pool of global gene expression profile and contains huge amounts of cancer genomics data, which makes it possible to inquire the relationship between gene expression and prognosis of a series of malignant tumors including BLCA. Immune and stromal cells are two major components of tumor microenvironment (TME) which play an important role in judging the prognosis of tumor and influencing the progression of malignant, inflammatory, and metabolic disorders. In our study, we conducted a quantitative analysis of immune and stromal elements based on the ESTIMATE algorithm and thus divided BLCA cases into high and low groups. Then the differentially expressed genes closely related to tumor prognosis between groups were identified and had been shown to correlate with immune response and stromal alterations, which was further confirmed by functional enrichment analysis and protein-protein interaction networks. We validated those genes through BLCA dates downloaded from ArrayExpress and thus got the marker genes to predict prognosis of BLCA. Additionally, immune cell infiltration analysis explored the correlation between the verified genes and immune cells. In conclusion, we identified a series of TME-related genes that assess the prognosis and explored the interaction between TME and tumor prognosis to guide clinical individualized treatment.

scholarly journals ADAMTS12 acts as a tumor microenvironment related cancer promoter in gastric cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yangming Hou ◽  
Yingjuan Xu ◽  
Dequan Wu
Keyword(s):  
Gastric Cancer ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Tumor Promoter ◽  
Protein Protein Interaction ◽  
Oxidative Phosphorylation Pathway ◽  
Cox Proportional Hazard Regression

AbstractThe infiltration degree of immune and stromal cells has been shown clinically significant in tumor microenvironment (TME). However, the utility of stromal and immune components in Gastric cancer (GC) has not been investigated in detail. In the present study, ESTIMATE and CIBERSORT algorithms were applied to calculate the immune/stromal scores and the proportion of tumor-infiltrating immune cell (TIC) in GC cohort, including 415 cases from The Cancer Genome Atlas (TCGA) database. The differentially expressed genes (DEGs) were screened by Cox proportional hazard regression analysis and protein–protein interaction (PPI) network construction. Then ADAMTS12 was regarded as one of the most predictive factors. Further analysis showed that ADAMTS12 expression was significantly higher in tumor samples and correlated with poor prognosis. Gene Set Enrichment Analysis (GSEA) indicated that in high ADAMTS12 expression group gene sets were mainly enriched in cancer and immune-related activities. In the low ADAMTS12 expression group, the genes were enriched in the oxidative phosphorylation pathway. CIBERSORT analysis for the proportion of TICs revealed that ADAMTS12 expression was positively correlated with Macrophages M0/M1/M2 and negatively correlated with T cells follicular helper. Therefore, ADAMTS12 might be a tumor promoter and responsible for TME status and tumor energy metabolic conversion.

scholarly journals Metabolic Factors Affecting Tumor Immunogenicity: What Is Happening at the Cellular Level?

2021 ◽  
Vol 22 (4) ◽  
pp. 2142
Author(s):  
Rola El Sayed ◽  
Yolla Haibe ◽  
Ghid Amhaz ◽  
Youssef Bouferraa ◽  
Ali Shamseddine
Keyword(s):  
Fatty Acid ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Immune Modulation ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Effector Memory ◽  
Acid Oxidation ◽  
Checkpoint Inhibition ◽  
Inflammatory Phenotypes

Immunotherapy has changed the treatment paradigm in multiple solid and hematologic malignancies. However, response remains limited in a significant number of cases, with tumors developing innate or acquired resistance to checkpoint inhibition. Certain “hot” or “immune-sensitive” tumors become “cold” or “immune-resistant”, with resultant tumor growth and disease progression. Multiple factors are at play both at the cellular and host levels. The tumor microenvironment (TME) contributes the most to immune-resistance, with nutrient deficiency, hypoxia, acidity and different secreted inflammatory markers, all contributing to modulation of immune-metabolism and reprogramming of immune cells towards pro- or anti-inflammatory phenotypes. Both the tumor and surrounding immune cells require high amounts of glucose, amino acids and fatty acids to fulfill their energy demands. Thus, both compete over one pool of nutrients that falls short on needs, obliging cells to resort to alternative adaptive metabolic mechanisms that take part in shaping their inflammatory phenotypes. Aerobic or anaerobic glycolysis, oxidative phosphorylation, tryptophan catabolism, glutaminolysis, fatty acid synthesis or fatty acid oxidation, etc. are all mechanisms that contribute to immune modulation. Different pathways are triggered leading to genetic and epigenetic modulation with consequent reprogramming of immune cells such as T-cells (effector, memory or regulatory), tumor-associated macrophages (TAMs) (M1 or M2), natural killers (NK) cells (active or senescent), and dendritic cells (DC) (effector or tolerogenic), etc. Even host factors such as inflammatory conditions, obesity, caloric deficit, gender, infections, microbiota and smoking status, may be as well contributory to immune modulation, anti-tumor immunity and response to immune checkpoint inhibition. Given the complex and delicate metabolic networks within the tumor microenvironment controlling immune response, targeting key metabolic modulators may represent a valid therapeutic option to be combined with checkpoint inhibitors in an attempt to regain immune function.

scholarly journals “Skull base meningiomas have a distinct immune landscape.”

