Genetic and Epigenetic landscape of leukocyte infiltration identifies an immune prognosticator in lung adenocarcinoma

2021 ◽  
pp. 1-13
Author(s):  
Seema Khadirnaikar ◽  
Annesha Chatterjee ◽  
Sudhanshu Kumar Shukla
Keyword(s):  
Lung Adenocarcinoma ◽  
Immune Cell ◽  
Cox Regression ◽  
Strong Association ◽  
Critical Role ◽  
Significant Proportion ◽  
Immune Gene ◽  
Leukocyte Infiltration ◽  
Clinical Genetic ◽  
Factors Affecting

BACKGROUND: Leukocyte infiltration plays an critical role in outcome of various diseases including Lung adenocarcinoma (LUAD). OBJECTIVES: To understand the genetic and epigenetic factors affecting leukocyte infiltration and identification and validation of immune based biomarkers. METHOD: Correlation analysis was done to get the associations of the factors. CIBERSORT analysis was done for immune cell infiltration. Genetic and epigenetic analysis were performed. Cox regression was carried out for survival. RESULTS: We categorized the TCGA-LUAD patients based on Leukocyte fraction (LF) and performed extensive immunogenomic analysis. Interestingly, we showed that LF has a negative correlation with copy number variation (CNV) but not with mutational load. However, several individual genetic mutations, including KRAS and KEAP1, were significantly linked with LF. Also, as expected, patients with high LF showed significantly increased expression of genes involved in leukocyte migration and activation. DNA methylation changes also showed a strong association with LF and regulated a significant proportion of genes associated with LF. We also developed and validated an independent prognostic immune signature using the top six prognostic genes associated with LF. CONCLUSION: Together, we have identified clinical, genetic, and epigenetic variations associated with LUAD LF and developed an immune gene-based signature for disease prognostication.

scholarly journals Low Expression of RILPL2 Predicts Poor Prognosis and Correlates With Immune Infiltration in Endometrial Carcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Jinhui Liu ◽  
Mengting Xu ◽  
Zhipeng Wu ◽  
Yan Yang ◽  
Shuning Yuan ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Endometrial Carcinoma ◽  
Immune Cell ◽  
Cox Regression ◽  
Critical Role ◽  
Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Promising Target

Increasing numbers of biomarkers have been identified in various cancers. However, biomarkers associated with endometrial carcinoma (EC) remain largely to be explored. In the current research, we downloaded the RNA-seq data and corresponding clinicopathological features from the Cancer Genome Atlas (TCGA) database. We conducted an expression analysis, which resulted in RILPL2 as a novel diagnostic biomarker in EC. The dysregulation of RILPL2 in EC was also validated in multiple datasets. The correlations between clinical features and RILPL2 expression were assessed by logistic regression analysis. Then, Kaplan-Meier analysis, univariate and multivariate Cox regression analysis were performed to estimate prognostic values of RILPL2 in the TCGA cohort, which revealed that increased level of RILPL2 was remarkably associated with better prognosis and could act as an independent prognostic biomarker in patients with EC. Moreover, correlation analysis of RILPL2 and tumor-infiltrating immune cells (TIICs) indicated that RILPL2 might play a critical role in regulating immune cell infiltration in EC and is related to immune response. Besides, high methylation level was a significant cause of low RILPL2 expression in EC. Subsequently, weighted gene co-expression network analysis (WGCNA) and enrichment analysis were conducted to explore the RILPL2-involved underlying oncogenic mechanisms, and the results indicated that RILPL2 mainly regulated cell cycle. In conclusion, our findings provided evidence that downregulation of RILPL2 in EC is an indicator of adverse prognosis and RILPL2 may act as a promising target for the therapeutics of EC.

