scholarly journals The Prognostic Value of a Tumor Microenvironment-Based Immune Cell Infiltration Score Model in Colon Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Xingkui Tang ◽  
Minling Liu ◽  
Xijun Luo ◽  
Mengyuan Zhu ◽  
Shan Huang ◽  
...  

The current study aimed to construct a prognostic predictive model based on tumor microenvironment. CIBERSORT and ESTIMATE algorithms were used to reveal the immune cell infiltration (ICI) landscape of colon cancer. Patients were classified into three clusters by ConsensusClusterPlus algorithm. ICI scores of each patient were determined by principal component analysis. Patients were divided into high and low ICI score groups. Survival, gene expression, and somatic mutation of the two groups were compared. We found that patients with no lymph node invasion, no metastasis, T1–2 disease, and stage I–II had higher ICI scores. Calcium signaling pathway, leukocyte transendothelial migration pathway, MAPK signaling pathway, TGF β pathway, and Wnt signaling pathway were enriched in the high ICI score group. Immune-checkpoint and immune-activity associated genes were decreased in high ICI score patients. Patients in the high ICI score group had better survival. Prognostic value of ICI score was independent of tumor mutational burden (TMB). The ICI score model constructed in the current study may serve as an independent prognostic biomarker in colon cancer.

2021 ◽  
Author(s):  
Xiaofen Pan ◽  
Xingkui Tang ◽  
Minling Liu ◽  
Xijun Luo ◽  
Mengyuan Zhu ◽  
...  

Abstract BackgroundTumor microenvironment consists of tumor cells, immune cells and other matric components. Tumor infiltration immune cells are associated with prognosis. But all the current prognosis evaluation system dose not take tumor immune cells other matrix component into consideration. In the current study, we aimed to construct a prognosis predictive model based on tumor microenvironment.MethodCIBERSORT and ESTIMATE algorithms were used to reveal the immune cell infiltration landscape of colon cancer. Patients were classified into three clusters by ConsensusClusterPlus algorithm. Immune cell infiltration (ICI) scores of each patient were determine by principal-component analysis. Patients were divided to high and low ICI score groups. Survival, gene expression and somatic mutation of the two groups were compared.ResultsPatients with no lymph node invasion, no metastasis, T1-2 disease and stage I-II had higher ICI scores. Calcium signaling pathway, leukocyte transendothelial migration pathway, MAPK signaling pathway, TGF β pathway, and WNT signaling pathway were enriched in high ICI score group. Immune-checkpoint genes and immune-activity associated genes were significantly decreased in high ICI score. Patients in high ICI score group had better survival than low ICI score group. Prognostic value of ICI score was independent of TMB.ConclusionICI score might serve as an independent prognostic biomarker in colon cancer.


2020 ◽  
Author(s):  
Biao Huang ◽  
Wei Han ◽  
Zu-Feng Sheng ◽  
Guo-Liang Shen

Abstract Background Skin cutaneous melanoma (SKCM) is known as the most malignancy and treatment-resistant in human tumor, causing about 72% of deaths in skin carcinoma. However, the potential mechanism and new effective targets remain to be further elucidated. Available datasets such as Gene Expression Omnibus (GEO) can be utilized to search for novel therapeutic targets and prognostic biomarkers. Methods Three data sets were downloaded from GEO database . The differentially expressed genes (DEGs) were identified via Venn software. Protein‐protein interaction network of DEGs was developed and the module hub genes analysis was constructed by Cytoscape. Subsequently, multiple online tools and Kaplan-Meier survival curves were analyzed to detect underlying signaling pathways, gene expression, drug-gene interaction and prognostic value of hub genes. In addition, we explored the correlation between hub genes and immune cell infiltration. At last, the related miRNA, lncRNA networks were constructed by R software. Results A total of 308 DEGs and 12 hub genes were identified. Function and pathway enrichment results demonstrated a correlation between DEGs and the tumor microenvironment, immune response and melanoma tumorigenesis. Subsequently, we focused on assessing potential value of 12 hub genes. Seven hub genes ( CCL4, CCL5, NMU, GAL, CXCL9, CXCL10, CXCL13 ) were identified with significant overall survival for prognosis. What’s more, five of these seven hub genes were found to be related to clinical stages (P values<0.05). In addition, the most important pathways of hub genes include interleukin-10 signaling, peptide ligand-binding receptors, which play important roles in tumor microenvironment for immune activation or immunosuppressive by regulating the infiltration of immune cells. Our results revealed a strong positive correlation between gene expression (CCL4, CCL5, CXCL9, CXCL10 and CXCL13) and immune cell infiltration (B-cell, CD8+ T cells, CD4+ T cells, macrophages, Neutrophils, Dendritic cells). Interestingly, 8 of 12 hub genes (CXCL10, CCL4, CCL5, IL6, CXCL2, PTGER3, GAL, NPY1R) were also found in the predicted drug-gene interaction. The related miRNA, lncRNA for diagnosis and prognosis were found in networks. Conclusion In conclusion, CCL4, CCL5, NMU, GAL, CXCL9, CXCL10, CXCL13 were of high prognostic value and may be potential targets for the diagnosis and therapy of patients with melanoma.


