m<sup>6</sup>A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer

Chong, Wei; Shang, Liang; Liu, Jin; Fang, Zhen; Du, Fengying; Wu, Hao; Yang, Liu; Wang, Zhe; Yang, Chen; Jia, Shengtao; Chen, Liming; Li, Leping; Chen, Hao

doi:10.7150/thno.52717

Cited by 168 publications

(136 citation statements)

References 82 publications

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“…Zhang et al ( 13) identified three distinct m6A modification patterns based on 21 m6A regulators in 1938 GC patients and found that these three patterns were highly associated with different immune phenotypes. Similar findings were also determined in colon cancer (14). LncRNAs are also crucial in mediating the development of diverse immune cells (24).…”

Section: Discussionsupporting

confidence: 80%

“…Meanwhile, m6A modification was reported to be critically associated with tumor microenvironment immune pattern and PD-L1 expression in gastric cancer, colon cancer and head and neck squamous cell carcinoma (13)(14)(15), from these above studies, it could be referred that m6A modification served as a powerful predictor for recruiting candidates for immune checkpoint blockade immunotherapy. Another study showed that a nine m6A-related lncRNAs based prognostic model could forecast the 5-year overall survival (OS) of patients with lower-grade glioma with the C-index of 0.781 (16).…”

Section: Introductionmentioning

confidence: 97%

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Comprehensive Analysis of Tumor Immune Microenvironment and Prognosis of m6A-Related lncRNAs in Gastric Cancer

Wang

Zhu

Tian

et al. 2021

Preprint

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Background N6-methyladenosine (m6A) modification and long non-coding RNAs (lncRNAs) play pivotal role in gastric cancer (GC) progression. The emergence of immunotherapy in GC has created a paradigm shift in the approach of treatment, whereas there is significant heterogeneity with regard to degree of treatment responses, which results from the variability of tumor immune microenvironment (TIME). How the interplay between them enrolled in the shaping of TIME remains unclear. Methods The RNA sequencing and clinical data of GC patients were collected from TCGA database. Pearson correlation test and univariate Cox analysis were used to screen out m6A-related lncRNAs. Consensus clustering was implemented to classify GC patients into 2 subtypes. Survival analysis, the infiltration of immune cells, Gene set enrichment analysis (GSEA) and the mutation profiles were analyzed and compared between two clusters. Then least absolute shrinkage and selection operator (LASSO) COX regression was implemented to select pivotal genes and risk score model was constructed accordingly. The prognosis value of the risk model was explored. In addition, the discrepancies of response to immune checkpoints inhibitor (ICIs) therapy were compared between different risk groups. Finally, we performed qRT-PCR to detect the expression pattern in 35 tumor tissues and paired adjacent normal tissue, and validated the prognostic value of risk model in the our cohort (N=35). Results The expression profiles of 23 lncRNAs were included to cluster patients into different subtypes. Cluster1 with worse prognosis harbored higher immune score, stromal score, ESTIMATE score and mutation rate of genes. Different immune cell infiltration pattern were also displayed between different clusters. GSEA showed that cluster1 was preferentially enriched with tumor hallmarks and tumor correlated biological pathways. Next, 9 lncRNAs were selected by LASSO regression model to construct risk model. Patients in the high risk group had poor prognosis. The prognosis value of this model was also validated in our cohort. As for predicting responses to the ICIs therapy, we found that patients from high risk group had lower TMB score and lower proportion of MSI-H subtype. Moreover, patients had distinct immunophenoscores in different risk groups. Conclusion Our study revealed that the potential interplay between m6A modification and lncRNAs might have critical role in predicting GC prognosis, sculpting TIME landscape and predicting the responses to immune checkpoints inhibitors therapy.

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Section: Discussionsupporting

confidence: 80%

Section: Introductionmentioning

confidence: 97%

Comprehensive Analysis of Tumor Immune Microenvironment and Prognosis of m6A-Related lncRNAs in Gastric Cancer

Wang

Zhu

Tian

et al. 2021

Preprint

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“…To date, there are some studies have analyzed the relationship among m6A modification patterns, m6A scores, tumor progression, and immune cell infiltration in many solid malignancies. Consistently, Zhang B. et al (2020) and Chong et al (2021) identified three different m6A subtypes according to the expression of m6A regulators in colon and gastric cancer. After comprehensively evaluated the association among immune cell infiltration, prognosis, and pathway scores, three m6A patterns to different immune phenotypes (immune-inflamed, immune-excluded, and immune-desert) were constructed.…”

Section: Discussionmentioning

confidence: 56%

m6A Regulator-Associated Modification Patterns and Immune Infiltration of the Tumor Microenvironment in Hepatocarcinoma

Wang

Zhou

et al. 2021

Front. Cell Dev. Biol.