scholarly journals Integrated Bioinformatics Analysis Identifies Heat Shock Factor 2 as a Prognostic Biomarker Associated With Immune Cell Infiltration in Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Yumei Fan ◽  
Jiajie Hou ◽  
Xiaopeng Liu ◽  
Bihui Han ◽  
Yanxiu Meng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Heat Shock ◽  
Immune Cells ◽  
Immune Cell ◽  
Cox Regression ◽  
Critical Role ◽  
Enrichment Analysis ◽  
Normal Liver ◽  
Heat Shock Factor ◽  
Gene Set Enrichment Analysis

Hepatocellular carcinoma (HCC) is one of the most common malignancies and ranks as the second leading cause of cancer-related mortality worldwide. Heat shock factor 2 (HSF2) is a transcription factor that plays a critical role in development, particularly corticogenesis and spermatogenesis. However, studies examining the expression and prognostic value of HSF2 and its association with tumor-infiltrating immune cells in HCC are still rare. In the present study, we found that HSF2 expression was significantly upregulated in HCC tissues compared with normal liver tissues using the TCGA, ICGC, GEO, UALCAN, HCCDB and HPA databases. High HSF2 expression was associated with shorter survival of patients with HCC. Cox regression analyses and nomogram were used to evaluate the association of HSF2 expression with the prognosis of patients with HCC. Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and gene set enrichment analysis (GSEA) revealed that HSF2 was associated with various signaling pathways, including the immune response. Notably, HSF2 expression was significantly correlated with the infiltration levels of different immune cells using the TIMER database and CIBERSORT algorithm. HSF2 expression also displayed a significant correlation with multiple immune marker sets in HCC tissues. Knockdown of HSF2 significantly inhibited the proliferation, migration, invasion and colony formation ability of HCC cells. In summary, we explored the clinical significance of HSF2 and provided a therapeutic basis for the early diagnosis, prognostic judgment, and immunotherapy of HCC.

scholarly journals Construction of a solid Cox model for AML patients based on multiomics bioinformatic analysis

2021 ◽  
Author(s):  
Lei Gao ◽  
Fu Li ◽  
Jiao Cai ◽  
Jia Liu ◽  
Xi Zhang ◽  
...  
Keyword(s):  
Immune Cell ◽  
Cox Regression ◽  
Cox Model ◽  
Expression Profiles ◽  
Bioinformatic Analysis ◽  
The Cancer Genome Atlas ◽  
Clinical Samples ◽  
Immune Gene ◽  
Hub Genes ◽  
Immune Infiltration

Acute myeloid leukemia (AML) is a highly heterogeneous hematological malignancy. The bone marrow (BM) microenvironment in AML plays an important role in leukemogenesis, drug resistance and leukemia relapse. In this study, we aimed to identify reliable immune-related biomarkers for AML prognosis by multiomics analysis. We obtained expression profiles from The Cancer Genome Atlas (TCGA) database and constructed a LASSO-Cox regression model to predict the prognosis of AML using multiomics bioinformatic analysis data. This was followed by independent validation of the model in the GSE106291 (n=251), GSE12417 (n=163) and GSE37642 (n=137) datasets and mutated genes in clinical samples for predicting overall survival (OS). Molecular docking was performed to predict the most optimal ligands to these hub genes. The single-cell RNA sequence dataset GSE116256 was used to clarify the expression of the hub genes in different immune cell types. According to their significant differences in immune gene signatures and survival trends, we concluded that the immune infiltration-lacking subtype (IL type) is associated with better prognosis than the immune infiltration-rich subtype (IR type). Using the LASSO model, we built a classifier based on 5 hub genes to predict the prognosis of AML (risk score = -0.086×ADAMTS3 + 0.180×CD52 + 0.472×CLCN5 - 0.356×HAL + 0.368×ICAM3). In summary, we constructed a prognostic model of AML using integrated multiomics bioinformatic analysis that could serve as a therapeutic classifier.

scholarly journals β2-Adrenergic receptor-dependent chemokine receptor 2 expression regulates leukocyte recruitment to the heart following acute injury

