Infiltration of Immunoinflammatory Cells and Related Chemokine/Interleukin Expression in Different Gastric Immune Microenvironments

Gastric mucosal immune microenvironment plays an important role in the occurrence and development of diseases such as inflammation and cancer. In the present study, single-sample gene set enrichment analysis (ssGSEA) was used to evaluate the expression of cytokines and the degree of immune cell infiltration in four different gastric mucosa tissues from normal gastric mucosa, simple gastritis, and atrophic gastritis to gastric cancer. Here, we show the immune microenvironments of these four gastric mucosae were significantly different. From inflammation to gastric cancer, most immunoinflammatory cells showed a downward trend such as central memory CD4 T cell. Instead, several cells showed an upward trend such as macrophage. Additionally, we found some chemokines/interleukins were illustrated to be low expressed (or highly expressed) in precancerous stage and highly expressed (or low expressed) in postcancerous stage, which demonstrated an opposite expression characteristic in pre-/postcancerous stage.

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

Scientific Reports ◽

10.1038/s41598-021-90330-3 ◽

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.

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Increased IGFBP7 Expression Correlates with Poor Prognosis and Immune Infiltration in Gastric Cancer: An Integrated Bioinformatics Analysis

10.21203/rs.3.rs-33369/v1 ◽

2020 ◽

Author(s):

Qiaoyun Zhao ◽

Rulin Zhao ◽

Conghua Song ◽

Huan Wang ◽

Jianfang Rong ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Poor Prognosis ◽

Bioinformatics Analysis ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Biological Processes ◽

Coexpressed Genes

Abstract Background Insulin-like growth factor binding protein-7 (IGFBP7) contributes to multiple biological processes in various tumors. However, the role of IGFBP7 in gastric cancer (GC) is still undetermined. The study aims to explore the role of IGFBP7 in GC via an integrated bioinformatics analysis.Methods IGFBP7 expression levels in GC and its normal gastric tissues were analyzed using multiple databases, including the Tumor Immune Estimation Resource (TIMER), Oncomine, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The methylation analysis was conducted with MEXPRESS, UALCAN and Xena online tools. The survival analysis was conducted using the Kaplan-Meier Plotter and Gene Expression Profiling Interactive Analysis (GEPIA) databases. Coexpressed genes of IGFBP7 were selected with the cBioPortal tool and enrichment analysis was conducted with the clusterProfiler package in R software. Gene set enrichment analysis (GSEA) was performed to explore the IGFBP7-related biological processes involved in GC. Correlations between IGFBP7 and immune cell infiltrates were analyzed using the TIMER database.Results IGFBP7 expression was significantly upregulated in GC and correlated with stage, grade, tumor status and Helicobacter pylori infection. High IGFBP7 expression and low IGFBP7 methylation levels were significantly associated with short survival of patients with GC. Univariate and multivariate analyses revealed that IGFBP7 was an independent risk factor for GC. The coexpressed genes LHFPL6, SEPTIN4, HSPB2, LAYN and GGT5 predicted unfavorable outcomes of GC. Enrichment analysis showed that the coexpressed genes were involved in extracellular matrix (ECM)-related processes. GSEA indicated that IGFBP7 was positively related to ECM and inflammation-related pathways. TIMER analysis indicated that the IGFBP7 expression level was strongly correlated with genes related to various infiltrating immune cells in GC, especially with gene markers of tumor associated macrophages (TAMs).Conclusions We demonstrate that increased IGFBP7 expression correlates with poor prognosis and immune cell infiltration in GC. IGFBP7 might be a potential biomarker for the diagnosis and targeted therapy for GC.

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PVT1 is a prognostic marker associated with immune invasion of bladder urothelial carcinoma

Mathematical Biosciences and Engineering ◽

10.3934/mbe.2022009 ◽

2021 ◽

Vol 19 (1) ◽

pp. 169-190

Author(s):

Peiyuan Li ◽

◽

Gangjie Qiao ◽

Jian Lu ◽

Wenbin Ji ◽

...

