scholarly journals Identification of m6A Regulator-Associated Methylation Modification Clusters and Immune Profiles in Melanoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Fengying Du ◽  
Han Li ◽  
Yan Li ◽  
Yang Liu ◽  
Xinyu Li ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Molecular Mechanisms ◽  
Nk Cell ◽  
Comprehensive Evaluation ◽  
Nonnegative Matrix ◽  
Principal Component ◽  
Gene Signature ◽  
Melanoma Tumor ◽  
Immune Infiltration ◽  
Clinical Benefits

RNA N6-methyladenosine (m6A) modification in tumorigenesis and progression has been highlighted and discovered in recent years. However, the molecular and clinical implications of m6A modification in melanoma tumor microenvironment (TME) and immune infiltration remain largely unknown. Here, we utilized consensus molecular clustering with nonnegative matrix factorization based on the melanoma transcriptomic profiles of 23 m6A regulators to determine the m6A modification clusters and m6A-related gene signature. Three distinct m6A modification patterns (m6A-C1, C2, and C3), which are characterized by specific m6A regulator expression, survival outcomes, and biological pathways, were identified in more than 1,000 melanoma samples. The immune profile analyses showed that these three m6A modification subtypes were highly consistent with the three known immune phenotypes: immune-desert (C1), immune-excluded (C2), and immune-inflamed (C3). Tumor digital cytometry (CIBERSORT, ssGSEA) algorithm revealed an upregulated infiltration of CD8+ T cell and NK cell in m6A-C3 subtype. An m6A scoring scheme calculated by principal component of m6A signatures stratified melanoma patients into high- and low-m6sig score subgroups; a high score was significantly associated with prolonged survival and enhanced immune infiltration. Furthermore, fewer somatic copy number alternations (SCNA) and PD-L1 expression were found in patients with high m6Sig score. In addition, patients with high m6Sig score demonstrated marked immune responses and durable clinical benefits in two independent immunotherapy cohorts. Overall, this study indicated that m6A modification is involved in melanoma tumor microenvironment immune regulation and contributes to formation of tumor immunogenicity. Comprehensive evaluation of the m6A modification pattern of individual tumors will provide more insights into molecular mechanisms of TME characterization and promote more effective personalized biotherapy strategies.

scholarly journals The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3542
Author(s):  
Joanna Domagala ◽  
Mieszko Lachota ◽  
Marta Klopotowska ◽  
Agnieszka Graczyk-Jarzynka ◽  
Antoni Domagala ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Nk Cell ◽  
Metabolic Changes ◽  
Immune Effector ◽  
Effector Cells ◽  
Immune Effector Cells ◽  
Almost All

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.

scholarly journals Characterization of a Tumor-Microenvironment-Relevant Gene Set Based on Tumor Severity in Colon Cancer and Evaluation of Its Potential for Dihydroartemisinin Targeting

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Bo Liang ◽  
Biao Zheng ◽  
Yan Zhou ◽  
Zheng-Quan Lai ◽  
Citing Zhang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Tumor Microenvironment ◽  
Clinical Outcomes ◽  
Molecular Mechanisms ◽  
In Silico Analysis ◽  
Adverse Outcomes ◽  
Therapeutic Implications ◽  
Immune Infiltration ◽  
Highly Correlated

Colon cancer (COAD) is a leading cause of cancer mortality in the world. Most patients with COAD die as a result of cancer cell metastasis. However, the mechanisms underlying the metastatic phenotype of COAD remain unclear. Instead, particular features of the tumor microenvironment (TME) could predict adverse outcomes including metastasis in patients with COAD, and the role of TME in governing COAD progression is undeniable. Therefore, exploring the role of TME in COAD may help us better understand the molecular mechanisms behind COAD progression which may improve clinical outcomes and quality of patients. Here, we identified a Specific TME Regulatory Network including AEBP1, BGN, POST, and FAP (STMERN) that is highly involved in clinical outcomes of patients with COAD. Comprehensive in silico analysis of our study revealed that the STMERN is highly correlated with the severity of COAD. Meanwhile, our results reveal that the STMERN might be associated with immune infiltration in COAD. Importantly, we show that dihydroartemisinin (DHA) potentially interacts with the STMERN. We suggest that DHA might contribute to immune infiltration through regulating the STMERN in COAD. Taken together, our data provide a set of biomarkers of progression and poor prognosis in COAD. These findings could have potential prognostic and therapeutic implications in the progression of COAD.

