Integrative characterization and validation of tumor-associated immune signature combined with immune-infiltration analysis in clear cell renal cell carcinoma

2020 ◽  
Author(s):  
Hongxi Chen ◽  
Jinliang Xie ◽  
Peng Jin
Keyword(s):  
Functional Analysis ◽  
Immune Cells ◽  
Immune Cell ◽  
Differential Analysis ◽  
T Regulatory Cell ◽  
Cell Renal Cell Carcinoma ◽  
Differential Abundance ◽  
Immune Signature ◽  
Immune Infiltration ◽  
Public Datasets

Abstract Background We aimed to explore and validate a prognostic immune signature for predicting the prognosis of ccRCC patients, combined with immune-infiltration analysis. Methods We obtained the multi-omics data from public datasets. Differential analysis was performed by edgeR package. Prognostic immune signature was identified by univariate Cox analysis, and we constructed an integrative tumor-associated immune Genes (TAIG) model from the multivariate Cox results. Functional analysis was conducted to uncover the related crosstalk. Importantly, we implemented the CIBERSORT algorithm to estimate the immune cell fractions in ccRCC samples and analyzed the differential abundance of tumor-infiltrating immune cells in two TAIG groups using Wilcoxon rank-sum test. The prognostic role of differential immune cells was further assessed by Kaplan-Meier analysis. In addition, we investigated the associations of single immune signature with specific immune cells. Results A total of 628 ccRCC patients were included in our integrative analysis, including 537 ccRCC patients in discovery group and 91 patients in validation group. Then, we identified the 14 key immune signatures. The AUC was 0.802 and patients with higher TAIG suffered from worse prognosis. Correlation analysis indicated that TAIG correlated tightly with clinical variables and TMB. Moreover, functional analysis also implicated the immune-related GO items or crosstalk. Therefore, we discovered the relationships of TAIG with tumor-infiltrating immune cells. The differential abundance of immune cells showed significant prognostic difference consisted of memory activated CD4 + T cell, T follicular helper cells, T regulatory cell, and so on. Moreover, we also characterized the associations between identified signature with specific immune cells. Finally, the 5-year AUC in ICGC cohort was 0.72, suggesting the robustness of TAIG that we constructed. Conclusions Totally, our team characterized the tumor-associated immune signature in ccRCC and further uncovered the prognostic tumor-infiltrating immune cells related with TAIG, providing a comprehensive foundation for investigating mechanisms or individualized immunotherapy.

scholarly journals Identification of Biomarkers Related to Immune Cell Infiltration in Hepatocellular Carcinoma Using Gene Co-Expression Network

2021 ◽  
Vol 27 ◽  
Author(s):  
Wanbang Zhou ◽  
Yiyang Chen ◽  
Ruixing Luo ◽  
Zifan Li ◽  
Guanwei Jiang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Network Analysis ◽  
Tumor Progression ◽  
Protein Interactions ◽  
Immune Cells ◽  
Immune Cell ◽  
Immune Microenvironment ◽  
Hub Genes ◽  
Expression Levels ◽  
Immune Infiltration

Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis. Due to the lack of effective biomarkers and its complex immune microenvironment, the effects of current HCC therapies are not ideal. In this study, we used the GSE57957 microarray data from Gene Expression Omnibus database to construct a co-expression network. The weighted gene co-expression network analysis and CIBERSORT algorithm, which quantifies cellular composition of immune cells, were used to identify modules related to immune cells. Four hub genes (EFTUD2, GAPDH, NOP56, PA2G4) were identified by co-expression network and protein-protein interactions network analysis. We examined these genes in TCGA database, and found that the four hub genes were highly expressed in tumor tissues in multiple HCC groups, and the expression levels were significantly correlated with patient survival time, pathological stage and tumor progression. On the other hand, methylation analysis showed that the up-regulation of EFTUD2, GAPDH, NOP56 might be due to the hypomethylation status of their promoters. Next, we investigated the correlations between the expression levels of four hub genes and tumor immune infiltration using Tumor Immune Estimation Resource (TIMER). Gene set variation analysis suggested that the four hub genes were associated with numerous pathways that affect tumor progression or immune microenvironment. Overall, our results showed that the four hub genes were closely related to tumor prognosis, and may serve as targets for treatment and diagnosis of HCC. In addition, the associations between these genes and immune infiltration enhanced our understanding of tumor immune environment and provided new directions for the development of drugs and the monitoring of tumor immune status.

scholarly journals Identification and validation of dichotomous immune subtypes based on intratumoral immune cells infiltration in clear cell renal cell carcinoma patients