Keyword(s):

Urothelial Carcinoma ◽

Immune Cell ◽

Cox Regression ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Gene Set Enrichment ◽

Cox Regression Analysis ◽

Gene Set ◽

Bladder Urothelial Carcinoma

<abstract> <p>Plasmacytoma variant translocation 1 (PVT1) is involved in multiple signaling pathways and plays an important regulatory role in a variety of malignant tumors. However, its role in the prognosis and immune invasion of bladder urothelial carcinoma (BLCA) remains unclear. This study investigated the expression of PVT1 in tumor tissue and its relationship with immune invasion, and determined its prognostic role in patients with BLCA. Patients were identified from the cancer genome atlas (TCGA). The enrichment pathway and function of PVT1 were explained by gene ontology (GO) term analysis, gene set enrichment analysis (GSEA) and single-sample gene set enrichment analysis (ssGSEA), and the degree of immune cell infiltration was quantified. Kaplan–Meier analysis and Cox regression were used to analyze the correlation between PVT1 and survival rate. PVT1-high BLCA patients had a lower 10-year disease-specific survival (DSS P < 0.05) and overall survival (OS P < 0.05). Multivariate Cox regression analysis showed that PVT1 (high vs. low) (P = 0.004) was an independent prognostic factor. A nomogram was used to predict the effect of PVT1 on the prognosis. PVT1 plays an important role in the progression and prognosis of BLCA and can be used as a medium biomarker to predict survival after cystectomy.</p> </abstract>

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RNA N6-Methyladenosine Regulator-Mediated Methylation Modifications Pattern and Immune Infiltration Features in Glioblastoma

Frontiers in Oncology ◽

10.3389/fonc.2021.632934 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yimin Pan ◽

Kai Xiao ◽

Yue Li ◽

Yuzhe Li ◽

Qing Liu

Keyword(s):

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Lasso Regression ◽

Gene Set Enrichment ◽

Clinical Prognosis ◽

Prognostic Assessment ◽

The Relationship

Glioblastoma (GBM) is a group of intracranial neoplasms with intra-tumoral heterogeneity. RNA N6-methyladenosine (m6A) methylation modification reportedly plays roles in immune response. The relationship between the m6A modification pattern and immune cell infiltration in GBM remains unknown. Utilizing expression data of GBM patients, we thoroughly explored the potential m6A modification pattern and m6A-related signatures based on 21 regulators. Thereafter, the m6A methylation modification-based prognostic assessment pipeline (MPAP) was constructed to quantitatively assess GBM patients’ clinical prognosis combining the Robustness and LASSO regression. Single-sample gene-set enrichment analysis (ssGSEA) was used to estimate the specific immune cell infiltration level. We identified two diverse clusters with diverse m6A modification characteristics. Based on differentially expressed genes (DEGs) within two clusters, m6A-related signatures were identified to establish the MPAP, which can be used to quantitatively forecast the prognosis of GBM patients. In addition, the relationship between 21 m6A regulators and specific immune cell infiltration was demonstrated in our study and the m6A regulator ELAVL1 was determined to play an important role in the anticancer response to PD-L1 therapy. Our findings indicated the relationship between m6A methylation modification patterns and tumor microenvironment immune cell infiltration, through which we could comprehensively understand resistance to multiple therapies in GBM, as well as accomplish precise risk stratification according to m6A-related signatures.