scholarly journals 9-Gene Signature Correlated With CD8+ T Cell Infiltration Activated by IFN-γ: A Biomarker of Immune Checkpoint Therapy Response in Melanoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Kexin Yan ◽  
Yuxiu Lu ◽  
Zhangyong Yan ◽  
Yutao Wang
Keyword(s):  
T Cell ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Cellular Response ◽  
Antigen Processing ◽  
Checkpoint Inhibitors ◽  
Prognostic Significance ◽  
Gene Signature ◽  
Melanoma Tumor ◽  
Related Factors

PurposeTo identify CD8+ T cell-related factors and the co-expression network in melanoma and illustrate the interactions among CD8+ T cell-related genes in the melanoma tumor microenvironment.MethodWe obtained melanoma and paracancerous tissue mRNA matrices from TCGA-SKCM and GSE65904. The CIBERSORT algorithm was used to assess CD8+ T cell proportions, and the “estimate” package was used to assess melanoma tumor microenvironment purity. Weighted gene co-expression network analysis was used to identify the most related co-expression modules in TCGA-SKCM and GSE65904. Subsequently, a co-expression network was built based on the joint results in the two cohorts. Subsequently, we identified the core genes of the two most relevant modules of CD8+T lymphocytes according to the module correlation, and constructed the signature using ssGSEA. Later, we compared the signature with the existing classical pathways and gene sets, and confirmed the important prognostic significance of the signature in this paper.ResultsNine co-expressed genes were identified as CD8+ T cell-related genes enriched in the cellular response to interferon−gamma process and antigen processing and presentation of peptide antigen. In the low expression level group, inflammation and immune responses were weaker. Single-cell sequencing and immunohistochemistry indicated that these nine genes were highly expressed in CD8+ T cells group.ConclusionWe identified nine-gene signature, and the signature is considered as the biomarker for T lymphocyte response and clinical response to immune checkpoint inhibitors for melanoma

Molecular characterization, biological function, tumor microenvironment association and clinical significance of m6A regulators in lung adenocarcinoma

2020 ◽  
Author(s):  
Yin Li ◽  
Jie Gu ◽  
Fengkai Xu ◽  
Qiaoliang Zhu ◽  
Yiwei Chen ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Lung Adenocarcinoma ◽  
Web Application ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Interaction Network ◽  
Pathway Interaction ◽  
Clinical Benefits ◽  
Pathway Interaction Network ◽  
Scoring Tool

Abstract N6-methyladenosine (m6A) modification can regulate a variety of biological processes. However, the implications of m6A modification in lung adenocarcinoma (LUAD) remain largely unknown. Here, we systematically evaluated the m6A modification features in more than 2400 LUAD samples by analyzing the multi-omics features of 23 m6A regulators. We depicted the genetic variation features of m6A regulators, and found mutations of FTO and YTHDF3 were linked to worse overall survival. Many m6A regulators were aberrantly expressed in tumors, among which FTO, IGF2BP3, YTHDF1 and RBM15 showed consistent alteration features across 11 independent cohorts. Besides, the regulator-pathway interaction network demonstrated that m6A modification was associated with various biological pathways, including immune-related pathways. The correlation between m6A regulators and tumor microenvironment was also assessed. We found that LRPPRC was negatively correlated with most tumor-infiltrating immune cells. On the other hand, we established a scoring tool named m6Sig, which was positively correlated with PD-L1 expression and could reflect both the tumor microenvironment characterization and prognosis of LUAD patients. Comparison of CNV between high and low m6Sig groups revealed differences on chromosome 7. Application of m6Sig on an anti-PD-L1 immunotherapy cohort confirmed that the high m6Sig group demonstrated therapeutic advantages and clinical benefits. Our study indicated that m6A modification is involved in many aspects of LUAD and contributes to tumor microenvironment formation. A better understanding of m6A modification will provide more insights into the molecular mechanisms of LUAD and facilitate developing more effective personalized treatment strategies. A web application was built along with this study (http://www.bioinfo-zs.com/luadexpress/).