2020 ◽  
Vol 8 (1) ◽  
pp. e000447
Author(s):  
Ying Xiong ◽  
Zewei Wang ◽  
Quan Zhou ◽  
Han Zeng ◽  
Hongyu Zhang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Treatment Response ◽  
Immune Cells ◽  
Renal Cell ◽  
Immune Cell ◽  
Clear Cell ◽  
Biological Pathways ◽  
Cell Renal Cell Carcinoma ◽  
Free Survival

BackgroundIncreasing evidence has elucidated the clinical significance of tumor infiltrating immune cells in predicting outcomes and therapeutic efficacy. In this study, we comprehensively analyze the tumor microenvironment (TME) immune cell infiltrations in clear cell renal cell carcinoma (ccRCC) and correlated the infiltration patterns with anti-tumor immunity and clinical outcomes.MethodsWe analyzed immune cell infiltrations in four independent cohorts, including the KIRC cohort of 533 patients, the Zhongshan ccRCC cohorts of 259 patients, the Zhongshan fresh tumor sample cohorts of 20 patients and the Zhongshan metastatic ccRCC cohorts of 87 patients. Intrinsic patterns of immune cell infiltrations were evaluated for associations with clinicopathological characteristics, underlying biological pathways, genetic changes, oncological outcomes and treatment responses.ResultsUnsupervised clustering of tumor infiltrating immune cells identified two microenvironment subtypes, TMEcluster-A and TMEcluster-B. Gene markers and biological pathways referring to immune evasion were upregulated in TMEcluster-B. TMEcluster-B associated with poor overall survival (p<0.001; HR 2.629) and recurrence free survival (p=0.012; HR 1.870) in ccRCC validation cohort. TMEcluster-B cases had worse treatment response (p=0.009), overall survival (p<0.001; HR 2.223) and progression free survival (p=0.015; HR 2.7762) in metastatic ccRCC cohort. The predictive accuracy of International Metastatic Database Consortium risk score was improved after incorporation of TME clusters.ConclusionsTMEcluster-A featured increased mast cells infiltration, prolonged survival and better treatment response. TMEcluster-B was a heavily infiltrated but immunosuppressed phenotype enriched for macrophages, CD4+T cells, Tregs, CD8+T cells and B cells. TMEcluster-B predicted dismal survival and worse treatment response in clear cell renal cell carcinoma patients.

scholarly journals Immune signature driven by ADT-induced immune microenvironment remodeling in prostate cancer is correlated with recurrence-free survival and immune infiltration

2020 ◽  
Vol 11 (9) ◽  
Author(s):  
Xingbo Long ◽  
Huimin Hou ◽  
Xuan Wang ◽  
Shengjie Liu ◽  
Tongxiang Diao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Cell ◽  
Locally Advanced ◽  
Underlying Mechanism ◽  
Immune Microenvironment ◽  
Hub Genes ◽  
Free Survival ◽  
Immune Signature ◽  
Immune Infiltration ◽  
Patient Prognosis

Abstract Androgen deprivation therapy (ADT) is a cornerstone treatment for locally advanced or metastatic prostate cancer (PCa). However, its potential effects on the tumor immune microenvironment (TIM) of PCa patients and the underlying mechanism remain largely unclear. To explore the effects of ADT on PCa TIM, RNA sequencing was performed on six paired pre-ADT biopsy and post-ADT PCa lesions, and five paired paracancerous benign tissues from patients receiving neoadjuvant ADT with locally advanced PCa. Bioinformatics methods including ESTIMATE and ssGSEA were used to evaluate the stromal immune score and immune cell infiltration in PCa and paracancerous tissues. Weighted correlation network analysis was used to screen hub genes in the ADT-induced immune remodeling process. The results showed differences exist between PCa and paracancerous tissues in response to ADT. Compared with paracancerous tissues, the immune remodeling effect of ADT in PCa was more intense. ZFP36, JUNB, and SOCS3 served as hub genes in the ADT-induced immune remodeling process and were associated with PSA recurrent-free survival in the TCGA and our neoadjuvant ADT cohort. To investigate the joint action of the above three hub genes, an immune signature score was constructed. The results showed that immune signature score-based immune subtypes reveal the heterogeneity of the immune microenvironment of PCa and showed significant differences in patient prognosis, tumor immune infiltration, mutation burden, and landscape.

scholarly journals Profiles of immune infiltration and its relevance to survival outcome in meningiomas