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m6A-Mediated Tumor Invasion and Methylation Modification in Breast Cancer Microenvironment

Journal of Oncology ◽

10.1155/2021/9987376 ◽

2021 ◽

Vol 2021 ◽

pp. 1-17

Author(s):

Fei Liu ◽

Xiaopeng Yu ◽

Guijin He

Keyword(s):

Breast Cancer ◽

Tumor Microenvironment ◽

Immune Cell ◽

Principal Component ◽

Enrichment Analysis ◽

Genomic Variation ◽

Gene Set Enrichment Analysis ◽

Single Sample ◽

Gene Set Enrichment ◽

Gene Set

Background. We analyzed the n6-methyladenosine (m6A) modification patterns of immune cells infiltrating the tumor microenvironment of breast cancer (BC) to provide a new perspective for the early diagnosis and treatment of BC. Methods. Based on 23 m6A regulatory factors, we identified m6A-related gene characteristics and m6A modification patterns in BC through unsupervised cluster analysis. To examine the differences in biological processes among various m6A modification modes, we performed genomic variation analysis. We then quantified the relative infiltration levels of different immune cell subpopulations in the tumor microenvironment of BC using the CIBERSORT algorithm and single-sample gene set enrichment analysis. Univariate Cox analysis was used to screen for m6A characteristic genes related to prognosis. Finally, we evaluated the m6A modification pattern of patients with a single BC by constructing the m6Ascore based on principal component analysis. Results. We identified three different m6A modification patterns in 2128 BC samples. A higher abundance of the immune infiltration of the m6Acluster C was indicated by the results of CIBERSORT and the single-sample gene set enrichment analysis. Based on the m6A characteristic genes obtained through screening, the m6Ascore was determined. The BC patients were segregated into m6Ascore groups of low and high categories, which revealed significant survival benefits among patients with low m6Ascores. Additionally, the high-m6Ascore group had a higher mutation frequency and was associated with low PD-L1 expression, and the m6Ascore and tumor mutation burden showed a positive correlation. In addition, treatment effects were better in patients in the high-m6Ascore group. Conclusions. In case of a single patient with BC, the immune cell infiltration characteristics of the tumor microenvironment and the m6A methylation modification pattern could be evaluated using the m6Ascore. Our results provide a foundation for improving personalized immunotherapy of BC.

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Immune Infiltration Landscape in Lung Squamous Cell Carcinoma Implications

BioMed Research International ◽

10.1155/2020/5981870 ◽

2020 ◽

Vol 2020 ◽

pp. 1-21

Author(s):

Jungang Zhao ◽

Wenming Bao ◽

Weiyang Cai

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Clustering Analysis ◽

Immune Cell ◽

Lung Squamous Cell Carcinoma ◽

Principal Component ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Immune Microenvironment

Intrinsic cancer cells and the tumor-infiltrating immune cells (TIICs) recruited to the immune microenvironment define the malignant phenotype of lung squamous cell carcinoma (LUSC). Understanding more about the immune microenvironment of LUSC enables the selection of high-risk patients who would derive benefit from immunotherapy. Based on large public LUSC cohorts obtained from TCGA and GEO datasets, 22 types of infiltrating immune cell subgroups were evaluated by CIBERSORT. Meta-analysis, principal component analysis (PCA), single-sample gene set enrichment analysis (ssGSEA), and hierarchical clustering analysis were used to evaluate specific immune responses of LUSC. The distribution of TIICs of LUSC was entirely different from normal. TIIC subpopulations were also found to be closely associated with clinical features and molecular subtypes. Unsupervised clustering analysis revealed that three distinct TIIC subgroups existed with different survival patterns. TIICs are extensively implicated in the pathogenesis and development of LUSC. Characterizing the composition of TIICs influences the metabolism, pathological stage, and survival of tumor patients. It is hoped that this immune landscape could provide a more accurate understanding of the development and immunotherapy of LUSC.

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Immune cell confrontation in the papillary thyroid carcinoma microenvironment

10.21203/rs.3.rs-33230/v1 ◽

2020 ◽

Author(s):

Zhenyu Xie ◽

Xin Li ◽

Yuzhen He ◽

Song Wu ◽

Shiyue Wang ◽

...

