m5C Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Papillary Thyroid Carcinoma

Recently, immune response modulation at the epigenetic level is illustrated in studies, but the possible function of RNA 5-methylcytosine (m5C) modification in cell infiltration within the tumor microenvironment (TME) is still unclear. Three different m5C modification patterns were identified, and high differentiation degree was observed in the cell infiltration features within TME under the above three identified patterns. A low m5C-score, which was reflected in the activated immunity, predicted the relatively favorable prognostic outcome. A small amount of effective immune infiltration was seen in the high m5C-score subtype, indicating the dismal patient survival. Our study constructed a diagnostic model using the 10 signature genes highly related to the m5C-score, discovered that the model exhibited high diagnostic accuracy for PTC, and screened out five potential drugs for PTC based on this m5C-score model. m5C modification exerts an important part in forming the TME complexity and diversity. It is valuable to evaluate the m5C modification patterns in single tumors, so as to enhance our understanding towards the infiltration characterization in TME.

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m5C regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in papillary thyroid carcinoma

10.21203/rs.3.rs-82174/v1 ◽

2020 ◽

Author(s):

Fei Li ◽

Qingmei Deng ◽

Xiaoxi Pang ◽

Shan Huang ◽

Jingmiao Zhang ◽

...

Keyword(s):

Papillary Thyroid Carcinoma ◽

Tumor Microenvironment ◽

Thyroid Carcinoma ◽

Cell Counting ◽

Cell Infiltration ◽

Support Vector ◽

Diagnostic Model ◽

Papillary Thyroid ◽

Signature Genes ◽

Score Model

Abstract BackgroundRecently, immune response modulation at epigenetic level is illustrated in studies, but it is still unclear about the possible function of RNA 5-methylcytosine (m5C) modification in the cell infiltration within tumor microenvironment (TME).MethodsIn this study, the m5C modification patterns from altogether 493 papillary thyroid carcinoma (PTC) samples were assessed completely according to 9 m5C regulators. Afterwards, the modification patterns were correlated with the cell infiltration features in TME. The m5C modification patterns in tumor samples were quantified through the principal component analysis (PCA) algorithms to establish the m5C-score. Moreover, this study mined the signature genes related to the m5C-score, constructed the PTC diagnostic model by the support vector machine (SVM) method, and verified its accuracy based on samples in TCGA and GEO databases. The effects of 5 potential drugs based on the PTC m5C-score model in PTC cells were investigated through in vitro and in vivo assays (i.e., cell counting kit 8 and xenograft model). ResultsA total of 3 different m5C modification patterns were identified, and high differentiation degree was observed in the cell infiltration features within TME under the above 3 identified patterns. It was revealed that, evaluating m5C modification patterns in single tumor samples helped to estimate the stromal activity in TME, expression of immune checkpoint genes, and prognosis for patients. Typically, a low m5C-score, which was reflected in the activated immunity, predicted the relatively favorable prognostic outcome. Few effective immune infiltration was seen in high m5C-score subtype, indicating the dismal patient survival. Finally, this study constructed a diagnostic model using the 10 signature genes highly related to the m5C-score, discovered that the model exhibited high diagnostic accuracy for PTC, and screened out 5 potential drugs for PTC based on this m5C-score model. ConclusionsAccording to findings in the present study, m5C modification exerts an important part in forming the TME complexity and diversity. It is valuable to evaluate the m5C modification patterns in single tumors, so as to enhance our understanding towards the infiltration characterization in TME and to better guide clinical diagnosis as well as immunotherapies.

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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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Characterization of m6A RNA Methylation Regulators Predicts Survival and Immunotherapy in Lung Adenocarcinoma

Frontiers in Immunology ◽

10.3389/fimmu.2021.782551 ◽

2021 ◽

Vol 12 ◽

Author(s):

Minggao Zhu ◽

Yachao Cui ◽

Qi Mo ◽

Junwei Zhang ◽

Ting Zhao ◽

...

Keyword(s):

Tumor Microenvironment ◽

Lung Adenocarcinoma ◽

Immune Cell ◽

Clinical Success ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Consensus Clustering ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Score Model

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.

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Review for "CD8+CD73+ T cells in the tumor microenvironment of head and neck cancer patients are linked to diminished T cell infiltration and activation in tumor tissue"

10.1002/eji.202048626/v1/review2 ◽

2020 ◽

Keyword(s):

T Cells ◽

Head And Neck Cancer ◽

T Cell ◽

Tumor Microenvironment ◽

Head And Neck ◽

Cancer Patients ◽

Neck Cancer ◽

Tumor Tissue ◽

Cell Infiltration ◽

T Cell Infiltration

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Faculty Opinions recommendation of Facilitating T Cell Infiltration in Tumor Microenvironment Overcomes Resistance to PD-L1 Blockade.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726218958.793518487 ◽

2016 ◽

Author(s):

Surender Kharbanda

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Cell Infiltration ◽

T Cell Infiltration

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Semiautomated microfluorometric instrument and reagent system for monitoring disease-related immunosuppression.

Clinical Chemistry ◽

10.1093/clinchem/28.9.1887 ◽

1982 ◽

Vol 28 (9) ◽

pp. 1887-1893 ◽

Cited By ~ 1

Author(s):

D F Ranney ◽

A J Quattrone

Keyword(s):

Immune Response ◽

Dna Content ◽

Peripheral Blood ◽

Fluorescence Enhancement ◽

Photon Counting ◽

Peripheral Blood Lymphocytes ◽

Response Modulation ◽

Blood Lymphocytes ◽

Complex Test ◽

Immune Response Modulation

Abstract Several common metabolites and drugs in the serum in of patients with inflammatory, infectious, autoimmune, immunodeficient, neoplastic, and toxicant-induced diseases can produce artifactual suppression of the [methyl-3H]-thymidine assay, which is widely used to evaluate lymphocyte responsiveness. We have developed a sensitive, semiautomated, fluorescence-enhancement assay in which true immunosuppressors are measured in the presence of absence of such interfering substances. Peripheral blood lymphocytes are activated with mitogens in standard microtiter culture trays. Changes in lymphocyte DNA content are quantified with a reagent formulation containing mithramycin, the fluorescence of which is enhanced on binding to DNA in the presence of MgCl2. We solubilize cells within the intact microtiter tray by using an automated, inverted "Array Sonicator," and measure fluorescence with an automated, photon-counting fluorometer. With this system, immune response modulation can be accurately assessed in the presence of patients' sera and other complex test substances (e.g., supernates from hybridomas, fermentation vats, viral preparations, and macrophage cultures.

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