2020 ◽  
Vol 40 (5) ◽  
Author(s):  
Xiaodong Chen ◽  
Fen Tian ◽  
Peng Lun ◽  
Yugong Feng
Keyword(s):  
Immune Cells ◽  
Clustering Analysis ◽  
Immune Cell ◽  
Cox Regression ◽  
Cell Types ◽  
Survival Outcome ◽  
Cox Regression Analysis ◽  
Immune Infiltration ◽  
Online Databases ◽  
The Relationship

Abstract Tumor-infiltrating immune cells play a decisive part in prognosis and survival. Until now, previous researches have not made clear about the diversity of cell types involved in the immune response. The objective of this work was to confirm the composition of tumor-infiltrating immune cells and their correlation with prognosis in meningiomas based on a metagene approach (known as CIBERSORT) and online databases. A total of 22 tumor-infiltrating immune cells were detected to determine the relationship between the immune infiltration pattern and survival. The proportion of M2 macrophages was more abundant in 68 samples, reaching more than 36%. Univariate Cox regression analysis displayed that the proportion of dendritic cells was obviously related to prognosis. Hierarchical clustering analysis identified two clusters by the method of within sum of squares errors, which exhibited different infiltrating immune cell composition and survival. To summarize, our results indicated that proportions of tumor-infiltrating immune cells as well as cluster patterns were associated with the prognosis, which offered clinical significance for research of meningiomas.

scholarly journals Upregulated CCNE1 Correlates with Poor Prognosis, Tumor Immune Infiltration and Escape in Breast Cancer

2021 ◽  
Author(s):  
Jiaxi Feng ◽  
Yanan Hu ◽  
Dan Liu ◽  
Shanshan Wang ◽  
Mengci Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cells ◽  
Poor Prognosis ◽  
Immune Cell ◽  
High Expression ◽  
Expression Level ◽  
Immune Cell Infiltration ◽  
Immune Infiltration ◽  
Kaplan Meier ◽  
Kaplan Meier Plotter

Abstract Background Breast cancer (BC) is the most common malignant tumor in women and widely known for its poor prognosis. More and more research has discovered that cyclin E1 (CCNE1) plays an important role in progression of various types of cancer. But its specific mechanism in BC progression still needs further research to explore.Methods At first, we determined the expression and prognostic value of CCNE1 through The Cancer Genome Atlas (TCGA) database and The Genotype-Tissue Expression (GTEx) data. Then, we predicted the upstream non-coding RNAs of CCNE1 through StarBase, GEPIA, and Kaplan-Meier plotter database. We further studied the correlation of CCNE1 expression with BC immune cell infiltration, biomarkers of immune cells and immune checkpoints expression through TIMER and GEPIA databases.Results The results suggested that CCNE1 was significantly upregulated in BC and its high expression was correlated with poor prognosis in BC patients. Next, we identified long noncoding RNA (lncRNA) LINC00511 / microRNA-195-5p (miR-195-5p) / CCNE1 axis as the most potential pathway that could regulate CCNE1 expression in BC through StarBase, GEPIA, and Kaplan-Meier plotter database. Furthermore, our in-depth research discovered that CCNE1 expression level was significantly correlated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression in BC. conclusions In summary, high expression level of CCNE1 was significantly correlated with poor prognosis, tumor immune infiltration and escape in BC.

scholarly journals Integrative Transcriptomic, Proteomic and Functional Analysis Reveals ATP1B3 as a Diagnostic and Potential Therapeutic Target in Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Shanshan Lu ◽  
Shenglan Cai ◽  
Xiaozhen Peng ◽  
Ruochan Cheng ◽  
Yiya Zhang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Functional Analysis ◽  
Prognostic Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Immune Cell ◽  
Prognostic Significance ◽  
Independent Prognostic Factor ◽  
Mesenchymal Transition ◽  
Immune Infiltration ◽  
Geo Database

The Na+/K+-ATPase (NKA), has been proposed as a signal transducer involving various pathobiological processes, including tumorigenesis. However, the clinical relevance of NKA in hepatocellular carcinoma (HCC) has not been well studied. This study revealed the upregulation of mRNA of ATP1A1, ATP1B1, and ATP1B3 in HCC using TCGA, ICGC, and GEO database. Subsequently, ATP1B3 was demonstrated as an independent prognostic factor of overall survival (OS) of HCC. To investigate the potential mechanisms of ATP1B3 in HCC, we analyzed the co-expression network using LinkedOmics and found that ATP1B3 co-expressed genes were associated with immune-related biological processes. Furthermore, we found that ATP1B3 was correlated immune cell infiltration and immune-related cytokines expression in HCC. The protein level of ATP1B3 was also validated as a prognostic significance and was correlated with immune infiltration in HCC using two proteomics datasets. Finally, functional analysis revealed that ATP1B3 was increased in HCC cells and tissues, silenced ATP1B3 repressed HCC cell proliferation, migration, and promoted HCC cell apoptosis and epithelial to mesenchymal transition (EMT). In conclusion, these findings proved that ATP1B3 could be an oncogene and it was demonstrated as an independent prognostic factor and correlated with immune infiltration in HCC, revealing new insights into the prognostic role and potential immune regulation of ATP1B3 in HCC progression and provide a novel possible therapeutic strategy for HCC.