2016 ◽  
Vol 113 (52) ◽  
pp. 15126-15131 ◽  
Author(s):  
Laurel A. Grisanti ◽  
Christopher J. Traynham ◽  
Ashley A. Repas ◽  
Erhe Gao ◽  
Walter J. Koch ◽  
...  
Keyword(s):  
Chemokine Receptor ◽  
Immune Cell ◽  
Critical Role ◽  
Cardiac Injury ◽  
Leukocyte Recruitment ◽  
Acute Injury ◽  
Leukocyte Infiltration ◽  
Activator Protein 1 ◽  
Ccr2 Expression

Following cardiac injury, early immune cell responses are essential for initiating cardiac remodeling and tissue repair. We previously demonstrated the importance of β2-adrenergic receptors (β2ARs) in the regulation of immune cell localization following acute cardiac injury, with deficient leukocyte infiltration into the damaged heart. The purpose of this study was to investigate the mechanism by which immune cell-expressed β2ARs regulate leukocyte recruitment to the heart following acute cardiac injury. Chemokine receptor 2 (CCR2) expression and responsiveness to C-C motif chemokine ligand 2 (CCL2)-mediated migration were abolished in β2AR knockout (KO) bone marrow (BM), both of which were rescued by β2AR reexpression. Chimeric mice lacking immune cell-specific CCR2 expression, as well as wild-type mice administered a CCR2 antagonist, recapitulated the loss of monocyte/macrophage and neutrophil recruitment to the heart following myocardial infarction (MI) observed in mice with immune cell-specific β2AR deletion. Converse to β2AR ablation, β2AR stimulation increased CCR2 expression and migratory responsiveness to CCL2 in BM. Mechanistically, G protein-dependent β2AR signaling was dispensable for these effects, whereas β-arrestin2–biased β2AR signaling was required for the regulation of CCR2 expression. Additionally, activator protein 1 (AP-1) was shown to be essential in mediating CCR2 expression in response to β2AR stimulation in both murine BM and human monocytes. Finally, reconstitution of β2ARKO BM with rescued expression of a β-arrestin–biased β2AR in vivo restored BM CCR2 expression as well as cardiac leukocyte infiltration following MI. These results demonstrate the critical role of β-arrestin2/AP-1–dependent β2AR signaling in the regulation of CCR2 expression and recruitment of leukocytes to the heart following injury.

Large-Scale Transcriptome Analysis Identified Novel Ferroptosis-Related Gene Signatures for Predicting the Prognostic of Patients with Lung Adenocarcinoma

2020 ◽  
Author(s):  
Lei Sun ◽  
Jia Gu ◽  
Wenke Liu ◽  
Zhe Zhang ◽  
Yao Yao ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Risk Score ◽  
Cox Regression ◽  
Risk Group ◽  
Tumor Staging ◽  
Critical Role ◽  
The Cancer Genome Atlas ◽  
Wilcoxon Test ◽  
Glutathione Depletion ◽  
The Impact

Abstract Background: Lung cancer is the most common of all malignant tumors. Traditional tumor staging has general sensitivity and specificity in predicting patient prognosis. Ferroptosis is a novel form of non-apoptotic form of cell death promoted by lipid peroxidation. Ferroptosis may be involved in the malignant progression of tumors through the regulation of glutathione depletion or the P53 signaling pathway. However, there are fewer studies on the impact of ferroptosis on tumor prognosis.Methods: We summarized 22 molecules that regulate ferroptosis. The transcriptome and corresponding clinical data were obtained from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. The Wilcoxon test was utilized to analyze the expression of ferroptosis-related genes. We established risk score signatures, and all patients divided into two groups. Survival curves and multifactorial Cox regression analyses were performed to explore the prognostic value of ferroptosis on lung adenocarcinoma (LUAD).Results: We found that most ferroptosis-related genes are specifically expressed in LUAD tissue. We established a six‑mRNA signature and a seven‑IncRNA signature. All the models showed high predictive performance (AUC: 0.66–0.8), and patients in the low-risk group had higher overall survival than those in the high-risk group (P<0.05). The risk score is an independent risk factor for predicting the prognosis of LUAD.Conclusions: Our study demonstrates the critical role of ferroptosis in LUAD, and it is expected to supply a reference for the prognostic stratification of LUAD.

