Deciphering the Pyroptosis-Related Prognostic Signature and Immune Cell Infiltration Characteristics of Colon Cancer

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.

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Glucose-6-Phosphate Dehydrogenase is a Prognostic Biomarker and Correlated with Immune Infiltrates in Hepatocellular Carcinoma

10.21203/rs.3.rs-1232206/v1 ◽

2022 ◽

Author(s):

Yang Bu ◽

Kejun Liu ◽

Yiming Niu ◽

Ji Hao ◽

Lei Cui ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Tumor Microenvironment ◽

Liver Cancer ◽

Immune Cell ◽

Cox Regression ◽

Functional Enrichment ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Potential Biomarker ◽

Glucose 6 Phosphate Dehydrogenase

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.

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A Ferroptosis-Related Signature Robustly Predicts Clinical Outcomes and Associates With Immune Microenvironment for Thyroid Cancer

Frontiers in Medicine ◽

10.3389/fmed.2021.637743 ◽

2021 ◽

Vol 8 ◽

Author(s):

Mingqin Ge ◽

Jie Niu ◽

Ping Hu ◽

Aihua Tong ◽

Yan Dai ◽

...

Keyword(s):

Thyroid Cancer ◽

High Risk ◽

Risk Score ◽

Immune Cell ◽

Cox Regression ◽

Low Risk ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Immune Microenvironment ◽

Cox Regression Analysis

Objective: This study aimed to construct a prognostic ferroptosis-related signature for thyroid cancer and probe into the association with tumor immune microenvironment.Methods: Based on the expression profiles of ferroptosis-related genes, a LASSO cox regression model was established for thyroid cancer. Kaplan-Meier survival analysis was presented between high and low risk groups. The predictive performance was assessed by ROC. The predictive independency was validated via multivariate cox regression analysis and stratified analysis. A nomogram was established and verified by calibration curves. The enriched signaling pathways were predicted via GSEA. The association between the signature and immune cell infiltration was analyzed by CIBERSORT. The ferroptosis-related genes were validated in thyroid cancer tissues by immunohistochemistry and RT-qPCR.Results: A ferroptosis-related eight gene model was established for predicting the prognosis of thyroid cancer. Patients with high risk score indicated a poorer prognosis than those with low risk score (p = 1.186e-03). The AUCs for 1-, 2-, and 3-year survival were 0.887, 0.890, and 0.840, respectively. Following adjusting other prognostic factors, the model could independently predict the prognosis (p = 0.015, HR: 1.870, 95%CI: 1.132–3.090). A nomogram combining the signature and age was constructed. The nomogram-predicted probability of 1-, 3-, and 5-year survival approached the actual survival time. Several ferroptosis-related pathways were enriched in the high-risk group. The signature was distinctly associated with the immune cell infiltration. After validation, the eight genes were abnormally expressed between thyroid cancer and control tissues.Conclusion: Our findings established a prognostic ferroptosis-related signature that was associated with the immune microenvironment for thyroid cancer.

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SERPINE1 associated with remodeling of the tumor microenvironment in colon cancer progression: a novel therapeutic target

BMC Cancer ◽

10.1186/s12885-021-08536-7 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Shaokun Wang ◽

Li Pang ◽

Zuolong Liu ◽

Xiangwei Meng

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Immune Cells ◽

Immune Cell ◽

Cox Regression ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

The Relationship

Abstract Background The change of immune cell infiltration essentially influences the process of colorectal cancer development. The infiltration of immune cells can be regulated by a variety of genes. Thus, modeling the immune microenvironment of colorectal cancer by analyzing the genes involved can be more conducive to the in-depth understanding of carcinogenesis and the progression thereof. Methods In this study, the number of stromal and immune cells in malignant tumor tissues were first estimated by using expression data (ESTIMATE) and cell-type identification with relative subsets of known RNA transcripts (CIBERSORT) to calculate the proportion of infiltrating immune cell and stromal components of colon cancer samples from the Cancer Genome Atlas database. Then the relationship between the TMN Classification and prognosis of malignant tumors was evaluated. Results By investigating differentially expressed genes using COX regression and protein-protein interaction network (PPI), the candidate hub gene serine protease inhibitor family E member 1 (SERPINE1) was found to be associated with immune cell infiltration. Gene Set Enrichment Analysis (GSEA) further projected the potential pathways with elevated SERPINE1 expression to carcinogenesis and immunity. CIBERSORT was subsequently utilized to investigate the relationship between the expression differences of SERPINE1 and immune cell infiltration and to identify eight immune cells associated with SERPINE1 expression. Conclusion We found that SERPINE1 plays a role in the remodeling of the colon cancer microenvironment and the infiltration of immune cells.