scholarly journals LAG3(LAG-3,CD223) DNA methylation correlates with LAG3 expression by tumor and immune cells, immune cell infiltration, and overall survival in clear cell renal cell carcinoma

2020 ◽  
Vol 8 (1) ◽  
pp. e000552 ◽  
Author(s):  
Niklas Klümper ◽  
Damian J Ralser ◽  
Emma Grace Bawden ◽  
Jenny Landsberg ◽  
Romina Zarbl ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Cell Lines ◽  
Immune Cells ◽  
Immune Cell ◽  
Clear Cell ◽  
Immune Cell Infiltration ◽  
Strongly Correlated ◽  
Cell Renal Cell Carcinoma ◽  
Immune Cell Infiltrates

BackgroundLymphocyte activating 3 (LAG3, LAG-3, CD223) is a promising target for immune checkpoint inhibition in clear cell renal cell carcinoma (KIRC). The aim of this study was to investigate the epigenetic regulation ofLAG3in KIRC by methylation.MethodsWe correlated quantitativeLAG3methylation levels with transcriptional activity, immune cell infiltration, and overall survival in a cohort of n=533 patients with KIRC and n=160 normal adjacent tissue (NAT) samples obtained from The Cancer Genome Atlas (TCGA). Furthermore, we analyzedLAG3methylation in peripheral blood mononuclear cells (PBMCs) and KIRC cell lines. We validated correlations between LAG3 expression, immune cell infiltrates, survival, and methylation in an independent KIRC cohort (University Hospital Bonn (UHB) cohort, n=118) by means of immunohistochemistry and quantitative methylation-specific PCR.ResultsWe found differential methylation profiles among PBMCs, NAT, KIRC cell lines, and KIRC tumor tissue. Methylation strongly correlated with LAG3 mRNA expression in KIRCs (TCGA cohort) and KIRC cell lines. In the UHB cohort, methylation correlated with LAG3-positive immune cells and tumor-intrinsic LAG3 protein expression. Furthermore,LAG3methylation strongly correlated with signatures of distinct immune cell infiltrates, an interferon-y signature (TCGA cohort), and immunohistochemically quantified CD45+, CD8+, and CD4+immune cell infiltrates (UHB cohort). LAG3 mRNA expression (TCGA cohort), methylation (both cohorts), and tumor cell-intrinsic protein expression (UHB cohort) was significantly associated with overall survival.ConclusionOur data suggest an epigenetic regulation of LAG3 expression in tumor and immune cells via DNA methylation. LAG3 expression and methylation is associated with a subset of KIRCs showing a distinct clinical course and immunogenicity. Our study provides rationale for further testingLAG3DNA methylation as a predictive biomarker for response to LAG3 immune checkpoint inhibitors.

scholarly journals Identification of recurrence marker associated with immune infiltration in prostate cancer with radical resection and build prognostic nomogram

BMC Cancer ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Xin Rui ◽  
Siliang Shao ◽  
Li Wang ◽  
Jiangyong Leng
Keyword(s):  
Prostate Cancer ◽  
Immune Cells ◽  
Prediction Models ◽  
Immune Cell ◽  
Cox Regression ◽  
Cancer Recurrence ◽  
Th2 Cells ◽  
Cox Regression Analysis ◽  
Immune Infiltration ◽  
Prostate Cancer Recurrence