scholarly journals Comprehensive Analysis of m6A Regulators Characterized by the Immune Cell Infiltration in Head and Neck Squamous Cell Carcinoma to Aid Immunotherapy and Chemotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiqiang Yang ◽  
Xiaoping Ming ◽  
Shuo Huang ◽  
Minlan Yang ◽  
Xuhong Zhou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Immune Cell ◽  
Comprehensive Evaluation ◽  
Principal Component ◽  
Response To Therapy ◽  
The Cancer Genome Atlas ◽  
Mutation Burden ◽  
Number Variation ◽  
Clinical Benefits ◽  
Cancer Genome Atlas

BackgroundN6-Methyladenosine (m6A), which is a prevalent regulator of mRNA expression, has gathered increasing study interests. Though the role of m6A as being important in many biological processes (such as growth and proliferation of cancers) has been well documented, its potential role in tumor immune microenvironment (TIME) has rarely been analyzed.MethodsWe downloaded RNA expression, single nucleotide polymorphism (SNP), and copy number variation (CNV) data from The Cancer Genome Atlas (TCGA). We then curated 21 m6A regulators and clustered patients into three m6A subtypes and m6A-related gene subtypes and compared them based on overall survival (OS). The combination of CIBERSORT as well as ssGSEA quantified the infiltration levels of immune cells and immune-related functions. The m6A scores were determined by using principal component analysis (PCA) algorithm. Furthermore, we evaluate the correlation of m6A regulators with immune and response to therapy.ResultsThree m6A clusters were identified based on the TCGA-HNSCC cohort, and there were significant associations among them in overall outcomes and caner-related pathways. We found that three m6A clusters were consistent with three phenotypes: immune-inflamed, immune-dessert, and immune-excluded. HNSCC patients were divided into high– and low–m6A score groups based on the cutoff of m6A score. Patients with lower m6A score had better overall survival outcome. Further analysis indicated that patients with higher m6A score presented higher tumor mutation burden (TMB). In addition, patients in low–m6A score subgroup had high chemotherapeutics sensitivity. GEO cohort confirmed patients with low m6A score demonstrated significant overall survival advantages and clinical benefits. Low m6A score carry an increased neoantigen load, eliciting a response to immunotherapy, and its value in predicting survival outcomes of immunotherapy was also confirmed in three anti-PD-1 cohorts.ConclusionsOur study demonstrated that m6A regulators are closely related to TIME and the m6A score was an effective prognostic biomarker and predictive indicator for immunotherapy and chemotherapeutics. Comprehensive evaluation of m6A regulators in tumors will extend our understanding of TIME and effectively guide increasing study investigations on immunotherapy and chemotherapy strategies for HNSCC.

scholarly journals Exploration of a Metabolism-Related Gene Signature Predicting Prognosis for Ovarian Cancer

2021 ◽  
Author(s):  
Jinling Zhang ◽  
Yifan Zhang ◽  
Lin Zhang ◽  
Haili Li
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
Tumor Microenvironment ◽  
Drug Sensitivity ◽  
Cox Regression ◽  
Risk Group ◽  
Gene Signature ◽  
Prognostic Signature ◽  
Immune Infiltration ◽  
Metabolic Genes

Abstract Background: Dysregulation of metabolism plays a critical role in the pathogenesis and progression of ovarian cancer (OC). However, the expression pattern of metabolic genes in OC and the prognostic value of metabolism-related genes for OC patients remains to be elucidated. Thus, this study aimed to identify a metabolism-related prognostic gene signature for OC. Methods: The expression profiles of metabolism-related genes and associated clinicopathological characteristics were obtained from online datasets (The Cancer Genome Atlas, TCGA and The Genotype-Tissue Expression, GTEx). The differently expressed genes were subjected to functional enrichment analysis. By means of LASSO, univariate and multivariate Cox regression analyses, this predictive signature was constructed and validated by internal and external databases. Genomic alterations, immune infiltration, tumor microenvironment, and drug sensitivity associated with the signature were also described.Results: A total of 302 metabolism-related differentially expressed genes were identified. These genes were mainly enriched in functions associated with substance and energy metabolism. Based on the 302 identified genes, a prognostic signature of 21 metabolic genes was constructed and validated across internal and external cohorts. The patients in the high-risk group had significantly longer overall survival compared to those in the low-risk group. By univariate and multivariate Cox regression, the signature was identified as an independent prognostic predictor for overall survival. There were also noticeable differences with regards to genetic alteration, immune infiltration, tumor microenvironment and drug sensitivity between the two groups.Conclusion: Our study suggests that clinical outcomes of OC patients are associated with dysregulated metabolic genes and that the metabolism-related prognostic signature can be used as a predictor for the overall survival of OC patients.

