scholarly journals Noncoding RNAs link metabolic reprogramming to immune microenvironment in cancers

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Yiyin Zhang ◽  
Qijiang Mao ◽  
Qiming Xia ◽  
Jiaxi Cheng ◽  
Zhengze Huang ◽  
...  
Keyword(s):  
Immune Cell ◽  
Noncoding Rnas ◽  
Tumor Metabolism ◽  
Metabolic Reprogramming ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Immune Microenvironment ◽  
Immunosuppressive Microenvironment ◽  
And Function ◽  
Transcriptional Output

AbstractAltered metabolic patterns in tumor cells not only meet their own growth requirements but also shape an immunosuppressive microenvironment through multiple mechanisms. Noncoding RNAs constitute approximately 60% of the transcriptional output of human cells and have been shown to regulate numerous cellular processes under developmental and pathological conditions. Given their extensive action mechanisms based on motif recognition patterns, noncoding RNAs may serve as hinges bridging metabolic activity and immune responses. Indeed, recent studies have shown that microRNAs, long noncoding RNAs and circRNAs are widely involved in tumor metabolic rewiring, immune cell infiltration and function. Hence, we summarized existing knowledge of the role of noncoding RNAs in the remodeling of tumor metabolism and the immune microenvironment, and notably, we established the TIMELnc manual, which is a free and public manual for researchers to identify pivotal lncRNAs that are simultaneously correlated with tumor metabolism and immune cell infiltration based on a bioinformatic approach.

scholarly journals Hypoxic Characteristic in the Immunosuppressive Microenvironment of Hepatocellular Carcinoma

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.

Distinct genomic and immune microenvironment between thymomas and thymic carcinomas.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e13529-e13529
Author(s):  
Kaicheng Wang ◽  
Suxia Lin ◽  
Xue Hou ◽  
Yongdong Liu ◽  
Meichen Li ◽  
...  
Keyword(s):  
Immune Cell ◽  
Immune Escape ◽  
Nk Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Immune Microenvironment ◽  
Tissue Samples ◽  
Thymic Epithelial Tumors ◽  
Immune Infiltration ◽  
Thymic Carcinomas

e13529 Background: Thymomas and thymic carcinomas which uniformly known as thymic epithelial tumors (TETs) are rare intrathoracic malignancies and a limited studies have been reported addressing the molecular biology and immune discrepancy. The main purpose of this study was to depict the genomic and transcriptomic landscape of thymomas and thymic carcinomas, as well as elucidate the differentiated immune microenvironment. Methods: Totally 15 thymomas and 7 thymic carcinomas patients were enrolled from January 2014 to July 2018. Treatment-naïve tissue samples were collected, and we also obtained matched peripheral blood mononucleocytes as negative control. DNA and RNA were co-extracted and performed with whole exon and transcriptome sequencing. The immune cell infiltration scores were estimated using ssGSEA algorithm. Results: Exome sequencing revealed that GTF2I mutation occurred in all of type A thymomas but was absent in the aggressive subtypes. The median tumor mutation burden of thymomas was 0.12/Mb, significantly lower than thymic carcinomas (median: 1.02/Mb, p = 0.001). Copy number variation was more common in thymic carcinomas than thymomas (83.3% vs 9.1%, p = 0.005). Top mutational signatures enriched in both thymomas and thymic carcinomas included age and Aristolochic acid exposure, while the APOBEC signature was more common in thymomas than thymic carcinomas (81.8% vs 16.7%, p = 0.03). As a confirmed immune escape event, loss of heterozygosity of human leukocyte antigen was identified in 9.1% of thymomas and 50% of thymic carcinomas. Via unsupervised clustering of immune infiltration, all tissue samples were classified into high- and low-infiltration subgroups. Remarkably, up to 71.4% of samples from thymic carcinomas and only 6.7% of samples from thymomas were defined as low immune cell infiltration. In consideration of specific immune cell types, macrophage ( p = 0.01) and neutrophil ( p = 0.02) were enriched in thymic carcinomas while CD56+ NK cell ( p = 0.005) was enriched in thymomas, indicating the evidential discrepancy about immune cell infiltration between two subtypes of TETs. Conclusions: This study elucidated the molecular and immune microenvironment discrepancy between two subtypes of TETs. From molecular perspective, thymomas and thymic carcinomas are entirely different diseases with different etiology and characterized by distinct immune infiltration, and thus should be managed with disparate therapeutic strategies. Findings in this study may also be useful in future targets development and exploration of immunotherapies in TETs.

scholarly journals Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer

2013 ◽  
Vol 108 (4) ◽  
pp. 914-923 ◽  
Author(s):  
Y Ino ◽  
R Yamazaki-Itoh ◽  
K Shimada ◽  
M Iwasaki ◽  
T Kosuge ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Immune Microenvironment

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

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.