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

Frontiers in Oncology ◽

10.3389/fonc.2021.728842 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xingkui Tang ◽

Minling Liu ◽

Xijun Luo ◽

Mengyuan Zhu ◽

Shan Huang ◽

...

Keyword(s):

Colon Cancer ◽

Tumor Microenvironment ◽

Signaling Pathway ◽

Prognostic Value ◽

Immune Cell ◽

Wnt Signaling Pathway ◽

Mapk Signaling ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Score Model

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.

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Crosstalk between the MSI status and tumor microenvironment in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15236 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15236-e15236

Author(s):

Peng Luo ◽

Anqi Lin ◽

Jian Zhang

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Microsatellite Instability ◽

Immune Cell ◽

The Cancer Genome Atlas ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Immune Microenvironment ◽

Mutation Data ◽

Immune Related Genes

e15236 Background: In recent years, cancer immunotherapy has been extensively studied, and colorectal cancer (CRC) patients have also derived clinical benefits from immunotherapy, especially CRC patients with mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H), whose sensitivity to immune checkpoint inhibitors (ICIs) is significantly higher than that of patients with microsatellite-stable (MSS)/microsatellite instability-low (MSI-L) disease. This study suggests that patients with MSI-H CRC have a higher mutational burden and more immune cell infiltration than those with MSS/MSI-L disease. However, most studies have not systematically evaluated the immune characteristics and immune microenvironments of MSI-H and MSS/MSI-L CRC. Methods: A published CRC cohort with mutation and immunotherapy-related prognostic data was collected. We analyzed the relationship between the MSI status and prognosis of ICI treatment in an immunotherapy cohort. We then further used mutation data for the immunotherapy and The Cancer Genome Atlas (TCGA)-CRC (colon adenocarcinoma (COAD) + rectum adenocarcinoma (READ) cohorts. For mRNA expression, mutation data analysis of the immune microenvironment and immunogenicity under different MSI status was performed. Results: Compared with MSS/MSI-L CRC patients, patients with MSI-H CRC significantly benefited from ICI treatment. We found that MSI-H CRC had more immune cell infiltration, higher expression of immune-related genes and higher immunogenicity than MSS/MSI-L disease. The MANTIS score used to predict the MSI status was positively correlated with immune cells, immune-related genes, and immunogenicity. In addition, subtype analysis showed that COAD and READ might have different tumor immune microenvironments. Conclusions: MSI-H CRC may have an inflammatory tumor microenvironment and increased sensitivity to ICIs. Unlike those of MSI-H READ, the immune characteristics of MSI-H COAD may be consistent with those of MSI-H CRC. Furthermore, the possible mechanism underlying the prognostic differences among CRC patients receiving ICIs in relation to the immune microenvironment were elucidated to provide theoretical guidance for further improving the curative effect of ICIs treatment on MSI-H CRC patients in the future and solve the problems underlying why MSS/MSI-L CRC patients do not benefit from ICIs treatment.

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Hypoxic Characteristic in the Immunosuppressive Microenvironment of Hepatocellular Carcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.611058 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhuomao Mo ◽