2019 ◽  
Author(s):  
Zsolt Zador ◽  
Alexander P. Landry ◽  
Michael Balas ◽  
Michael D. Cusimano
Keyword(s):  
Tumor Microenvironment ◽  
Skull Base ◽  
Immune Cell ◽  
Adult Brain ◽  
Anatomical Location ◽  
Transcriptomics Data ◽  
Tumor Phenotype ◽  
Cell Fractions ◽  
Cytokine Interactions ◽  
Skull Base Meningiomas

AbstractModulation of tumor microenvironment is an emerging frontier for new therapeutics. However in meningiomas, the most frequent adult brain tumor, the correlation of microenvironment with tumor phenotype is scarcely studied. We applied a variety of systems biology approaches to bulk tumor transcriptomics to explore the immune environments of both skull base and convexity (hemispheric) meningiomas. We hypothesized that the more benign biology of skull base meningiomas parallels the relative composition and activity of immune cells that oppose tumor growth and/or survival. We firstly applied gene co-expression networks to tumor bulk transcriptomics from 107 meningiomas (derived from 3 independent studies) and found immune processes to be the sole biological mechanism correlated with anatomical location while correcting for tumour grade. We then derived tumor immune cell fractions from bulk transcriptomics data and examined the immune cell-cytokine interactions using a network-based approach. We demonstrate that oncolytic M1 macrophages dominate skull base meningiomas while mast cells, known to play a role in oncogenesis, show greater activity in convexity tumors. Our results are the first to suggest the importance of tumor microenvironment in meningioma biology in the context of anatomic location and immune landscape. These findings may help better inform surgical decision making and yield location-specific therapies through modulation of immune microenvironment.

scholarly journals Comprehensive analysis of tumor microenvironment landscape and potential therapeutic agents based on tumor-infiltrating immune cells in colorectal cancer

2021 ◽  
Author(s):  
Wenhui Zhong ◽  
Feng Zhang ◽  
Xin Lu ◽  
Kaijun Huang ◽  
Junming Bi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Cancer Therapeutics ◽  
The Cancer Genome Atlas ◽  
Receptor Interaction ◽  
Chemotherapy Drugs ◽  
Drug Compounds

Abstract Background: Tumor-infiltrating immune cells (TIIC) are the major components of the tumor microenvironment (TME) and play vital roles in the tumorigenesis and progression of colorectal cancer (CRC). Increasing evidence has elucidated their significances in predicting prognosis and therapeutic efficacy. Nonetheless, the immune infiltrative landscape of CRC remains largely unknown. Methods: All the RNA-seq transcriptome data and full clinical annotation of 1213 colorectal cancer patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene-Expression Omnibus (GEO) database. The “CIBERSORT” and “estimate” R package were applied to calculate 22 infiltrated immune cell fractions and stromal and immune score. Three TIIC patterns were determined by Unsupervised clustering methods. Through using principal-component analysis, TIIC scores were established. Data for potential agents comes from the Profiling Relative Inhibition Simultaneously in Mixtures (PRISM) and Cancer Therapeutics Response Portal database (CTRP). Results：In this study, we identified three distinct TIIC patterns characterized by distinct immunological features in 1213 CRC samples from multiple platforms. Base on the TIIC-related gene signatures from three clusters, we constructed a scoring system to quantify the immune infiltration level of individual samples in the CRC cohort and the clinical benefits of different groups. The high TIIC score group was marked by increased immune activation status and favorable prognosis. Conversely, low TIIC score group was featured with immune-desert phenotype and poor prognosis, along with the activation of transforming growth factor-β (TGF-β), WNT, ECM receptor interaction, and VEGF signaling pathways. Meanwhile, the high TIIC score group was also correlated with enhanced efficacy of immunotherapy. Additional, four chemotherapy drugs, seven CTRP-derived drug compounds and six PRISM-derived drug compounds were identified as potential drug for CRC among high and low TIIC subgroups.Conclusions: Collectively, as an effective prognostic biomarker and predictive indicator, the TIIC score plays an important role in the evaluation of CRC prognosis and the response of immunotherapy. Investigation of the TIIC patterns might provide us a promising target for improving immunotherapeutic efficacy in CRC.

scholarly journals Tumor Microenvironment Characteristics of Pancreatic Cancer to Determine Prognosis and Immune-Related Gene Signatures

2021 ◽  
Vol 8 ◽  
Author(s):  
Congjun Zhang ◽  
Jun Ding ◽  
Xiao Xu ◽  
Yangyang Liu ◽  
Wei Huang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Microenvironment ◽  
Immune Cell ◽  
Inhibitory Effect ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Diagnosis And Prognosis ◽  
Gap Statistic ◽  
New Strategy ◽  
Immune Cell Subpopulations