Keyword(s):

T Cells ◽

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Immune Cell Infiltration ◽

M2 Macrophages ◽

Papillary Thyroid ◽

Gene Set Enrichment

Abstract Background Papillary thyroid carcinoma (PTC) is classified as an inflammation-driven cancer. A systematic understanding of immune cell infiltration in PTC is essential for subsequent immune research and new diagnostic and therapeutic strategies. Methods Three different algorithms, single-sample gene set enrichment analysis (ssGSEA), immune cell marker and CIBERSORT, were used to evaluate the immune cell infiltration levels (abundance and proportion) in 10 data sets (The Cancer Genome Atlas [TCGA], GSE3467, GSE3678, GSE5364, GSE27155, GSE33630, GSE50901, GSE53157, GSE58545, and GSE60542; a total of 799 PTC and 194 normal thyroid samples). Consensus unsupervised clustering divided PTC patients into low-immunity and high-immunity groups. Weighted gene coexpression network analysis (WGCNA) and gene set enrichment analysis (GSEA) were used to analyze the potential mechanisms that cause differences in the immune response. Results Compared with normal tissues, PTC tissues had a higher overall immune level, and the M2 macrophages, Tregs, monocytes, neutrophils, dendritic cells (DCs), mast cells (MCs), and M0 macrophages had higher abundances and proportions in PTC tissues. Compared with early PTC, advanced PTC had higher immune infiltration, and M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages had higher abundances and proportions in advanced PTC. Compared to the low-immunity group patients, the high-immunity group patients presented with a more advanced stage, a larger tumor size, greater lymph node metastasis, higher tall-cell PTC, lower follicular PTC proportions, more BRAF mutations and fewer RAS mutations. Epstein-Barr virus (EBV) infection was the most significantly enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway for key module genes. Conclusions In human PTC, M2 macrophages, Tregs, monocytes, neutrophils, DCs, MCs, and M0 macrophages played a tumor-promoting role, while M1 macrophages, CD8 + T cells, B cells, NK cells, and T follicular helper (TFH) cells (including eosinophils, γδ T cells, and Th17 cells, with weak supporting evidence) played an antitumor role. During the occurrence and development of PTC, the overall immune level was increased, and the abundance and proportion of tumor-promoting immune cells were significantly increased, indicating that immune escape had aggravated. Finally, we speculate that EBV may play an important role in changing the immune microenvironment of PTC tumors.

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Hepcidin Upregulation in Lung Cancer: A Potential Therapeutic Target Associated With Immune Infiltration

Frontiers in Immunology ◽

10.3389/fimmu.2021.612144 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yumei Fan ◽

Bing Liu ◽

Fei Chen ◽

Zhiyuan Song ◽

Bihui Han ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Prognostic Value ◽

Immune Cell ◽

Enrichment Analysis ◽

Gene Set Enrichment Analysis ◽

Gene Set Enrichment ◽

Hepcidin Expression ◽

Lung Cancer Patients ◽

Immune Infiltration

Lung cancer has the highest death rate among cancers globally. Hepcidin is a fascinating regulator of iron metabolism; however, the prognostic value of hepcidin and its correlation with immune cell infiltration in lung cancer remain unclear. Here, we comprehensively clarified the prognostic value and potential function of hepcidin in lung cancer. Hepcidin expression was significantly increased in lung cancer. High hepcidin expression was associated with sex, age, metastasis, and pathological stage and significantly predicted an unfavorable prognosis in lung cancer patients. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) results suggested that hepcidin is involved in the immune response. Furthermore, hepcidin expression was positively correlated with the infiltration levels of immune cells and the expression of diverse immune cell marker sets. Importantly, hepcidin may affect prognosis partially by regulating immune infiltration in lung cancer patients. Hepcidin may serve as a candidate prognostic biomarker for determining prognosis associated with immune infiltration in lung cancer.

