Dataset Information

M⁶A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.

ABSTRACT: Recent studies have highlighted the biological significance of exosomes and m⁶A modifications in immunity. Nonetheless, it remains unclear whether the m⁶A modification gene in exosomes of body fluid has potential roles in the tumor microenvironment (TME). Herein, we identified three different m⁶A-related exosomal gene modification patterns based on 59 m⁶A-related exosomal genes, which instructed distinguishing characteristics of TME in colon cancer (CC). We demonstrated that these patterns could predict the stage of tumor inflammation, subtypes, genetic variation, and patient prognosis. Furthermore, we developed a scoring mode-m⁶A-related exosomal gene score (MREGS)-by detecting the level of m⁶A modification in exosomes to classify immune phenotypes. Low MREGS, characterized by prominent survival and immune activation, was linked to a better response to anti-PDL1 immunotherapy. In contrast, the higher MREGS group displayed remarkable stromal activation, high activity of innate immunocytes, and a lower survival rate. Hence, this work provides a novel approach for evaluating TME cell infiltration in colon cancer and guiding more effective immunotherapy strategies.

SUBMITTER: Zheng J

PROVIDER: S-EPMC9423980 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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m6A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.

Zheng Junjie J Feng Panpan P Chen Dawei D Zhang Cuiyu C Ji Yuge Y Liu Yanting Y Fan Xiaohua X Li Jingxin J

Oxidative medicine and cellular longevity 20220822

Recent studies have highlighted the biological significance of exosomes and m6A modifications in immunity. Nonetheless, it remains unclear whether the m6A modification gene in exosomes of body fluid has potential roles in the tumor microenvironment (TME). Herein, we identified three different m6A-related exosomal gene modification patterns based on 59 m6A-related exosomal genes, which instructed distinguishing characteristics of TME in colon cancer (CC ...[more]

PMID: 36046691

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Project description:Recent studies have highlighted the biological significance of RNA N6-methyladenosine (m6A) modification in tumorigenicity and progression. However, it remains unclear whether m6A modifications also have potential roles in immune regulation and tumor microenvironment (TME) formation. Methods: In this study, we curated 23 m6A regulators and performed consensus molecular subtyping with NMF algorithm to determine m6A modification patterns and the m6A-related gene signature in colon cancer (CC). The ssGSEA and CIBERSORT algorithms were employed to quantify the relative infiltration levels of various immune cell subsets. An PCA algorithm based m6Sig scoring scheme was used to evaluate the m6A modification patterns of individual tumors with an immune response. Results: Three distinct m6A modification patterns were identified among 1307 CC samples, which were also associated with different clinical outcomes and biological pathways. The TME characterization revealed that the identified m6A patterns were highly consistent with three known immune profiles: immune-inflamed, immune-excluded, and immune-desert, respectively. Based on the m6Sig score, which was extracted from the m6A-related signature genes, CC patients can be divided into high and low score subgroups. Patients with lower m6Sig score was characterized by prolonged survival time and enhanced immune infiltration. Further analysis indicated that lower m6Sig score also correlated with greater tumor mutation loads, PD-L1 expression, and higher mutation rates in SMGs (e.g., PIK3CA and SMAD4). In addition, patients with lower m6Sig scores showed a better immune responses and durable clinical benefits in three independent immunotherapy cohorts. Conclusions: This study highlights that m6A modification is significantly associated with TME diversity and complexity. Quantitatively evaluating the m6A modification patterns of individual tumors will strengthen our understanding of TME characteristics and promote more effective immunotherapy strategies.

Project description:BackgroundRecently, many studies have been conducted to examine immune response modification at epigenetic level, but the candidate effect of RNA 5-methylcytosine (m5 C) modification on tumor microenvironment (TME) of acute myeloid leukemia (AML) is still unknown at present.MethodsWe assessed the patterns of m5 C modification among 417 AML cases by using nine m5 C regulators. Thereafter, we associated those identified modification patterns with TME cell infiltration features. Additionally, stepwise regression and LASSO Cox regression analyses were conducted for quantifying patterns of m5 C modification among AML cases to establish the m5 C-score. Meanwhile, we validated the expression of genes in the m5C-score model by qRT-PCR. Finally, the present work analyzed the association between m5 C-score and AML clinical characteristics and prognostic outcomes.ResultsIn total, three different patterns of m5 C modification (m5 C-clusters) were identified, and highly differentiated TME cell infiltration features were also identified. On this basis, evaluating patterns of m5 C modification in single cancer samples was important for evaluating the immune/stromal activities in TME and for predicting prognosis. In addition, the m5 C-score was established, which showed a close relation with the overall survival (OS) of test and training set samples. Moreover, multivariate Cox analysis suggested that our constructed m5 C-score served as the independent predicting factor for the prognosis of AML (hazard ratio = 1.57, 95% confidence interval = 1.38-1.79, p < 1e-5 ).ConclusionsThis study shows that m5 C modification may be one of the key roles in the formation of diversity and complexity of TME. Meanwhile, assessing the patterns of m5 C modification among individual cancer samples is of great importance, which provides insights into cell infiltration features within TME, thereby helping to develop relevant immunotherapy and predict patient prognostic outcomes.

Dataset Information

M⁶A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.

Publications

m<sup>6</sup>A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.

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Dataset Information

M6A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.

Publications

m<sup>6</sup>A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

M⁶A Regulator-Based Exosomal Gene Methylation Modification Patterns Identify Distinct Microenvironment Characterization and Predict Immunotherapeutic Responses in Colon Cancer.