m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization in Acute Myeloid Leukemia.

Recent studies have demonstrated epigenetic regulation of immune responses. Nevertheless, the underlying effect of RNA N6-methyladenosine (m6A) modifications on tumor microenvironment cell infiltration remains elusive. In this study, we thoroughly assessed m6A modification patterns of 255 myeloid leukemia specimens based on 23 m6A regulators. Consensus clustering of the 23 m6A regulators was performed to determine three distinct m6A modification patterns that were remarkably consistent with three immunophenotypes of tumors: immunorejection, immune activation, and immune inertness. Further evaluation and prognostic analysis of the m6A modification patterns of individual tumors revealed that low m6A score was characterized by increased mutational burden, immune activation, and survival rates, whereas high m6A score was characterized by poorer survival rates and the absence of effective immune infiltration. In addition, this study investigated the association between m6A regulators and antitumor immune responses and discovered higher expression of the immune regulators PD-L1, PD-L2, MRP1, and MRP2 in low m6A scores. Generally, the expression pattern of m6A regulators was remarkably associated with prognostic results and antitumor immune responses in acute myeloid leukemia and may be an underlying target and biological marker for immune therapies.

Du A ，Wu X ，Gao Y ，Jiang B ，Wang J ，Zhang P ，Zhao Q ... -  《Frontiers in Immunology》

Comprehensive Analysis of PD-L1 Expression, Immune Infiltrates, and m6A RNA Methylation Regulators in Esophageal Squamous Cell Carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the most common cancer types and represents a threat to global public health. N6-Methyladenosine (m6A) methylation plays a key role in the occurrence and development of many tumors, but there are still few studies investigating ESCC. This study attempts to construct a prognostic signature of ESCC based on m6A RNA methylation regulators and to explore the potential association of these regulators with the tumor immune microenvironment (TIME). The transcriptome sequencing data and clinical information of 20 m6A RNA methylation regulators in 453 patients with ESCC (The Cancer Genome Atlas [TCGA] cohort, n = 95; Gene Expression Omnibus [GEO] cohort, n = 358) were obtained. The differing expression levels of m6A regulators between ESCC and normal tissue were evaluated. Based on the expression of these regulators, consensus clustering was performed to investigate different ESCC clusters. PD-L1 expression, immune score, immune cell infiltration and potential mechanisms among different clusters were examined. LASSO Cox regression analysis was utilized to obtain a prognostic signature based on m6A RNA methylation modulators. The relationship between the risk score based on the prognostic signature and the TIME of ESCC patients was studied in detail. Six m6A regulators (METTL3, WTAP, IGF2BP3, YTHDF1, HNRNPA2B1 and HNRNPC) were observed to be significantly highly expressed in ESCC tissues. Two molecular subtypes (clusters 1/2) were determined by consensus clustering of 20 m6A modulators. The expression level of PD-L1 in ESCC tissues increased significantly and was significantly negatively correlated with the expression levels of YTHDF2, METL14 and KIAA1429. The immune score, CD8 T cells, resting mast cells, and regulatory T cells (Tregs) in cluster 2 were significantly increased. Gene set enrichment analysis (GSEA) shows that this cluster involves multiple hallmark pathways. We constructed a five-gene prognostic signature based on m6A RNA methylation, and the risk score based on the prognostic signature was determined to be an independent prognostic indicator of ESCC. More importantly, the prognostic value of the prognostic signature was verified using another independent cohort. m6A regulators are related to TIME, and their copy-number alterations will dynamically affect the number of tumor-infiltrating immune cells. Our study established a strong prognostic signature based on m6A RNA methylation regulators; this signature was able to accurately predict the prognosis of ESCC patients. The m6A methylation regulator may be a key mediator of PD-L1 expression and immune cell infiltration and may strongly affect the TIME of ESCC.

Guo W ，Tan F ，Huai Q ，Wang Z ，Shao F ，Zhang G ，Yang Z ，Li R ，Xue Q ，Gao S ，He J ... -  《Frontiers in Immunology》

Characterization of m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration in acute myeloid leukemia.

Previous studies have confirmed the existence of epigenetic regulation of immune responses in acute myeloid leukemia. However, the potential role of RNA N6-methyladenosine (m6A) remodeling in tumor microenvironment (TME) infiltration remains unclear. m6A patterns of 469 AML patients (420 of which provided survival data) based on 18 m6A regulators were systematically evaluated. Based on the expression of 18 m6A regulators, unsupervised agglomerative cluster analysis was applied to recognize the various m6A modification types and to classify patients. We linked these patterns to TME infiltration characteristics and identified three distinct populations of m6A modifications. These three TME cell infiltration patterns are characterized by a high degree of concordance with the three tumor immunophenotypes, which include immunoinflammatory, immunorejection, and immune inert patterns. We showed that assessment of m6A modification patterns within individually neoplasms can forecast the stage of neoplasmic inflammation, TME basal activity, subtype, hereditary mutation, and clinical patient prognosis. Limited low m6Ascore, featuring increased mutational load and immune activation, indicates an inflammatory phenotype of TME with a 5-year survival rate at 14.4% compared to the high-m6Ascore group (40.9%). Data from two different cohorts demonstrated that a higher m6Ascore showed a marked therapeutic superiority as well as clinical advantage. Assessing m6A modification patterns in AML patients could improve our knowledge of the TME infiltrative profile as well as directing effective immunotherapeutic approaches.

Han S ，Qi J ，Fang K ，Wang H ，Tang Y ，Wu D ，Han Y ... -  《Cancer Medicine》

Correlation analysis of m6A-modified regulators with immune microenvironment infiltrating cells in lung adenocarcinoma.

Ye W ，Huang T 《PLoS One》

m6A Regulators Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration Characterization In Nasopharyngeal Carcinoma.

The role of RNA N6-methyladenosine (m6A) modification in tumor progression and metastasis has been demonstrated. Nonetheless, potential biological function of m6A modification patterns in nasopharyngeal carcinoma (NPC) remains unknown. The m6A modification patterns were comprehensively evaluated based on 26 m6A regulators in NPC, and m6A subtype and also m6A score were identified and systematically correlated with representative tumor characteristics. Two distinct m6A subtypes were determined and were highly consistent with immune activated and immune suppressed phenotypes, respectively. More representative m6A scores of individual tumors could predict tumor microenvironment (TME) infiltration, mRNA based stemness index (mRNAsi), EBV gene expression, genetic variation, and prognosis of NPC patients. Low m6A score, characterized by activation of immunity and suppression of mRNAsi and EBV gene, indicated an activated TME phenotype and better PFS and also lower risk of recurrence and metastasis. High m6A score, characterized by activation of Wnt and NF-κB signaling pathway and lack of effective immune infiltration, indicated an immune suppressed TME phenotype and poorer survival. Low m6A score was also correlated with increased tumor mutation burden (TMB) and better response to immunotherapy, and vice versa. A significant therapeutic advantage in patients with low m6A score was confirmed with an anti-PDL1 immunotherapy cohort. m6A patterns played an important role in the diversity and complexity of TME. m6A score could be used to evaluate the m6A pattern of individual tumor to enhance our understanding of TME infiltration and guide more effective immunotherapy strategies.

Liu Z ，He J ，Han J ，Yang J ，Liao W ，Chen N ... -  《Frontiers in Immunology》