scholarly journals Landscape of Immune Microenvironment Under Immune Cell Infiltration Pattern in Breast Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Qianhui Xu ◽  
Shaohuai Chen ◽  
Yuanbo Hu ◽  
Wen Huang
Keyword(s):  
Breast Cancer ◽  
Immune Cells ◽  
Immune Cell ◽  
Principal Component ◽  
Gene Set Enrichment Analysis ◽  
Cell Infiltration ◽  
Signal Pathways ◽  
Immune Cell Infiltration ◽  
Consensus Clustering ◽  
Immune Microenvironment

BackgroundIncreasing evdence supports the suggestion that the immune cell infiltration (ICI) patterns play a pivotal role in tumor progression in breast cancer (BRCA). Nonetheless, there has been no comprehensive analysis of the ICI patterns effects on the clinical outcomes and immunotherapy.MethodsMultiomic data for BRCA samples were downloaded from TCGA. ESTIMATE algorithm, ssGSEA method, and CIBERSORT analysis were used to uncover the landscape of the tumor immune microenvironment (TIME). BRCA subtypes based on the ICI pattern were identified by consensus clustering and principal-component analysis was performed to obtain the ICI scores to quantify the ICI patterns in individual tumors. Their prognostic value was validated by the Kaplan-Meier survival curves. Gene set enrichment analysis (GSEA) was applied for functional annotation. Immunophenoscore (IPS) was employed to explore the immunotherapeutic role of the ICI scores. Finally, the mutation data was analyzed by using the “maftools” R package.ResultsThree different immune infiltration patterns with a distinct prognosis and biological signature were recognized among 1,198 BRCA samples. The characteristics of TIME under these three patterns were highly consistent with three known immune profiles: immune- excluded, immune-desert, and immune-inflamed phenotypes, respectively. The identification of the ICI patterns within individual tumors based on the ICI score, developed under the ICI-related signature genes, contributed into dissecting biological processes, clinical outcome, immune cells infiltration, immunotherapeutic effect, and genetic variation. High ICI score subtype, characterized with a suppression of immunity, suggested an immune-exhausted phenotype. Abundant effective immune cells were discovered in the low ICI score patients, which corresponded to an immune-activated phenotype and might present an immunotherapeutic advantage. Immunophenoscore was implemented as a surrogate of immunotherapeutic outcome, low-ICI scores samples obtained a significantly higher immunophenoscore. Enrichment of the JAK/STAT and VEGF signal pathways were activated in the ICI low-score subgroup. Finally, the synergistic effect between the ICI score and the tumor mutation burden (TMB) was confirmed.ConclusionThis work comprehensively elucidated that the ICI patterns served as an indispensable player in complexity and diversity of TIME. Quantitative identification of the ICI patterns in individual tumor will contribute into mapping the landscape of TIME further optimizing precision immunotherapy.

scholarly journals The Correlation Between Novel Survival-related Alternative Splicing Signature and Prognostic Prediction and Immune Microenvironment in Clear Cell Renal Cell Carcinoma

2021 ◽  
Author(s):  
Wengang Jian ◽  
Gang Wang ◽  
Yipeng Yu ◽  
Licheng Cai ◽  
Yongchun Yu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Immune Cell ◽  
Risk Model ◽  
Clear Cell ◽  
Cell Infiltration ◽  
Immune Checkpoints ◽  
Splicing Factors ◽  
Immune Cell Infiltration ◽  
Immune Microenvironment ◽  
Cell Renal Cell Carcinoma

Abstract BackgroundAlthough extensive researches related alternative splicing (AS) as the prognostic markers of patients in cancers, which remains unknown in clear cell renal cell carcinoma (ccRCC), especially in immunotherapy. Therefore, a novel survival-associated AS signature was established to predict prognosis of patients and explored its correlation with immune cell infiltration or immune checkpoint expression to explain the phenomenon of resistance to immunotherapy in ccRCC.Methodsccording to AS data, clinical information and gene expression data in ccRCC, overall survival-related AS events was identified and further the AS-related prognostic risk model established by LASSO regression and multi-Cox regression analysis was evaluated by Kaplan-Meier survival analysis, the ROC curves and a nomogram model. Then we clarified the biological processes and pathways by GSEA, and further measured the immune cell infiltration by ESTIMATE, CIBERSORT and ssGSEA. Finally we analysed the clinical features and immune features of different parental genes, and quested the splicing factors regulating riskScore-related AS events by Spearman correlation analysis.ResultsWe obtained the most significant 5 AS events, including C4orf19|69001|AT, UACA|31438|AP, FAM120C|89237|AT, TRIM16L|39629|AP and SEC31A|100881|ES, to establish the prognostic risk model, and further illustrated the stability and importance of the riskScore prognostic signatures. Then we found that in high risk group, most of the top 10 GO enrichments and the KEGG pathway were closely related to the immunity, and the higher immune cell infiltration, and higher expression of classic immune checkpoints such as PD1 and CTLA4. In addition, 6 different parental genes were obtained, including C4orf19, ARHGAP24 DNASE1L3, P4HA1, SLC39A14 and TAF1D. These 6 genes could not be the independent prognostic signatures, but the expression of these genes was closely related to immune cells infiltration and the expression of immune checkpoints. Finally, we got aberrant 52 splicing factors regulating riskScore-related AS events.ConclusionOur study discovered that overall survival-related AS events mediated by aberrant splicing factors can be constructed a prognostic risk model to predict prognosis of patiens and utilized to index the situation of immune cell infiltration and immune checkpoint expression that impact tumor immune microenvironment in ccRCC.

scholarly journals Nuf2 Is a Prognostic-Related Biomarker and Correlated With Immune Infiltrates in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Xingwei Xie ◽  
Shanshan Jiang ◽  
Xiang Li
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Cell ◽  
Progression Free Survival ◽  
Cell Infiltration ◽  
Immune Cell Infiltration ◽  
Free Survival ◽  
Immune Infiltration ◽  
Kaplan Meier ◽  
Immune Biomarkers ◽  
And Function

Nuf2 participates in the regulation of cell apoptosis and proliferation by regulating the binding of centromere and spindle microtubules to achieve the correct separation of chromosomes. Previous reports have suggested that Nuf2 may play a role in various human cancers. However, the mechanism and function of Nuf2 in the development of Hepatocellular carcinoma (HCC) remains uncertain. This study investigated the prognostic potential of Nuf2 and its relation with immune cell infiltration in HCC. Nuf2 expression in tumor cells was examined using the TIMER and Oncomine databases, and its prognostic potential was assessed via the Kaplan-Meier plotter and GEPIA databases. The relationships between Nuf2 and tumor immune infiltration were analyzed using TIMER. The relationships between Nuf2 and biomarkers of tumor immune infiltration were analyzed using TIMER and GEPIA. Here we revealed that Nuf2 expression increased in tumor tissues containing HCC, and this correlated with poor relapse-free survival, disease-specific survival, progression-free survival, and overall survival in patients with HCC regardless of grades, genders, races, drinking behaviors and other clinical factors. Additionally, high expression of Nuf2 was positively correlated with differential immune cell infiltration and various immune biomarkers. Our work demonstrated that Nuf2 could be a potential prognostic biomarker and could be related to tumor immune cell infiltration in HCC.

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

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.

Gene Signatures And Cancer-Immune Phenotypes Based On m6A Regulators In Breast Cancer

2021 ◽  
Author(s):  
Guanghui Zhao ◽  
Junhua An ◽  
Qian Pu ◽  
Wenwen Geng ◽  
Haiyun Song ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Cell Infiltration ◽  
Clinical Samples ◽  
Immune Cell Infiltration ◽  
Related Gene ◽  
Immune Microenvironment ◽  
Gene Signatures ◽  
Immune Phenotypes ◽  
Processing Stability

Abstract Background: The N6-methyladenosine (m6A) has been considered as a new layer of epitranscriptomic regulation on mRNA processing, stability and translation. However, potential roles of m6A RNA methylation modification in tumor immune microenvironment (TIME) of breast cancer are yet fully understood.Methods: We comprehensively evaluated the genetic variations and transcript expressions of 15 m6A regulators, and clinicopathological features in 1,079 breast cancer samples from The Cancer Genome Atlas (TCGA) database. The mRNA and protein levels of several m6A regulators were validated by RT-qPCR, western blot and immunohistochemistry staining in clinical samples from 39 patients with breast cancer. The prognostic values of m6A regulators were systematically evaluated in different database. We correlated the m6A modification patterns of breast cancer with the immune microenvironment and cancer-immune phenotypes. The m6A regulators-related gene signatures were also analyzed to predict the survival of patients.Results: Some m6A regulators’ CNV events might be potential biomarkers for patient’s stage and prognosis in breast cancer. Major regulators had significantly differential mRNA and protein expression in tumor tissue compared to normal samples among different molecular subtypes of breast cancer, and especially high expression of m6A readers YTHDF1 and YTHDF3 predicted poor survival. Two clusters of breast cancer patients identified by the 15 m6A regulators’ pattern showed distinct overall survival, immune activation status and immune cell infiltration. The profiles of these two clusters accorded with that of two classical cancer-immune phenotypes, immune-excluded and immune-inflamed phenotypes. Moreover, the m6A phenotype-related gene signatures could also be survival predictor in breast cancer.Conclusions: The m6A regulators-based patterns might serve as crucial mediators of TIME in breast cancer. Comprehensive evaluation of tumor m6A modification pattern will contribute to enhance our understanding of the characterization of immune cell infiltration in the tumor microenvironment and promote the responsiveness of breast cancer to immunotherapy.

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