Abstract Background Some historic breakthroughs have been made in immunotherapy of advanced cancer. However, there is still little research on immunotherapy in prostate cancer. We explored the relationship between immune cell infiltration and prostate cancer recurrence and tried to provide new ideas for the treatment of prostate cancer. Methods Prostate cancer RNA-seq data and clinical information were downloaded from the TCGA database and GEO database. The infiltration of 24 immune cells in tissues was quantified by ssGSEA. Univariate Cox regression analysis was used to screen for immune cell types associated with tumor recurrence, weighted gene co-expression network analysis (WGCNA) and LASSO were used to identify hub genes which regulate prognosis in patients through immune infiltration. Then, the nomogram was constructed based on the hub gene to predict the recurrence of prostate cancer, and the decision curve analysis (DCA) was used to compare the accuracy with the PSA and Gleason prediction models. Result Analysis showed that Th2 cells and Tcm related to prostate cancer recurrence after radical prostatectomy, and they are independent protective factors for recurrence. Through WGCNA and Lasso, we identified that NDUFA13, UQCR11, and USP34 involved in the infiltration of Th2 cells and Tcm in tumor tissues, and the expression of genes is related to the recurrence of patients. Based on the above findings, we constructed a clinical prediction model and mapped a nomogram, which has better sensitivity and specificity for prostate cancer recurrence prediction, and performed better in comparison with PSA and Gleason’s predictions. Conclusion The immune cells Th2 cells and Tcm are associated with recurrence of PCa. Moreover, the genes NDUFA13, UQCR11, and USP34 may affect the recurrence of PCa by affecting the infiltration of Th2 cells and Tcm. Moreover, nomogram can make prediction effectively.

scholarly journals A dual immune signature of CD8+ T Cells and MMP9 improves the survival of hepatocellular carcinoma patients

2021 ◽  
Author(s):  
Huan Ding ◽  
Huan Hu ◽  
Feifei Tian ◽  
Huaping Liang
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Immune Cell ◽  
Cox Regression ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
High Recurrence Rate ◽  
Immune Signature

The 5-year survival of hepatocellular carcinoma (HCC) is difficult due to the high recurrence rate and metastasis. Tumor infiltrating immune cells (TICs) and immune-related genes (IRGs) bring hope to improve survival and treatment of HCC patients. However, there are problems in predicting immune signatures and identifying novel therapeutic targets. In the study, the CIBERSORT algorithm was used to evaluate 22 immune cell infiltration patterns in gene expression omnibus (GEO) and the cancer genome atlas (TCGA) data. Eight immune cells were found to have significant infiltration differences between the tumor and normal groups. The CD8+ T Cells immune signature was constructed by least absolute shrinkage and selection operator (LASSO) algorithm. The high infiltration level of CD8+ T Cells could significantly improve survival of patients. The weighted gene co-expression network analysis (WGCNA) algorithm identified MMP9 was closely related to the overall survival of HCC patients. K-M survival and tROC analysis confirmed that MMP9 had an excellent prognostic prediction. Cox regression showed that a dual immune signature of CD8+ T Cells and MMP9 was independent survival factor in HCC. Therefore, a dual prognostic immune signature could improve the survival of patient and may provide a new strategy for the immunotherapy of HCC.

scholarly journals ANLN and Lung Adenocarcinoma Prognosis and Immune Infiltration Research

2021 ◽  
Author(s):  
Meihua Ru ◽  
Ying-Bo Liu ◽  
Zhi-Hui Tian ◽  
IVAN STEVE GODJE GODJE ◽  
Jian-Qiang Li
Keyword(s):  
Lung Adenocarcinoma ◽  
Immune Cells ◽  
Prognostic Value ◽  
Immune Cell ◽  
Actin Binding ◽  
Immune Infiltration ◽  
Key Factor ◽  
New Ideas ◽  
N Stage ◽  
Cox Analysis

Abstract Objective: This study aims to explore the role of aniline-actin binding protein (ANLN) in the prognosis of lung adenocarcinoma (LUAD) and its role in immune infiltration, and to provide new ideas for clinical diagnosis and treatment.Methods: In this study, we applied bioinformatics methods to analyze the expression pattern and prognostic value of ANLN in LUAD ,and confirmed its independent prognostic value through Cox analysis. TIMER was used to evaluate the correlation between ANLN and tumor infiltrating immunity. LinkedOmics was used to study the co-expressed genes and functional networks related to ANLN.The TIMER database was used to analyze the correlation between ANLN co-expressed genes and tumor infiltrating immune cells. Results: ANLN is highly expressed in most cancers. In the TCGA-LUAD cohort, ANLN was highly expressed in LUAD. ANLN was significantly related to the grade , T stage and N stage of patients with LUAD. It was verified in multiple independent queues. The high expression and highly mutation of ANLN predicts poor survival .Multivariate COX analysis showed that ANLN was an independent risk factor for survival . GSEA analysis shows that ANLN regulates cell cycle, and other pathways. The expression of ANLN was significantly correlated with the level of B cell infiltration.Conclusions: ANLN is closely related to the prognosis of patients with LUAD and tumor immune cell infiltration suggesting that ANLN is a key factor regulating the recruitment of immune cells to LUAD and may play an important role in immune.

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