2022 ◽  
Author(s):  
Chengquan Shen ◽  
Jing Liu ◽  
Ye Liang ◽  
Zhijuan Liang ◽  
Liping Wang ◽  
...  

Abstract Background Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and lacking effective systemic treatment options. Recent studies showed that ferroptosis play a prominent role in the initiation and development of cancer. Nonetheless, the potential roles of ferroptosis regulators in the prognosis and tumor microenvironment immunomodulator factors expression remain not fully study. Methods TCGA and GEO ACC datasets were used to investigate the relationship between ferroptosis regulators with prognosis and clinical features. Consensus clustering analysis was performed to divided ACC patients into different ferroptosis subgroups. A ferroptosis scoring system was established for individual ACC using principal component analysis algorithms. The correlation between ferroptosis score and tumor microenvironment immune cell infiltration was analyzed. Results Twenty ferroptosis regulators were differentially expressed in ACC and 17 ferroptosis regulators were closely related to the prognosis of ACC. Three ferroptosis subgroups (Cluster A, B, and C) were determined based on the expression of ferroptosis regulators. Cluster C is preferentially associated with favorable OS, PFS, upregulated antigen-presenting genes expression, and higher immune cell infiltration. GSEA also indicated that Cluster C was prominently related to immune fully activation including chemokine signaling pathway, natural killer cell-mediated cytotoxicity, T cell receptor signaling pathway, and Toll-like receptor signaling pathway. A ferroptosis scoring system was constructed and it could serve as an independent prognostic factor for ACC. The ferroptosis scores were significantly correlated with TMB, immune-checkpoint genes expression, and tumor microenvironment immune cell infiltration in ACC. Further analyses indicated that the ferroptosis score integrated with TMB, immune-checkpoint genes expression, and CD4+ T cell infiltration, could predict the prognosis of ACC. Furthermore, a nomogram was constructed to monitor the prognosis of individual ACC patient. RNA isolation and reverse transcription‑quantitative PCR (RT-qPCR) demonstrated significant differences in the expression levels of ACSL4, FANCD2 and SLC7A1 between ACC and normal tissues. Conclusion Our study demonstrated ferroptosis regulators were significantly associated with the prognosis, clinical characteristics, immune-checkpoint genes expression, and tumor microenvironment immune cell infiltration in ACC. This current study provided comprehensive evidence for further research on ferroptosis regulators in ACC and provides new enlightenment for epigenetic regulation of antitumor immune response.


2021 ◽  
Vol 12 ◽  
Author(s):  
Minggao Zhu ◽  
Yachao Cui ◽  
Qi Mo ◽  
Junwei Zhang ◽  
Ting Zhao ◽  
...  