scholarly journals Deciphering the immunosuppressive tumor microenvironment in ALK- and EGFR-positive lung adenocarcinoma

2021 ◽  
Author(s):  
Jan Budczies ◽  
Martina Kirchner ◽  
Klaus Kluck ◽  
Daniel Kazdal ◽  
Julia Glade ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Expression Profiling ◽  
Immune Cell ◽  
Expression Profiles ◽  
Immune Therapy ◽  
Immune Reactivity ◽  
Immune Gene ◽  
Alk Positive

Abstract Introduction The advent of immune checkpoint blockade (ICB) has led to significantly improved disease outcome in lung adenocarcinoma (ADC), but response of ALK/EGFR-positive tumors to immune therapy is limited. The underlying immune biology is incompletely understood. Methods We performed comparative mRNA expression profiling of 31 ALK-positive, 40 EGFR-positive and 43 ALK/EGFR-negative lung ADC focused on immune gene expression. The presence and levels of tumor infiltration lymphocytes (TILs) as well as fourteen specific immune cell populations were estimated from the gene expression profiles. Results While total TILs were not lower in ALK-positive and EGFR-positive tumors compared to ALK/EGFR-negative tumors, specific immunosuppressive characteristics were detected in both subgroups: In ALK-positive tumors, regulatory T cells were significantly higher compared to EGFR-positive (fold change: FC = 1.9, p = 0.0013) and ALK/EGFR-negative tumors (FC = 2.1, p = 0.00047). In EGFR-positive tumors, cytotoxic cells were significantly lower compared to ALK-positive (FC =  − 1.7, p = 0.016) and to ALK/EGFR-negative tumors (FC =  − 2.1, p = 2.0E-05). A total number of 289 genes, 40 part of cytokine–cytokine receptor signaling, were differentially expressed between the three subgroups. Among the latter, five genes were differently expressed in both ALK-positive and EGFR-positive tumors, while twelve genes showed differential expression solely in ALK-positive tumors and eleven genes solely in EGFR-positive tumors. Conclusion Targeted gene expression profiling is a promising tool to read out tumor microenvironment characteristics from routine diagnostic lung cancer biopsies. Significant immune reactivity including specific immunosuppressive characteristics in ALK- and EGFR-positive lung ADC, but not a total absence of immune infiltration supports further clinical evaluation of immune-modulators as partners of ICB in such tumors.

scholarly journals Identification of an immune gene signature with prognostic value for patients with uterine corpus endometrial carcinoma

2020 ◽  
Author(s):  
Cankun Zhou ◽  
Chaomei Li ◽  
Fangli Yan ◽  
Yuhua Zheng
Keyword(s):  
Regression Analysis ◽  
Endometrial Carcinoma ◽  
Prognostic Value ◽  
Prognostic Model ◽  
Immune Cell ◽  
Cox Regression ◽  
Gene Signature ◽  
Immune Gene ◽  
Cox Regression Analysis ◽  
Immune Genes

Abstract Background: Uterine corpus endometrial carcinoma (UCEC) is a very common gynecological malignancy with a poor prognosis in the late stage. Therefore, the purpose of this study was to determine an immune-related gene signature that predicts the patients’ OS for UCEC. Methods: Based on TCGA, ImmPort, and Cistrome databases, the differential immune genes were screened and the TFs regulatory network was constructed. Functional enrichment and pathway analysis of differential immune genes were carried out. Prognostic value of 410 immune genes was analyzed by Cox regression analysis, a prognostic model was constructed, ROC curves were used to verify the accuracy of the model, and independent prognostic analysis was performed. Finally, the immune cell content was obtained by TIMER, and the correlation with the immune gene expression was evaluated by univariate Cox regression analysis. Results: It was found that the immune cell microenvironment and PI3K-Akt, MARK signaling pathways were involved in the development of UCEC. Based on the established prognostic model, ten-gene prognosis signature (PDIA3, LTA, PSMC4, TNF, SBDS, HDGF, HTR3E, NR3C1, PGR, CBLC) for UCEC prognostic prediction were finally identified, and our study has shown that risk-score can be a powerful prognostic factor for UCEC, independent of other clinical factors. The levels of B cells and neutrophils may be significantly correlated with the patient's risk score. Conclusions: Our studies showed that the ten-gene prognosis signature had important clinical value for the prognosis of UCEC, which was helpful for individualized treatment and provided a new target for tumor immunotherapy.

