Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells

Xiong, Jia; He, Jia; Zhu, Jianxin; Pan, Jiongli; Liao, Weijie; Ye, Hongying; Wang, Haofei; Song, Yinjing; Du, Yue; Cui, Bijun; Xue, Maoguang; Zheng, Wei; Kong, Xianglong; Jiang, Kai; Ding, Kefeng; Lai, Lihua; Wang, Qingqing

doi:10.1016/j.molcel.2022.02.033

Cited by 324 publications

(216 citation statements)

References 79 publications

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“…Metabolites can also mediate immunosuppressive functions through m 6 A methylation. For instance, lactic acid-driven METTL3 mediates RNA m 6 A modifications that promote immunosuppressive capacity [ 106 ].…”

Section: A Methylation and Metabolic Reprogramming In Tmementioning

confidence: 99%

“…Notably, differentiation of MDSCs is a complex and variable process, metabolic programming products can also mediate immunosuppression of MDSCs through m 6 A methylation. For instance, the metabolite lactic acid upregulates METTL3 expression in MDSCs by inducing histone lactonization, leading to increased m 6 A modification and immunosuppressive activity, and ultimately, tumor immune escape [ 106 ]. However, limited reports to date have focused on establishing the effects of hypoxia and metabolic reprogramming on the status and behavior of MDSCs.…”

Section: A Methylation Remodels Immunosuppressive Tme By Directly Aff...mentioning

confidence: 99%

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Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

et al. 2022

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The tumor microenvironment (TME), which is regulated by intrinsic oncogenic mechanisms and epigenetic modifications, has become a research hotspot in recent years. Characteristic features of TME include hypoxia, metabolic dysregulation, and immunosuppression. One of the most common RNA modifications, N6-methyladenosine (m6A) methylation, is widely involved in the regulation of physiological and pathological processes, including tumor development. Compelling evidence indicates that m6A methylation regulates transcription and protein expression through shearing, export, translation, and processing, thereby participating in the dynamic evolution of TME. Specifically, m6A methylation-mediated adaptation to hypoxia, metabolic dysregulation, and phenotypic shift of immune cells synergistically promote the formation of an immunosuppressive TME that supports tumor proliferation and metastasis. In this review, we have focused on the involvement of m6A methylation in the dynamic evolution of tumor-adaptive TME and described the detailed mechanisms linking m6A methylation to change in tumor cell biological functions. In view of the collective data, we advocate treating TME as a complete ecosystem in which components crosstalk with each other to synergistically achieve tumor adaptive changes. Finally, we describe the potential utility of m6A methylation-targeted therapies and tumor immunotherapy in clinical applications and the challenges faced, with the aim of advancing m6A methylation research.

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Section: A Methylation and Metabolic Reprogramming In Tmementioning

confidence: 99%

Section: A Methylation Remodels Immunosuppressive Tme By Directly Aff...mentioning

confidence: 99%

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

et al. 2022

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“…Recent studies on the interaction between tumors and tumor microenvironments (TMEs) have provided novel opportunities for immunotherapy. Tumor cells induce immune escape by inhibiting the response and function of infiltrative immune cells by suppressing signaling pathways, such as the programmed cell death protein 1/programmed cell death protein-ligand 1 (PD-1/PD-L1) ( Chen and Flies, 2013 ; Beatty and Gladney, 2015 ; Xiong et al, 2022 ). In addition, the metabolic reconstruction of tumor cells consumes excess sugar, and amino acids competitively deprive T cells of the required nutrients, promoting the deactivation and immunosuppression of T cells ( Li and Zhang, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

N6-Methyladenosine Modification Patterns and Tumor Microenvironment Immune Characteristics Associated With Clinical Prognosis Analysis in Stomach Adenocarcinoma

Zhang

Luo

Yang

2022

Front. Cell Dev. Biol.

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Background: N6-methyladenosine (m6A) modification is a part of epigenetic research that has gained increasing attention in recent years. m6A modification is widely involved in many biological behaviors of intracellular RNA by regulating mRNA, thus affecting disease progression and tumor occurrence. However, the effects of m6A modification on immune cell infiltration of the tumor microenvironment (TME) are uncertain in stomach adenocarcinoma (STAD).Methods: The Cancer Genome Map (TCGA) database was used to download transcriptome data, clinicopathological data, and survival data for m6A-regulated genes in 433 STAD tissues that meet the requirements of this study. GSE84437 data were obtained from the Gene Expression Omnibus (GEO) database. The correlation between 23 m6A regulated genes was analyzed using R software. Sample clustering analysis was carried out on the genes of the m6A regulatory factor, and survival analysis and differentiation comparison were made for patients in clustering grouping. Then, the Gene Set Enrichment Analysis (GSEA), the single-sample GSEA (ssGSEA), and other methods were conducted to assess the correlation among m6A modification patterns, TME cell infiltration characteristics, and immune infiltration markers. The m6A modification pattern of individual tumors was quantitatively evaluated using the m6A score scheme of the principal component analysis (PCA).Results: From the TCGA database, 94/433 (21.71%) samples were somatic cell mutations, and ZC3H13 mutations are the most common. Based on the consensus, matrix k-3 is an optimal clustering stability value to identify three different clusters. Three types of m6A methylation modification patterns were significantly different in immune infiltration. Thus, 1028 differentially expressed genes (DEGs) were identified. The survival analysis of the m6A score found that patients in the high m6A score group had a better prognosis than those in the low m6A score group. Further analysis of the survival curve combining tumor mutation burden (TMB) and m6A scores revealed that patients had a significantly lower prognosis in the low tumor mutant group and the low m6A score group (p = 0.003). The results showed that PD-L1 was significantly higher in the high m6A score group than in the low score group (p < 2.22e-16). The high-frequency microsatellite instability (MSI-H) subtype score was significantly different from the other two groups.Conclusions: This study systematically evaluated the modification patterns of 23 m6A regulatory factors in STAD. The m6A modification pattern may be a critical factor leading to inhibitory changes and heterogeneity in TME. This elucidated the TME infiltration characteristics in patients with STAD through the evaluation of the m6A modification pattern.

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“…Accordingly, YT521-B homology (YTH) domain family is the main “readers” ( Jones et al, 2022 ) and “erasers” consisting of FTO and ALKBH5 ( Kaur et al, 2022 ). Recent studies have focused on the importance of m6A modification in tumors ( Jiang et al, 2022 ; Ma et al, 2022 ; Xiong et al, 2022 ; Yadav et al, 2022 ) and non-neoplastic diseases like asthma and pulmonary hypertension ( Teng et al, 2021 ; Zeng et al, 2021 ; Zhou et al, 2021 ). Nevertheless, the expression pattern of m6A regulators in CHP and IPF remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Relevance of RNA N6-Methyladenosine Regulators for Pulmonary Fibrosis: Implications for Chronic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis

et al. 2022

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N6-methyladenosine (m6A) modification plays a pivotal role in post-transcriptionally regulating gene expression and biological functions. Nonetheless, the roles of m6A modification in the regulation of chronic hypersensitivity pneumonitis (CHP) and idiopathic pulmonary fibrosis (IPF) remain unclear. Twenty-two significant m6A regulators were selected from differential gene analysis between the control and treatment groups from the GSE150910 dataset. Five candidate m6A regulators (insulin-like growth factor binding protein 2, insulin-like growth factor binding protein 3, YTH domain-containing protein 1, zinc finger CCCH domain-containing protein 13, and methyltransferase-like 3) were screened by the application of a random forest model and nomogram model to predict risks of pulmonary fibrosis. The consensus clustering method was applied to divide the treatment samples into two groups with different m6A patterns (clusters A and B) based on the 22 m6A regulators. Our study performed principal component analysis to obtain the m6A-related score of the 288 samples to quantify the two m6A patterns. The study reveals that cluster A was linked to T helper cell (Th) 2-type cytokines, while the immune infiltration of Th1 cytokines was higher in cluster B. Our results suggest that m6A cluster A is likely related to pulmonary fibrosis, indicating m6A regulators play notable roles in the occurrence of pulmonary fibrosis. The m6A patterns could be considered as biomarkers to identify CHP and IPF, which will be helpful to develop immunotherapy strategies for pulmonary fibrosis in the future.

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Lactylation-driven METTL3-mediated RNA m6A modification promotes immunosuppression of tumor-infiltrating myeloid cells

Cited by 324 publications

References 79 publications

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

Crosstalk among m6A RNA methylation, hypoxia and metabolic reprogramming in TME: from immunosuppressive microenvironment to clinical application

N6-Methyladenosine Modification Patterns and Tumor Microenvironment Immune Characteristics Associated With Clinical Prognosis Analysis in Stomach Adenocarcinoma

Relevance of RNA N6-Methyladenosine Regulators for Pulmonary Fibrosis: Implications for Chronic Hypersensitivity Pneumonitis and Idiopathic Pulmonary Fibrosis

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