N6-methyladenosine (m6A) RNA modification is a reversible mechanism that regulates eukaryotic gene expression. Growing evidence has demonstrated an association between m6A modification and tumorigenesis and response to immunotherapy. However, the overall influence of m6A regulators on the tumor microenvironment and their effect on the response to immunotherapy in lung adenocarcinoma remains to be explored. Here, we comprehensively analyzed the m6A modification patterns of 936 lung adenocarcinoma samples based on 24 m6A regulators. First, we described the features of genetic variation in these m6A regulators. Many m6A regulators were aberrantly expressed in tumors and negatively correlated with most tumor-infiltrating immune cell types. Furthermore, we identified three m6A modification patterns using a consensus clustering method. m6A cluster B was preferentially associated with a favorable prognosis and enriched in metabolism-associated pathways. In contrast, m6A cluster A was associated with the worst prognosis and was enriched in the process of DNA repair. m6A cluster C was characterized by activation of the immune system and a higher stromal cell score. Surprisingly, patients who received radiotherapy had a better prognosis than patients without radiotherapy only in the m6A cluster C group. Subsequently, we constructed an m6A score model that qualified the m6A modification level of individual samples by using principal component analysis algorithms. Patients with high m6A score were characterized by enhanced immune cell infiltration and prolonged survival time and were associated with lower tumor mutation burden and PD-1/CTLA4 expression. The combination of the m6A score and tumor mutation burden could accurately predict the prognosis of patients with lung adenocarcinoma. Furthermore, patients with high m6A score exhibited greater prognostic benefits from radiotherapy and immunotherapy. This study demonstrates that m6A modification is significantly associated with tumor microenvironment diversity and prognosis. A comprehensive evaluation of m6A modification patterns in single tumors will expand our understanding of the tumor immune landscape. In addition, our m6A score model demonstrated that the level of immune cell infiltration plays a significant role in cancer immunotherapy and provides a basis to increase the efficiency of current immune therapies and promote the clinical success of immunotherapy.


2021 ◽  
Vol 12 ◽  
Author(s):  
Shuang Gao ◽  
Ye Jin ◽  
Hongmei Zhang

WNT signaling pathway inhibitor Dickkopf-1 (DKK1) is related to cancer progression; however, its diagnostic and prognostic potential have not been investigated in a pan-cancer perspective. In this study, multiple bioinformatic analyses were conducted to evaluate therapeutic value of DKK1 in human cancers. The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) project served as data resources. The Wilcoxon rank test was performed to evaluate the expression difference of DKK1 between cancer tissues and normal tissues. A Kaplan-Meier curve and Cox regression were used for prognosis evaluation. Single-sample gene set enrichment analysis (ssGSEA) was used to evaluate the association of DKK1 expression with the immune cell infiltration. The potential function of DKK1 was explored by STRING and clusterProfiler. We found that the expression level of DKK1 is significantly different in different cancer types. Importantly, we demonstrated that DKK1 is an independent risk factor in ESCA, LUAD, MESO, and STAD. Further analysis revealed that DKK1 had a large effect on the immune cell infiltration and markers of certain immune cells, such as Th1 and Th2 cells. PPI network analysis and further pathway enrichment analysis indicated that DKK1 was mainly involved in the WNT signaling pathway. Our findings suggested that DKK1 might serve as a marker of prognosis for certain cancers by affecting the WNT signaling pathway and tumor immune microenvironment.


2021 ◽  
Vol 12 ◽  
Author(s):  
Ran Wei ◽  
Shuofeng Li ◽  
Guanhua Yu ◽  
Xu Guan ◽  
Hengchang Liu ◽  
...  

Background: Colon cancer (CC) remains one of the most common malignancies with a poor prognosis. Pyroptosis, referred to as cellular inflammatory necrosis, is thought to influence tumor development. However, the potential effects of pyroptosis-related regulators (PRRs) on the CC immune microenvironment remain unknown.Methods: In this study, 27 PRRs reported in the previous study were used to cluster the 1,334 CC samples into three pyroptosis-related molecular patterns. Through subtype pattern differential analysis and structure network mining using Weighted Gene Co-expression Network Analysis (WGCNA), 854 signature genes associated with the PRRs were discovered. Further LASSO-penalized Cox regression of these genes established an eight-gene assessment model for predicting prognosis.Results: The CC patients were subtyped based on three distinct pyroptosis-related molecular patterns. These pyroptosis-related patterns were correlated with different clinical outcomes and immune cell infiltration characteristics in the tumor microenvironment. The pyroptosis-related eight-signature model was established and used to assess the prognosis of CC patients with medium-to-high accuracy by employing the risk scores, which was named “PRM-scores.” Greater inflammatory cell infiltration was observed in tumors with low PRM-scores, indicating a potential benefit of immunotherapy in these patients.Conclusions: This study suggests that PRRs have a significant effect on the tumor immune microenvironment and tumor development. Evaluating the pyroptosis-related patterns and related models will promote our understanding of immune cell infiltration characteristics in the tumor microenvironment and provide a theoretical basis for future research targeting pyroptosis in cancer.