scholarly journals Density of immunogenic antigens does not explain the presence or absence of the T-cell–inflamed tumor microenvironment in melanoma

2016 ◽  
Vol 113 (48) ◽  
pp. E7759-E7768 ◽  
Author(s):  
Stefani Spranger ◽  
Jason J. Luke ◽  
Riyue Bao ◽  
Yuanyuan Zha ◽  
Kyle M. Hernandez ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Gene Signature ◽  
The Cancer Genome Atlas ◽  
Immune Infiltration ◽  
Cancer Testis

Melanoma metastases can be categorized by gene expression for the presence of a T-cell–inflamed tumor microenvironment, which correlates with clinical efficacy of immunotherapies. T cells frequently recognize mutational antigens corresponding to nonsynonymous somatic mutations (NSSMs), and in some cases shared differentiation or cancer–testis antigens. Therapies are being pursued to trigger immune infiltration into non–T-cell–inflamed tumors in the hope of rendering them immunotherapy responsive. However, whether those tumors express antigens capable of T-cell recognition has not been explored. To address this question, 266 melanomas from The Cancer Genome Atlas (TCGA) were categorized by the presence or absence of a T-cell–inflamed gene signature. These two subsets were interrogated for cancer–testis, differentiation, and somatic mutational antigens. No statistically significant differences were observed, including density of NSSMs. Focusing on hypothetical HLA-A2+binding scores, 707 peptides were synthesized, corresponding to all identified candidate neoepitopes. No differences were observed in measured HLA-A2 binding between inflamed and noninflamed cohorts. Twenty peptides were randomly selected from each cohort to evaluate priming and recognition by human CD8+T cells in vitro with 25% of peptides confirmed to be immunogenic in both. A similar gene expression profile applied to all solid tumors of TCGA revealed no association between T-cell signature and NSSMs. Our results indicate that lack of spontaneous immune infiltration in solid tumors is unlikely due to lack of antigens. Strategies that improve T-cell infiltration into tumors may therefore be able to facilitate clinical response to immunotherapy once antigens become recognized.

scholarly journals M6A Classification Combined With Tumor Microenvironment Immune Characteristics Analysis of Bladder Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Huili Zhu ◽  
Xiaocan Jia ◽  
Yuping Wang ◽  
Zhijuan Song ◽  
Nana Wang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Cancer Progression ◽  
Cox Regression ◽  
Principal Component ◽  
Underlying Mechanism ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Cell Infiltration ◽  
Clinical Benefits

BackgroundStudies have shown that N6-methyl adenosine (m6A) plays an important role in cancer progression; however, the underlying mechanism of m6A modification in tumor microenvironment (TME) cell infiltration of bladder cancer remains unclear. This study aimed to investigate the role of m6A modification in TME cell infiltration of bladder cancer.MethodsThe RNA expression profile and clinical data of bladder cancer were obtained from The Cancer Genome Atlas and Gene Expression Omnibus. We assessed the m6A modification patterns of 664 bladder cancer samples based on 20 m6A regulators through unsupervised clustering analysis and systematically linked m6A modification patterns to TME cell infiltration characteristics. Gene ontology and gene set variation analyses were conducted to analyze the underlying mechanism based on the assessment of m6A methylation regulators. Principal component analysis was used to construct the m6A score to quantify m6A modification patterns of bladder cancer.ResultsThe genetic and expression alterations in m6A regulators were highly heterogeneous between normal and bladder tissues. Three m6A modification patterns were identified. The cell infiltration characteristics were highly consistent with the three immune phenotypes, including immune rejection, immune inflammation, and immune desert. The biological functions of three m6A modification patterns were different. Cox regression analyses revealed that the m6A score was an independent signature with patient prognosis (HR = 1.198, 95% CI: 1.031–1.390). Patients with a low-m6A score were characterized by increased tumor mutation burden, PD-L1 expression, and poorer survival. Patients in the low-m6A score group also showed significant immune responses and clinical benefits in the CTLA-4 immunotherapy cohort (p =0.0069).ConclusionsThe m6A methylation modification was related to the formation of TME heterogeneity and complexity. Assessing the m6A modification pattern of individual bladder cancer will improve the understanding of TME infiltration characteristics.