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Background: Immunotherapy elicits durable responses in many tumors. Nevertheless, the positive response to immunotherapy always depends on the dynamic interactions between the tumor cells and infiltrating lymphocytes in the tumor microenvironment (TME). Currently, the application of immunotherapy in hepatocellular carcinoma (HCC) has achieved limited success. The ectopic modification of N6-methyladenosine (m6A) is a common feature in multiple tumors. However, the relationship between m6A modification with HCC clinical features, prognosis, immune cell infiltration, and immunotherapy efficacy remains unclear.Materials and Methods: Here, we comprehensively evaluated m6A modification clusters based on 22 m6A regulators and systematically explored the relationship between m6A modification with tumor progression, prognosis, and immune cell infiltration characteristics. The m6Ascore was calculated by principal component analysis to quantify the m6A modifications of individual patients. Key regulators involved in immunoregulation in HCC were identified using immunohistochemistry and immunofluorescence.Results: Three distinct m6A modification clusters were identified. The m6A clusters were significantly associated with clinical features, prognosis, and immune cell infiltration. The three clusters were highly consistent with the three tumor immune phenotypes, i.e., immune-excluded, immune-inflamed, and immune-desert. Comprehensive bioinformatics analysis revealed that high m6Ascore was closely associated with tumor progression, poor prognosis, and immunotherapy non-response. m6A regulators were dysregulated in HCC tissues. Hence, they play a role as predictors of poor prognosis. Tissue microarray demonstrated that overexpressed YTHDF1 was associated with low CD3+ and CD8+ T cell infiltration in HCC.Conclusion: Our findings demonstrate that m6A modification patterns play a crucial role in the tumor immune microenvironment and the prognosis of HCC. High YTHDF1 expression is closely associated with low CD3+ and CD8+ T cell infiltration in HCC.

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“…As in the case of m6A RNA methylation regulators, it has been reported that m6A regulators play independent role of immune infiltration in several types of cancers (35,36,39). In this study, we first presented the evidence of the potential correlation between NAT10, RNA acetylation regulator, with immune infiltration.…”

Section: Discussionmentioning

confidence: 78%

Prognostic and Immunological Role of mRNA ac4C Regulator NAT10 in Pan-Cancer: New Territory for Cancer Research?

Yang

Zhang

et al. 2021

Front. Oncol.

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BackgroundNAT10 (also known as human N-acetyltransferase-like protein) is a critical gene that regulates N4-acetylcytidine formation in RNA, similar to the multiple regulators of N6-methyladenosine. However, the underlying functions and mechanisms of NAT10 in tumor progression and immunology are unclear.MethodsIn this study, we systematically analyzed the pan-cancer expression and correlations of NAT10, using databases including Oncomine, PrognoScan, GEPIA2, and Kaplan-Meier Plotter. The potential correlations of NAT10 with immune infiltration stages and gene marker sets were analyzed using the Tumor Immune Estimation Resource and GEPIA2.ResultsCompared with normal tissues, NAT10 showed higher expression in most cancers based on combined data from TCGA and GTEx. In different datasets, high NAT10 expression was significantly correlated with poor prognosis in adrenocortical carcinoma, head and neck squamous cell carcinoma, liver hepatocellular carcinoma, kidney renal papillary cell carcinoma, and pheochromocytoma and paraganglioma. Moreover, there were significant positive correlations between NAT10 expression and immune infiltrates, including B cells, CD8+ T cells, CD4+ T cells, neutrophils, macrophages, dendritic cells, endothelial cells, and fibroblasts in LIHC. NAT10 expression showed strong correlations with diverse immune marker gene sets in LIHC.ConclusionNAT10 expression affects the prognosis of pan-cancer patients and is significantly correlated with tumor immune infiltration. Furthermore, it represents a potential target for cancer therapy.

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m⁶A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer

Cited by 168 publications

References 82 publications

Comprehensive Analysis of Tumor Immune Microenvironment and Prognosis of m6A-Related lncRNAs in Gastric Cancer

Comprehensive Analysis of Tumor Immune Microenvironment and Prognosis of m6A-Related lncRNAs in Gastric Cancer

m6A Regulator-Associated Modification Patterns and Immune Infiltration of the Tumor Microenvironment in Hepatocarcinoma

Prognostic and Immunological Role of mRNA ac4C Regulator NAT10 in Pan-Cancer: New Territory for Cancer Research?

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m6A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer

Cited by 168 publications

References 82 publications

Comprehensive Analysis of Tumor Immune Microenvironment and Prognosis of m6A-Related lncRNAs in Gastric Cancer

Comprehensive Analysis of Tumor Immune Microenvironment and Prognosis of m6A-Related lncRNAs in Gastric Cancer

m6A Regulator-Associated Modification Patterns and Immune Infiltration of the Tumor Microenvironment in Hepatocarcinoma

Prognostic and Immunological Role of mRNA ac4C Regulator NAT10 in Pan-Cancer: New Territory for Cancer Research?

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m⁶A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer