scholarly journals CXCL12 and CD3E as Indicators for Tumor Microenvironment Modulation in Bladder Cancer and Their Correlations With Immune Infiltration and Molecular Subtypes

2021 ◽  
Vol 11 ◽  
Author(s):  
Yi Liu ◽  
YuCai Wu ◽  
PeiPei Zhang ◽  
ChaoJie Xu ◽  
ZeSen Liu ◽  
...  

Bladder cancer (BLCA) represents the ninth most common malignant tumor in the world and is characterized by high recurrence risk. Tumor microenvironment (TME) plays an important role in regulating the progression of BLCA. Immunotherapy, including Bacillus Calmette-Guerin (BCG) and programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1), is closely associated with TME and is widely used for treating BLCA. But parts of BLCA patients have no response to these treatment ways, thus a better understanding of the complex TME of BLCA is still needed. We downloaded the gene expression profile and corresponding clinical information of 414 BLCA patients from the TCGA database. Via the ESTIMATE and CIBERSORT algorithm, we identified the two hub genes (CXCL12 and CD3E) and explored their correlations with immune infiltration. We found that BLCA patients with higher expression of CXCL12 and lower expression of CD3E had prolonged survival. Gene set enrichment analysis (GSEA) revealed that both CXCL12 and CD3E were enriched in immune-related pathways. We also discovered that stromal score and the level of CXCL12 were higher in luminal subtype, and immune score and the level of CD3E were higher in the basal subtype. Furtherly, we found that CXCL12 was associated with naive B cells, resting mast cell, M2 macrophages, follicular helper T cells, and dendritic cells. CD8+ T cells, CD4+ T cells, regulatory T cells (Tregs), and macrophages were correlated with CD3E. In conclusions, we found that CXCL12 and CD3E might serve as indicators of TME modulation in BLCA. Therapy targeting CXCL12 and CD3E had the potential as novel therapeutic strategy.

2020 ◽  
Author(s):  
Peipei Gao ◽  
Ting Peng ◽  
Canhui Cao ◽  
Shitong Lin ◽  
Ping Wu ◽  
...  

Abstract Background: Claudin family is a group of membrane proteins related to tight junction. There are many studies about them in cancer, but few studies pay attention to the relationship between them and the tumor microenvironment. In our research, we mainly focused on the genes related to the prognosis of ovarian cancer, and explored the relationship between them and the tumor microenvironment of ovarian cancer.Methods: The cBioProtal provided the genetic variation pattern of claudin gene family in ovarian cancer. The ONCOMINE database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to exploring the mRNA expression of claudins in cancers. The prognostic potential of these genes was examined via Kaplan-Meier plotter. Immunologic signatures were enriched by gene set enrichment analysis (GSEA). The correlations between claudins and the tumor microenvironment of ovarian cancer were investigated via Tumor Immune Estimation Resource (TIMER).Results: In our research, claudin genes were altered in 363 (62%) of queried patients/samples. Abnormal expression levels of claudins were observed in various cancers. Among them, we found that CLDN3, CLDN4, CLDN6, CLDN10, CLDN15 and CLDN16 were significantly correlated with overall survival of patients with ovarian cancer. GSEA revealed that CLDN6 and CLDN10 were significantly enriched in immunologic signatures about B cell, CD4 T cell and CD8 T cell. What makes more sense is that CLDN6 and CLDN10 were found related to the tumor microenvironment. CLDN6 expression was negatively correlated with immune infiltration level in ovarian cancer, and CLDN10 expression was positively correlated with immune infiltration level in ovarian cancer. Further study revealed the CLDN6 expression level was negatively correlated with gene markers of various immune cells in ovarian cancer. And, the expression of CLDN10 was positive correlated with gene markers of immune cells in ovarian cancer.Conclusions: CLDN6 and CLDN10 were prognostic biomarkers, and correlated with immune infiltration in ovarian cancer. Our results revealed new roles for CLDN6 and CLDN10, and they were potential therapeutic targets in the treatment of ovarian cancer.


2021 ◽  
Author(s):  
Sheng Fang ◽  
Xiao Fang ◽  
Xin Xu ◽  
Lin Zhong ◽  
An-quan Wang ◽  
...  

Abstract Relevance Rheumatoid arthritis (RA) is a systemic autoimmune disease with an aggressive, chronic synovial inflammation as the main pathological change. However, the specific etiology, pathogenesis, and related biomarkers in diagnosis and treatment are still not fully elucidated. This study attempts to provide new perspectives and insights into RA at the genetic, molecular, and cellular levels through the tenet of personalized medicine. Methods Gene expression profiles of four individual knee synovial tissues were downloaded from a comprehensive gene expression database, R language was used to screen for significantly differentially expressed genes (DEGs), Gene Ontology Enrichment Analysis, Kyoto Gene Encyclopedia, and Gene Set Enrichment Analysis were performed to analyze the biological functions and signaling pathways of these DEGs, STRING online database was used to establish protein-protein interaction networks, Cytoscape software to obtain ten hub genes, Goplot to get six inflammatory immune-related hub genes, and CIBERSORT algorithm to impute immune infiltration. Results Molecular pathways that play important roles in RA were obtained: Toll-like receptors, AMPK, MAPK, TNF, FoxO, TGF-beta, PI3K and NF-κB pathways, Ten hub genes: Ccr1, Ccr2, Ccr5, Ccr7, Cxcl5, Cxcl6, Cxcl13, Ccl13, Adcy2, and Pnoc. among which Adcy2 and Pnoc have not been reported in RA studies, suggesting that they may be worthy targets for further study. It was also found that among the synoviocytes in RA, the proportions of plasma cells, CD8 T cells, follicular helper T cells, monocytes, γ delta T cells, and M0 macrophages were higher, while the proportions of CD4 memory resting T cells, regulatory T cells (Tregs), activated NK cells, resting dendritic cells, M1 macrophages, eosinophils, activated mast cells, resting mast cells were lower in proportion, and each cell played an important role in RA. Conclusions This study may help understand the key genes, molecular pathways, the role of inflammatory immune infiltrating cells in RA’s pathogenesis and provide new targets and ideas for the diagnosis and personalized treatment of RA.


2020 ◽  
Vol 10 ◽  
Author(s):  
Wen-Xiu Xu ◽  
Jian Zhang ◽  
Yu-Ting Hua ◽  
Su-Jin Yang ◽  
Dan-Dan Wang ◽  
...  

BackgroundLipocalin 2 (LCN2), an innate immune protein, plays a pivotal role in promoting sterile inflammation by regulating immune responses. However, the role of LCN2 in diverse cancers remains poorly defined. This research aimed to investigate the correlation between LCN2 expression and immunity and visualize its prognostic landscape in pan-cancer.MethodsRaw data in regard to LCN2 expression in cancer patients were acquired from TCGA and GTEx databases. Besides, we investigated the genomic alterations, expression pattern, and survival analysis of LCN2 in pan-cancer across numerous databases, including cBioPortal and GEPIA database. The correlation between LCN2 expression and tumor immune infiltration was explored via TIMER, and we utilized CIBERSORT and ESTIMATE computational methods to assess the proportion of tumor-infiltrating immune cells (TIICs) and the amount of stromal and immune components from TCGA database. Protein–Protein Interaction analysis was performed in GeneMANIA database, and gene functional enrichment was performed by Gene Set Enrichment Analysis (GSEA).ResultsOn balance, tumor tissue had a higher LCN2 expression level compared with that in normal tissue. Elevated expression of LCN2 was related to poor clinical regimen with OS and RFS. There were significant positive correlations between LCN2 expression and TIICs, including CD8+ T cells, CD4+ T cells, B cells, neutrophils, macrophages, and dendritic cells. Moreover, markers of TIICs exhibited different LCN2-related immune infiltration patterns. GSEA analysis showed that the expression of LCN2 was related to retinol metabolism, drug metabolism cytochrome P450 and metabolism of xenobiotics by cytochrome P450.ConclusionsThese findings suggested that LCN2 might serve as a biomarker for immune infiltration and poor prognosis in cancers, shedding new light on therapeutics of cancers.


Author(s):  
Cong Luo ◽  
Zhixiong Liu ◽  
Wenrui Ye ◽  
Fangkun Liu

Background: Tumor microenvironment, especially infiltrating immune cell, is crucial for solid tumors including glioma. However, the hub genes as well as their effects on patient prognosis and immunotherapy efficacy remain obscure.Methods: We employed a total of 952 lower grade glioma (LGG) patients from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases, and 24 samples in our hospital for subsequent analyses. Abundances of immune infiltrates were evaluated using CIBERSORT and ImmuCellAI. Their correlations with prognosis were assessed by log-rank test. Immune infiltration-related hub genes were obtained from overlapped differential expressed genes (DEGs) in various subsets of survival-related immune cell types. The risk signature was constructed by Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis. The functional analyses were estimated by GVSA and Gene Set Enrichment Analysis (GSEA) algorithms. And protein–protein interaction enrichment analysis was carried out with the Metascape database integrating STRING, BioGrid, OmniPath, and InWeb_IM.Results: Among the 21 infiltrates, the abundances of five immune infiltrates were correlated with overall survival (OS) in LGG patients. Higher abundances of naïve CD4+ T cells (p = 0.002), activated mast cells (p = 0.015), and monocytes (p = 0.014) were correlated with better prognosis, while higher abundances of resting memory CD4+ T cells (p = 0.015) and M1 macrophages (p = 0.020) correlated with poorer OS. We finally obtained 44 hub genes and constructed an immune infiltration-related signature (IIRS). The IIRS correlates with clinicopathological characteristics and exhibited potential power in predicting the immunotherapy efficacy. The IRRS correlates with cancer related pathways, especially “epithelial-mesenchymal transition (EMT),” and cytotoxic T lymphocytes.Conclusion: Our study constructed and validated a novel signature for risk stratification and prediction of immunotherapy response in grade II and III gliomas, which was closely associated with glioma immune microenvironment and could serve as a promising prognostic biomarker for glioma patients.