scholarly journals Identification of an Immune Gene Signature Based on Tumor Microenvironment Characteristics in Colon Adenocarcinoma

2021 ◽  
Vol 30 ◽  
pp. 096368972110013
Author(s):  
Ying Chen ◽  
Jia Zhao
Keyword(s):  
Tumor Microenvironment ◽  
Colon Adenocarcinoma ◽  
Principal Component ◽  
Enrichment Analysis ◽  
Tumor Infiltrating Lymphocytes ◽  
Risk Groups ◽  
Gene Signature ◽  
Gene Set Enrichment Analysis ◽  
The Cancer Genome Atlas ◽  
Immune Gene

Tumor microenvironment (TME) changes are related to the occurrence and development of colon adenocarcinoma (COAD). This study aimed to analyze the characteristics of the immune microenvironment in CC, as well as the microenvironment’s relationship with the clinical features of CC. Based on The Cancer Genome Atlas (TCGA) and GSE39582 cohorts, the scores of 22 tumor infiltrating lymphocytes (TILs) were calculated using CIBERSORT. ConsensusClusterPlus was used for unsupervised clustering. Three TME subtypes (TMEC1, TMEC2, and TME3) were identified based on TIL scores. TMEC2 was associated with the worst prognosis. Random forest, k-means clustering, and principal component analysis were used to construct the TME score risk signature. The median TME score was used to divide the samples into high- and low-risk groups. The prognoses of the patients with high TME scores were worse than those of the patients with low TME scores. A high TME score was an independent prognostic risk factor for patients with colon cancer. The Gene Set Enrichment Analysis (GSEA) results showed that those with high TME scores were enriched in FOCAL_ADHESION, ECM_RECEPTOR_INTERACTION, and PATHWAYS_IN_CANCER. Our findings will provide a new strategy for immunotherapy in patients with CC.

scholarly journals Comprehensive of N1-Methyladenosine Modifications Patterns and Immunological Characteristics in Ovarian Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinhui Liu ◽  
Can Chen ◽  
Yichun Wang ◽  
Cheng Qian ◽  
Junting Wei ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Comprehensive Evaluation ◽  
Principal Component ◽  
Rt Pcr ◽  
Immune Infiltration ◽  
Therapeutic Benefits ◽  
Small Molecule Drugs ◽  
Principal Component Analysis Algorithm ◽  
Immune Phenotypes ◽  
Essential Function

Backgroundrecently, many researches have concentrated on the relevance between N1-methyladenosine (m1A) methylation modifications and tumor progression and prognosis. However, it remains unknown whether m1A modification has an effect in the prognosis of ovarian cancer (OC) and its immune infiltration.MethodsBased on 10 m1A modulators, we comprehensively assessed m1A modification patterns in 474 OC patients and linked them to TME immune infiltration characteristics. m1Ascore computed with principal component analysis algorithm was applied to quantify m1A modification pattern in OC patients. m1A regulators protein and mRNA expression were respectively obtained by HPA website and RT-PCR in clinical OC and normal samples.ResultsWe finally identified three different m1A modification patterns. The immune infiltration features of these m1A modification patterns correspond to three tumor immune phenotypes, including immune-desert, immune-inflamed and immune-excluded phenotypes. The results demonstrate individual tumor m1A modification patterns can predict patient survival, stage and grade. The m1Ascore was calculated to quantify individual OC patient’s m1A modification pattern. A high m1Ascore is usually accompanied by a better survival advantage and a lower mutational load. Research on m1Ascore in the treatment of OC patients showed that patients with high m1Ascore showed marked therapeutic benefits and clinical outcomes in terms of chemotherapy and immunotherapy. Lastly, we obtained four small molecule drugs that may potentially ameliorate prognosis.ConclusionThis research demonstrates that m1A methylation modification makes an essential function in the prognosis of OC and in shaping the immune microenvironment. Comprehensive evaluation of m1A modifications improves our knowledge of immune infiltration profile and provides a more efficient individualized immunotherapy strategy for OC patients.

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