scholarly journals Immune-Related Gene SERPINE1 Is a Novel Biomarker for Diffuse Lower-Grade Gliomas via Large-Scale Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaoming Huang ◽  
Fenglin Zhang ◽  
Dong He ◽  
Xiaoshuai Ji ◽  
Jiajia Gao ◽  
...  
Keyword(s):  
Regression Analysis ◽  
Immune Cell ◽  
Cox Regression ◽  
Expression Patterns ◽  
Critical Role ◽  
Lower Grade ◽  
Hub Genes ◽  
Who Grade ◽  
Primary Tumors ◽  
Cox Regression Analysis

BackgroundGlioma is one of the highly fatal primary tumors in the central nervous system. As a major component of tumor microenvironment (TME), immune cell has been proved to play a critical role in the progression and prognosis of the diffuse lower-grade gliomas (LGGs). This study aims to screen the key immune-related factors of LGGs by investigating the TCGA database.MethodsThe RNA-sequencing data of 508 LGG patients were downloaded in the TCGA database. ESTIMATE algorithm was utilized to calculate the stromal, immune, and ESTIMATE scores, based on which, the differentially expressed genes (DEGs) were analyzed by using “limma” package. Cox regression analysis and the cytoHubba plugin of Cytoscape software were subsequently applied to screen the survival-related genes and hub genes, the intersection of which led to the identification of SERPINE1 that played key roles in the LGGs. The expression patterns, clinical features, and regulatory mechanisms of SERPINE1 in the LGGs were further analyzed by data mining of the TCGA database. What’s more, the above analyses of SERPINE1 were further validated in the LGG cohort from the CGGA database.ResultWe found that stromal and immune cell infiltrations were strongly related to the prognosis and malignancy of the LGGs. A total of 54 survival-related genes and 46 hub genes were screened out in the DEGs, within which SERPINE1 was identified to be significantly overexpressed in the LGG samples compared with the normal tissues. Moreover, the upregulation of SERPINE1 was more pronounced in the gliomas of WHO grade III and IDH wild type, and its expression was correlated with poor prognosis in the LGG patients. The independent prognostic value of SERPINE1 in the LGG patients was also confirmed by Cox regression analysis. In terms of the functions of SERPINE1, the results of enrichment analysis indicated that SERPINE1 was mainly enriched in the immune‐related biological processes and signaling pathways. Furthermore, it was closely associated with infiltrations of immune cells in the LGG microenvironment and acted synergistically with PD1, PD-L1, PD-L2.ConclusionThese findings proved that SERPINE1 could serve as a prognostic biomarker and potential immunotherapy target of LGGs.

scholarly journals Identification and validation of cellular senescence patterns to predict clinical outcomes and immunotherapeutic responses in lung adenocarcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Weihao Lin ◽  
Xin Wang ◽  
Zhenyi Xu ◽  
Zhen Wang ◽  
Tiejun Liu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Clinical Outcomes ◽  
Cellular Senescence ◽  
Scoring System ◽  
Immune Cell ◽  
Cox Regression ◽  
Expression Profiles ◽  
Intratumor Heterogeneity ◽  
Cancer Treatments ◽  
Cox Regression Analysis