Author(s):  
Mengjia Huang ◽  
Lin Liu ◽  
Junkai Zhu ◽  
Tong Jin ◽  
Yi Chen ◽  
...  

Tumors are closely related to the tumor microenvironment (TME). The complex interaction between tumor cells and the TME plays an indisputable role in tumor development. Tumor cells can affect the TME, promote tumor angiogenesis and induce immune tolerance by releasing cell signaling molecules. Immune cell infiltration (ICI) in the TME can affect the prognosis of patients with bladder cancer. However, the pattern of ICI of the TME in bladder cancer has not yet been elucidated. Herein, we identified three distinct ICI subtypes based on the TME immune infiltration pattern of 584 bladder cancer patients using the ESTIMATE and CIBERSORT algorithms. Then, we identified three gene clusters based on the differentially expressed genes (DEGs) between the three ICI subtypes. In addition, the ICI score was determined using single sample gene set enrichment analysis (ssGSEA). The results suggested that patients in the high ICI score subgroup had a favorable prognosis and higher expression of checkpoint-related and immune activity-related genes. The high ICI score subgroup was also linked to increased tumor mutation burden (TMB) and neoantigen burden. A cohort treated with anti-PD-L1 immunotherapy confirmed the therapeutic advantage and clinical benefit of patients with higher ICI scores. In the end, our study also shows that the ICI score represents an effective prognostic predictor for evaluating the response to immunotherapy. In conclusion, our study deepened the understanding of the TME, and it provides new ideas for improving patients’ response to immunotherapy and promoting individualized tumor immunotherapy in the future.


2021 ◽  
Vol 12 ◽  
Author(s):  
Jiazhou Liu ◽  
Yuxian Wei ◽  
Yushen Wu ◽  
Jie Li ◽  
Jiazheng Sun ◽  
...  

Tumor microenvironment (TME) is vital for the occurrence and development of breast cancer (BRCA). However, it remains challenging to understand the dynamic modulation of the stromal and immune components comprehensively in TME. Herein, we used ESTIMATE and CIBERSORT algorithm to estimate the number of stromal and immune components and the abundance of tumor-infiltrating immune cells (TICs) in 582 BRCA cases from gene expression omnibus (GEO) database. We employed three regression models including univariable Cox proportion, LASSO regression model and multivariate Cox regression, and identified 7 immune-specific genes related to BRCA survival. Of 7 genes, ATPase Secretory Pathway Ca2+ Transporting 2 (ATP2C2) attracts our attention for significantly predicting prognosis of BRCA patients. Further analysis indicated that ATP2C2 expression was closely related to the clinicopathological features (age, T- and N-staging) and negatively correlated with patients’ survival in BRCA. Gene Set Enrichment Analysis (GSEA) was performed to reveal pathway enrichment between ATP2C2high and ATP2C2low groups. The low ATP2C2 expression groups’ genes were mainly enriched for immune-related activities, while those in the ATP2C2 high-expression group were largely enriched in metabolic-related pathways. Notably, Pearson’s correlation analysis identified that ATP2C2 expression was positively correlated with T follicular helper (Tfh) cells, and negatively correlated with gamma delta (γδ) T cell, suggesting that ATP2C2 might be accountable for the maintenance of immune-dominant status for TME. To sum up, this study comprehensively analyzed the TME and shed light on prognostic immune-related biomarkers for BRCA. In particular, ATP2C2 might be helpful for predicting the prognosis of BRCA patients, which provided an extra insight for BRCA treatment.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yangming Hou ◽  
Yingjuan Xu ◽  
Dequan Wu

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.


2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110162
Author(s):  
Yangming Hou ◽  
Xin Wang ◽  
Junwei Wang ◽  
Xuemei Sun ◽  
Xinbo Liu ◽  
...  