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Identification of Novel Alternative Splicing Events Associated with Tumorigenesis, Protein Modification, and Immune Microenvironment in Early-Onset Gastric Cancer

10.21203/rs.3.rs-76246/v1 ◽

2020 ◽

Author(s):

Jian Zhang ◽

Ajay Goel ◽

Lin Zhu

Keyword(s):

Gastric Cancer ◽

Alternative Splicing ◽

Early Onset ◽

Protein Modification ◽

Immune Cell ◽

Alternative Polyadenylation ◽

Enrichment Analysis ◽

Functional Enrichment ◽

Immune Microenvironment ◽

Gene Isoforms

Abstract Background: Alternative splicing (AS), e.g. tandem alternative polyadenylation (TAPA), has emerged as major post-transcriptional modification events in human disease. However, the roles of AS and TAPA in early-onset gastric cancer (EOGC) have not been revealed.Methods: The global AS profiles of 80 EOGC patients were analyzed. The EOGC-specific AS events (ESASs) were identified in both EOGC and adjacent non-tumor tissues. Functional enrichment analysis, Splicing network, Alternative Polyadenylation (APA) core factor network, and cell abundancy analysis were performed. Furthermore, the landscapes of AS events in the varied subtypes of EOGC patients were evaluated. Results: Overall, 66,075 AS events and 267 ESASs were identified in EOGC. Furthermore, 4809 genes and 6152 gene isoforms were found to be aberrantly expressed in EOGC. The Gene Ontology (GO) and Kyoto Encyclopedia of Gene and Genome (KEGG) pathway analyses showed that significant pathway alterations might exist in these AS events, genes, and gene isoforms. Moreover, the Protein-protein interaction (PPI) network analysis revealed that UBC, NEK2, EPHB2, and DCTN1 genes were the hub genes in the AS events in EOGC. The immune cell infiltration analysis indicated a correlation between the AS events and the cancer immune microenvironment. The distribution of AS events in varied EOGC subtypes, protein phosphorylation and glycosylation was uneven. Conclusion: The study highlighted the vital roles of AS in EOGC, including modulating the specific protein modification and reshaping the cancer immune microenvironment, and yielded new insights into the diagnosis of EOGC as well as cancer treatment.

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Mining the TCGA Database for Microenvironment‐Related Genes with Prognostic Value in Gastric Cancer

10.21203/rs.3.rs-175261/v1 ◽

2021 ◽

Author(s):

Ting Liu ◽

Zheng Gong ◽

Hong Zhang ◽

Yi Wan ◽

Ming-Han Ren ◽

...

Keyword(s):

Gastric Cancer ◽

Distant Metastasis ◽

Clinical Stage ◽

Enrichment Analysis ◽

Clinicopathological Characteristics ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Gene Set Enrichment ◽

Gene Set ◽

Protein Protein Interaction

Abstract BackgroundGastric cancer (GC) is the fifth most common cancer worldwide. Previous studies have suggested that the tumor microenvironment (TME) plays an important role in the development and prognosis of GC. In this study, we aimed to identify genes in tumor-infiltrating immune cells (TICs) that influence the progression and prognosis of GC. MethodsWe used the ESTIMATE algorithm to calculate the scores of the stromal and immune components of the TME in 407 GC samples collected from The Cancer Genome Atlas (TCGA) database.The differentially expressed genes (DEGs) were intersected by a protein-protein interaction (PPI) network and analyzed by univariate Cox regression.Further analysis showed the correlation between MCEMP1 and the clinicopathological characteristics of GC patients (clinical stage, distant metastasis) and survival.Then we used Gene set enrichment analysis (GSEA) and CIBERSORT analysis to examine the relationship between MCEMP1 and the TME.ResultsThe analysis revealed that the expression of MCEMP1 was positively correlated with the clinicopathological characteristics of GC patients (clinical stage, distant metastasis) and negatively correlated with survival. Gene set enrichment analysis (GSEA) indicated that gene sets in the MCEMP1 high expression group were concentrated mainly in immune-related pathways. CIBERSORT analysis of the proportion of TICs revealed that neutrophils and M2 macrophages were positively correlated with MCEMP1 expression, suggesting that MCEMP1 is responsible for preservation of the immune-dominant status of the TME. ConclusionHigh MCEMP1 expression might be a biomarker of a poor prognosis in GC patients and provide a clue regarding the different statuses of the TME, offering additional insight into therapy for GC.

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