Abstract Background Aging and senescence can alter immune cell fitness and influence the efficacy of lung cancer treatments, especially immunotherapy. However, the correlations between cellular senescence and tumor microenvironment are still not clearly clarified and the value of cellular senescence-related genes in evaluating the immune infiltration and clinical outcomes of lung adenocarcinoma (LUAD) need further investigated. Methods We identified three cellular senescence clusters by NMF algorithm and correlated the cellular senescence clusters with the immune landscape in LUAD patients. A prognostic scoring system was established using random survival forest algorithm and validated in 4 external cohorts. Multivariate Cox regression analysis was performed to evaluate the prognostic value of the scoring system. Expression of LYPD3 was evaluated by immunohistochemistry in LUAD samples. Results Based on the mRNA expression profiles of 278 cellular senescence-related genes, three cellular senescence clusters with distinct prognosis were identified. We characterized three cellular senescence clusters by differences in biological processes, EMT score, expression of immunomodulatory genes, extent of intratumor heterogeneity and response to immunotherapy. Meanwhile, a cellular senescence-related scoring system (CSS) was established and validated as an independent prognostic factor and immunotherapy predictor of LUAD. Patients with low CSS was characterized by prolonged survival time. In response to anti-cancer drugs, patients with low CSS exhibited higher sensitivities to molecular drugs, such as Roscovitine (CDKs inhibitor), Lenaidornide (TNF-α inhibitor), MK2206 (Akt 1/2/3 inhibitor), and especially increased response to anti-PD-1/L1 immunotherapy. Conclusions This study demonstrated the correlations between cellular senescence patterns and tumor immune landscape in LUAD, which enhanced our understanding of the tumor immune microenvironment and provided new insights for improving the outcome of immunotherapy for LUAD patients.

scholarly journals PAFAH1B3 Predicts Poor Prognosis and Promotes Progression in Lung Adenocarcinoma

2021 ◽  
Author(s):  
Suping Tang ◽  
Jun Ni ◽  
Bohua Chen ◽  
Fei Sun ◽  
Songshi Ni ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Risk Factor ◽  
Western Blot ◽  
Lung Adenocarcinoma ◽  
Tissue Microarray ◽  
Immune Cell ◽  
Cox Regression ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Cox Regression Analysis

Abstract Background Recently, increasing evidence has indicated that platelet-activating factor acetylhydrolase 1b catalytic subunit 3 (PAFAH1B3) plays an important role in several cancers. However, the role in lung adenocarcinoma (LUAD) has not been reported until now. Methods Expression of PAFAH1B3 in LUAD was determined by Gene Expression Profiling Interactive Analysis (GEPIA), real-time PCR (RT-PCR), Western blot and Immunohistochemical (IHC) analysis. LUAD datasets with clinical information were obtained from The Cancer Genome Atlas Program (TCGA). Chi-square test was used to investigate the correlation between PAFAH1B3 expression and clinical parameters. Cox regression and Kaplan-Meier analysis were performed to analyzed the prognostic value of PAFAH1B3. CCK-8 assay, clone formation assay, transwell invasion assay and flow cytometry were conducted to detect cell proliferation, clone formation, invasion and cell cycle. Western blot was performed to detect epithelial-to-mesenchymal transition (EMT)-related markers. Immune Cell Abundance Identifier (ImmuneCellAI) was used to analyze the effect of PAFAH1B3 on immune cell infiltration. Results Our study showed that PAFAH1B3 was upregulated in LUAD, and silencing PAFAH1B3 suppressed cell proliferation, colony formation, invasion and increased the cell population in G0-G1 phases in vitro. In addition, tissue microarray IHC analysis showed that the PAFAH1B3 protein level was remarkably correlated with distant metastasis, TNM stage and clinical outcome. Furthermore, multivariate cox regression analysis based on TCGA-LUAD datasets and tissue microarray indicated that PAFAH1B3 was an independent prognostic risk factor for LUAD patients. Moreover, knockdown of PAFAH1B3 inhibited EMT in LUAD cells and PAFAH1B3 mRNA expression was correlated with immune infiltrates. Conclusion Our studies indicate that PAFAH1B3, a prognostic risk factor, promotes proliferation, invasion and EMT and affects immune infiltrates in LUAD.

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