Life ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 522
Author(s):  
Dehua Liu ◽  
Chenyu Sun ◽  
Nahyun Kim ◽  
Chandur Bhan ◽  
John Pocholo Whitaker Tuason ◽  
...  

Gastric cancer (GC) is the fifth most common cancer globally. Secreted frizzled-related proteins (SFRP) are important elements associated with the Wnt signaling pathway, and its dysregulated expression is found in multiple cancers. However, the function of distinct SFRPs in GC remains poorly understood. We investigated the differential expression, prognostic value, and immune cell infiltration of SFRPs in gastric cancer patients from the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), UALCAN, Kaplan–Meier plotter, cBioPortal, STRING, Gene-MANIA, DAVID, MethSurv, and TIMER databases. We found that the expression levels of SFRP2 and SFRP4 were significantly increased in GC tissues, whereas the SFRP1 and SFRP5 expressions were reduced. SFRP1, SFRP2, and SFRP5 were significantly correlated with the clinical cancer stage in GC patients. Higher expression of SFRPs was associated with short overall survival (OS) in GC patients. Besides, high SFRPs methylation showed favorable OS in GC patients. The functions of SFRPs were primarily related to the Wnt signaling pathway, immune system development, and basal cell carcinoma. The expression of SFRPs was strongly correlated with immune infiltrating cells, including CD4+ T cells and macrophages in GC. Our study indicated that SFRPs could be potential targets of precision therapy and prognostic biomarkers for the survival of GC patients.


2021 ◽  
Vol 15 ◽  
Author(s):  
Dezhi Shan ◽  
Xing Guo ◽  
Guozheng Yang ◽  
Zheng He ◽  
Rongrong Zhao ◽  
...  

Intracranial aneurysms (IAs) may cause lethal subarachnoid hemorrhage upon rupture, but the molecular mechanisms are poorly understood. The aims of this study were to analyze the transcriptional profiles to explore the functions and regulatory networks of differentially expressed genes (DEGs) in IA rupture by bioinformatics methods and to identify the underlying mechanisms. In this study, 1,471 DEGs were obtained, of which 619 were upregulated and 852 were downregulated. Gene enrichment analysis showed that the DEGs were mainly enriched in the inflammatory response, immune response, neutrophil chemotaxis, and macrophage differentiation. Related pathways include the regulation of actin cytoskeleton, leukocyte transendothelial migration, nuclear factor κB signaling pathway, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, and chemokine signaling pathway. The enrichment analysis of 20 hub genes, subnetworks, and significant enrichment modules of weighted gene coexpression network analysis showed that the inflammatory response and immune response had a causal relationship with the rupture of unruptured IAs (UIAs). Next, the CIBERSORT method was used to analyze immune cell infiltration into ruptured IAs (RIAs) and UIAs. Macrophage infiltration into RIAs increased significantly compared with that into UIAs. The result of principal component analysis revealed that there was a difference between RIAs and UIAs in immune cell infiltration. A 4-gene immune-related risk model for IA rupture (IRMIR), containing CXCR4, CXCL3, CX3CL1, and CXCL16, was established using the glmnet package in R software. The receiver operating characteristic value revealed that the model represented an excellent clinical situation for potential application. Enzyme-linked immunosorbent assay was performed and showed that the concentrations of CXCR4 and CXCL3 in serum from RIA patients were significantly higher than those in serum from UIA patients. Finally, a competing endogenous RNA network was constructed to provide a potential explanation for the mechanism of immune cell infiltration into IAs. Our findings highlighted the importance of immune cell infiltration into RIAs, providing a direction for further research.