Objectives The present study aimed to develop a gene signature based on the ESTIMATE algorithm in hepatocellular carcinoma (HCC) and explore possible cancer promoters. Methods The ESTIMATE and CIBERSORT algorithms were applied to calculate the immune/stromal scores and the proportion of tumor-infiltrating immune cells (TICs) in a cohort of HCC patients. The differentially expressed genes (DEGs) were screened by Cox proportional hazards regression analysis and protein–protein interaction (PPI) network construction. Cyclin B1 (CCNB1) function was verified using experiments. Results The stromal and immune scores were associated with clinicopathological factors and recurrence-free survival (RFS) in HCC patients. In total, 546 DEGs were up-regulated in low score groups, 127 of which were associated with RFS. CCNB1 was regarded as the most predictive factor closely related to prognosis of HCC and could be a cancer promoter. Gene Set Enrichment Analysis (GSEA) and CIBERSORT analyses indicated that CCNB1 levels influenced HCC tumor microenvironment (TME) immune activity. Conclusions The ESTIMATE signature can be used as a prognosis tool in HCC. CCNB1 is a tumor promoter and contributes to TME status conversion.


2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Chengquan Shen ◽  
Jing Liu ◽  
Jirong Wang ◽  
Xiaokun Yang ◽  
Haitao Niu ◽  
...  

PTPN6 (protein tyrosine phosphatase nonreceptor type 6), a tyrosine phosphatase, is known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. Previous studies have demonstrated that PTPN6 expression is relatively elevated in several malignancies. However, the role of PTPN6 in bladder cancer (BC) remains unclear. The purpose of this study was to explore the prognostic value of PTPN6 in BC. RNA-seq data from The Cancer Genome Atlas (TCGA) was used to identify the expression level of PTPN6 in BC. The relationship between clinical pathologic features and PTPN6 were analyzed with the Wilcoxon signed-rank test. The prognostic and predictive value of PTPN6 was evaluated by survival analysis and nomogram. Gene Set Enrichment Analysis (GSEA) was conducted to explore the potential molecular mechanisms of PTPN6 in BC. Finally, Tumor Immune Estimation Resource (TIMER) was applied to investigate the relationship between PTPN6 and immune cell infiltration in the tumor microenvironment. Results indicated that PTPN6 was overexpressed in BC tissues compared with normal bladder tissues and was significantly correlated with grade, stage, T, and N. Survival analysis showed that low expression of PTPN6 was significantly related to the poor overall survival (OS) in BC patients. Coexpression analysis showed that PTPN6 and TNFRSF14 (Tumor necrosis factor receptor superfamily member 14) have a close correlation in BC. GSEA showed that multiple cancer-associated signaling pathways are differentially enriched in the PTPN6 high expression phenotype. Moreover, the expression level of PTPN6 was positively associated with the infiltration of B cells, CD4+T cells, dendritic cells, and neutrophils and negatively associated with CD8+ T cells and macrophages in BC. In conclusion, we identified that PTPN6 may be a novel prognostic biomarker in BC based on the TCGA database. Further clinical trials are needed to confirm our observations and mechanisms underlying the prognostic value of PTPN6 in BC also deserve further experimental exploration.


2021 ◽  
Vol 18 (6) ◽  
pp. 9336-9356
Author(s):  
Sidan Long ◽  
◽  
Shuangshuang Ji ◽  
Kunmin Xiao ◽  
Peng Xue ◽  
...  

<abstract> <sec><title>Background</title><p>LTB4 receptor 1 (LTB4R), as the high affinity leukotriene B4 receptor, is rapidly revealing its function in malignancies. However, it is still uncertain.</p> </sec> <sec><title>Methods</title><p>We investigated the expression pattern and prognostic significance of LTB4R in pan-cancer across different databases, including ONCOMINE, PrognoScan, GEPIA, and Kaplan-Meier Plotter, in this study. Meanwhile, we explored the significance of LTB4R in tumor metastasis by HCMDB. Then functional enrichment analysis of related genes was performed using GeneMANIA and DAVID. Lastly, utilizing the TIMER datasets, we looked into the links between LTB4R expression and immune infiltration in malignancies.</p> </sec> <sec><title>Results</title><p>In general, tumor tissue displayed higher levels of LTB4R expression than normal tissue. Although LTB4R had a negative influence on pan-cancer, a high expression level of LTB4R was protective of LIHC (liver hepatocellular carcinoma) patients' survival. There was no significant difference in the distribution of LTB4R between non-metastatic and metastatic tumors. Based on Gene Set Enrichment Analysis, LTB4R was implicated in pathways involved in inflammation, immunity, metabolism, and cancer diseases. The correlation between immune cells and LTB4R was found to be distinct across cancer types. Furthermore, markers of infiltrating immune cells, such as Treg, T cell exhaustion and T helper cells, exhibited different LTB4R-related immune infiltration patterns.</p> </sec> <sec><title>Conclusion</title><p>The LTB4R is associated with immune infiltrates and can be used as a prognostic biomarker in pan-cancer.</p> </sec> </abstract>


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