Background: Pancreatic cancer (PC) is one of the most lethal types of cancer with extremely poor diagnosis and prognosis, and the tumor microenvironment plays a pivotal role during PC progression. Poor prognosis is closely associated with the unsatisfactory results of currently available treatments, which are largely due to the unique pancreatic tumor microenvironment (TME).Methods: In this study, a total of 177 patients with PC from The Cancer Genome Atlas (TCGA) cohort and 65 patients with PC from the GSE62452 cohort in Gene Expression Omnibus (GEO) were included. Based on the proportions of 22 types of infiltrated immune cell subpopulations calculated by cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT), the TME was classified by K-means clustering and differentially expressed genes (DEGs) were determined. A combination of the elbow method and the gap statistic was used to explore the likely number of distinct clusters in the data. The ConsensusClusterPlus package was utilized to identify radiomics clusters, and the samples were divided into two subtypes.Result: Survival analysis showed that the patients with TMEscore-high phenotype had better prognosis. In addition, the TMEscore-high had better inhibitory effect on the immune checkpoint. A total of 10 miRNAs, 311 DEGs, and 68 methylation sites related to survival were obtained, which could be biomarkers to evaluate the prognosis of patients with pancreatic cancer.Conclusions: Therefore, a comprehensive description of TME characteristics of pancreatic cancer can help explain the response of pancreatic cancer to immunotherapy and provide a new strategy for cancer treatment.

scholarly journals Highly Multiplexed Digital Spatial Profiling of the Tumor Microenvironment of Head and Neck Squamous Cell Carcinoma Patients

2021 ◽  
Vol 10 ◽  
Author(s):  
Arutha Kulasinghe ◽  
Touraj Taheri ◽  
Ken O’Byrne ◽  
Brett G. M. Hughes ◽  
Liz Kenny ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Tumor Microenvironment ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Neck Squamous Cell Carcinoma ◽  
Protein Markers ◽  
Spatial Profiling

BackgroundImmune checkpoint inhibitors (ICI) have shown durable and long-term benefits in a subset of head and neck squamous cell carcinoma (HNSCC) patients. To identify patient-responders from non-responders, biomarkers are needed which are predictive of outcome to ICI therapy. Cues in the tumor microenvironment (TME) have been informative in understanding the tumor-immune contexture.MethodsIn this preliminary study, the NanoString GeoMx™ Digital Spatial Profiling (DSP) technology was used to determine the immune marker and compartment specific measurements in a cohort of HNSCC tumors from patients receiving ICI therapy.ResultsOur data revealed that markers involved with immune cell infiltration (CD8 T-cells) were not predictive of outcome to ICI therapy. Rather, a number of immune cell types and protein markers (CD4, CD68, CD45, CD44, CD66b) were found to correlate with progressive disease. Cross platform comparison with the Opal Vectra (Perkin Elmer) for a number of markers across similar regions of interest demonstrated concordance for pan-cytokeratin, CD8, and PD-L1.ConclusionThis study, to our knowledge, represents the first digital spatial analysis of HNSCC tumors. A larger cohort of HNSCC will be required to orthogonally validate the findings.

scholarly journals Effects of Hypoxia in Intestinal Tumors on Immune Cell Behavior in the Tumor Microenvironment

2020 ◽  
Author(s):  
Luping Zhang ◽  
Shaokun Wang ◽  
Yachen Wang ◽  
Weidan Zhao ◽  
Yingli Zhang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Risk Score ◽  
Immune Cell ◽  
Risk Groups ◽  
Low Risk ◽  
Computational Method ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cell Behavior

Abstract Background: Imbalanced nutritional supply and demand in the tumor microenvironment often leads to hypoxia. The subtle interaction between hypoxia and immune cell behavior plays an important role in tumor occurrence and development. However, the functional relationship between hypoxia and the tumor microenvironment remains unclear. Therefore, we aimed to investigate the effect of hypoxia on the intestinal tumor microenvironment.Method: We extracted the names of hypoxia-related genes from the Gene Set Enrichment Analysis (GSEA) database and screened them for those associated with the prognosis of colorectal cancer, with the final list including ALDOB, GPC1, ALDOC, and SLC2A3. Using the sum of the expression levels of these four genes, provided by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and the expression coefficients, we developed a hypoxia risk score model. Using the median risk score value, we divided the patients in the two databases into high- and low-risk groups.GSEA was used to compare the enrichment differences between the two groups.We used the CIBERSORT computational method to analyze immune cell infiltration.Finally,the correlation between these five genes and hypoxia was analyzed. Result: The prognosis of the two groups differed significantly, with a higher survival rate in the low-risk group than in the high-risk group.We found that the different risk groups were enriched by immune-related and inflammatory pathways. We identified activated CD4 memory T cells and M0 macrophages in TCGA and GEO databases and found that CCL2/4/5, CSF1, and CX3CL1 contributed toward the increased infiltration rate of these immune cell types. Finally, we observed a positive correlation between the five candidate genes’ expression and the risk of hypoxia, with significant differences in the level of expression of each of these genes between patient risk groups.Conclusion: Overall, our data suggest that hypoxia is associated with the prognosis and rate of immune system infiltration in patients with colorectal cancer. This finding may improve immunotherapy for colorectal cancer.

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