2022 ◽  
Author(s):  
Yang Bu ◽  
Kejun Liu ◽  
Yiming Niu ◽  
Ji Hao ◽  
Lei Cui ◽  
...  

Abstract Background: Glucose-6-phosphate dehydrogenase (G6PD) plays an important role in the metabolic and immunological aspects of tumors. In hepatocellular carcinoma (HCC), the alteration of tumor microenvironment influences recurrence and metastasis. We extracted G6PD-related data from public databases of HCC tissues and used a bioinformatics approach to explore the correlation between G6PD expression and clinicopathological features and prognosis of immune cell infiltration in HCC.Methods: We extract G6PD expression information from TCGA and GEO databases in liver cancer tissues and normal tissues, validated by immunohistochemistry, and the correlation between G6PD expression and clinical features is analyzed, and the clinical significance of G6PD in liver cancer is assessed by Kaplan-Meier, Cox regression and prognostic line graph models. Functional enrichment analysis is performed by protein-protein interaction (PPI) network, GO/KEGG, GSEA and G6PD-associated differentially expressed genes (DEGs). TIMER and ssGSEA packages are used to assess the correlation between expression and the level of immune cell infiltration.Results: Our results show that G6PD expression is significantly upregulated in hepatocellular carcinoma tissues (P < 0.001). G6PD expression is associated with histological grade, pathological stage, T-stage, vascular infiltration and AFP level (P < 0.05); HCC patients in the low G6PD expression group had longer overall survival and better prognosis compared with the high G6PD expression group (P < 0.05). The level of G6PD expression also affects the levels of macrophages, unactivated dendritic cells, B cells, and follicular helper T cells in the tumor microenvironment.Conclusion: High expression of G6PD is a potential biomarker for poor prognosis of hepatocellular carcinoma, and G6PD may be a target for immunotherapy of HCC.


2021 ◽  
Vol 14 (8) ◽  
pp. 1151-1159
Author(s):  
Chen-Lu Liao ◽  
◽  
Xing-Yu Sun ◽  
Qi Zhou ◽  
Min Tian ◽  
...  

AIM: To investigate the role of tumor microenvironment (TME)-related long non-coding RNA (lncRNA) in uveal melanoma (UM), probable prognostic signature and potential small molecule drugs using bioinformatics analysis. METHODS: UM expression profile data were downloaded from the Cancer Genome Atlas (TCGA) and bioinformatics methods were used to find prognostic lncRNAs related to UM immune cell infiltration. The gene expression profile data of 80 TCGA specimens were analyzed using the single sample Gene Set Enrichment Analysis (ssGSEA) method, and the immune cell infiltration of a single specimen was evaluated. Finally, the specimens were divided into high and low infiltration groups. The differential expression between the two groups was analyzed using the R package ‘edgeR’. Univariate, multivariate and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analyses were performed to explore the prognostic value of TME-related lncRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses were also performed. The Connectivity Map (CMap) data set was used to screen molecular drugs that may treat UM. RESULTS: A total of 2393 differentially expressed genes were identified and met the criteria for the low and high immune cell infiltration groups. Univariate Cox analysis of lncRNA genes with differential expression identified 186 genes associated with prognosis. Eight prognostic markers of TME-included lncRNA genes were established as potentially independent prognostic elements. Among 269 differentially expressed lncRNAs, 69 were up-regulated and 200 were down-regulated. Univariate Cox regression analysis of the risk indicators and clinical characteristics of the 8 lncRNA gene constructs showed that age, TNM stage, tumor base diameter, and low and high risk indices had significant prognostic value. We screened the potential small-molecule drugs for UM, including W-13, AH-6809 and Imatinib. CONCLUSION: The prognostic markers identified in this study are reliable biomarkers of UM. This study expands our current understanding of the role of TME-related lncRNAs in UM genesis, which may lay the foundations for future treatment of this disease.


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