Daiyuan Liu ◽

Dade Rong ◽

Shijun Zhang

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Cell ◽

Cox Regression ◽

Cancer Genome ◽

Gene Set Enrichment Analysis ◽

The Cancer Genome Atlas ◽

Cell Infiltration ◽

Immune Checkpoints ◽

Immune Cell Infiltration ◽

Immunosuppressive Microenvironment

Background: Generally, hepatocellular carcinoma (HCC) exists in an immunosuppressive microenvironment that promotes tumor evasion. Hypoxia can impact intercellular crosstalk in the tumor microenvironment. This study aimed to explore and elucidate the underlying relationship between hypoxia and immunotherapy in patients with HCC.Methods: HCC genomic and clinicopathological datasets were obtained from The Cancer Genome Atlas (TCGA-LIHC), Gene Expression Omnibus databases (GSE14520) and International Cancer Genome Consortium (ICGC-LIRI). The TCGA-LIHC cases were divided into clusters based on single sample gene set enrichment analysis and hierarchical clustering. After identifying patients with immunosuppressive microenvironment with different hypoxic conditions, correlations between immunological characteristics and hypoxia clusters were investigated. Subsequently, a hypoxia-associated score was established by differential expression, univariable Cox regression, and lasso regression analyses. The score was verified by survival and receiver operating characteristic curve analyses. The GSE14520 cohort was used to validate the findings of immune cell infiltration and immune checkpoints expression, while the ICGC-LIRI cohort was employed to verify the hypoxia-associated score.Results: We identified hypoxic patients with immunosuppressive HCC. This cluster exhibited higher immune cell infiltration and immune checkpoint expression in the TCGA cohort, while similar significant differences were observed in the GEO cohort. The hypoxia-associated score was composed of five genes (ephrin A3, dihydropyrimidinase like 4, solute carrier family 2 member 5, stanniocalcin 2, and lysyl oxidase). In both two cohorts, survival analysis revealed significant differences between the high-risk and low-risk groups. In addition, compared to other clinical parameters, the established score had the highest predictive performance at both 3 and 5 years in two cohorts.Conclusion: This study provides further evidence of the link between hypoxic signals in patients and immunosuppression in HCC. Defining hypoxia-associated HCC subtypes may help reveal potential regulatory mechanisms between hypoxia and the immunosuppressive microenvironment, and our hypoxia-associated score could exhibit potential implications for future predictive models.

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Identification and validation of tumor microenvironment-related lncRNA prognostic signature for uveal melanoma

International Journal of Ophthalmology ◽

10.18240/ijo.2021.08.03 ◽

2021 ◽

Vol 14 (8) ◽

pp. 1151-1159

Author(s):

Chen-Lu Liao ◽

◽

Xing-Yu Sun ◽

Qi Zhou ◽

Min Tian ◽

...

Keyword(s):

Prognostic Value ◽

Prognostic Markers ◽

Immune Cell ◽

Cox Regression ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Prognostic Signature ◽

Profile Data ◽

Small Molecule Drugs

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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Colon Cancer and SARS-CoV-2: Impact of ACE2 Expression in Susceptibility to COVID-19

10.1101/2020.06.11.146878 ◽

2020 ◽

Cited By ~ 1

Author(s):

Mohsen Ahmadi ◽

Negin Saffarzadeh ◽

Mohammad Amin Habibi ◽

Fatemeh Hajiesmaeili ◽

Nima Rezaei

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Immune Cell ◽

Expression Patterns ◽

Methylation Status ◽

Functional Enrichment ◽

Cell Infiltration ◽

Survival Outcomes ◽

Immune Cell Infiltration ◽

Ace2 Gene

AbstractNovel coronavirus disease (COVID-19) pandemic has become a global health emergency. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) interacts with angiotensin-converting enzyme 2 (ACE2) to enter the cells and infects diverse human tissues. It has been reported that a few conditions, including cancer, predispose individuals to SARS-CoV-2 infection and severe form of COVID-19. These findings led us to evaluate the susceptibility of colon adenocarcinoma (COAD) patients to SARS-CoV-2 infection by investigation of ACE2 expression in their tumor tissues. The expression analysis revealed that both mRNA and protein levels of ACE2 had increased in colon cancer samples than normal group. Next, the prognosis analysis has indicated that the upregulation of ACE2 was not correlated with patient survival outcomes. Further assessment displayed the hypomethylation of the ACE2 gene promoter in COAD patients. Surprisingly, this methylation status has a strong negative correlation with ACE2 gene expression. The functional enrichment analysis of the genes that had similar expression patterns with ACE2 in colon cancer tissues demonstrated that they mainly enriched in Vitamin digestion and absorption, Sulfur relay system, and Fat digestion and absorption pathways. Finally, we found that ACE2 gene expression had a significant association with the immune cell infiltration levels in COAD patients. In conclusion, it has plausible that COAD patients are more likely to be infected with SARS-CoV-2 and experience severe injuries. Moreover, COVID-19 would bring unfavorable survival outcomes of patients with colon cancer by the way of immune cell infiltration linked process. The present study highlights the importance of preventive actions for COAD patients during the COVID-19 pandemic.

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