Analysis of N6-Methyladenosine Modification Patterns and Tumor Immune Microenvironment in Pancreatic Adenocarcinoma

Abstract

Background: Pancreatic adenocarcinoma (PAAD) is a rare cancer with a poor prognosis. N6-methyladenosine (m6A) is the most common mRNA modification. However, little is known about the relationship between m6A modification and the tumor immune microenvironment (TIME) in PAAD.Methods: Based on 22 m6A regulators, m6A modification patterns of PAAD samples extracted from public databases were systematically evaluated and correlated with the tumor immune and prognosis characteristics. An integrated model called the “m6Ascore” was constructed, and its prognostic role was evaluated.Results: Three different m6Aclusters and gene clusters were successively identified; these clusters were characterized by differences in prognosis, immune cell infiltration, and pathway signatures. The m6Ascore was constructed to quantify the m6A modifications of individual patients. Subsequent analysis revealed that m6Ascore was an independent prognostic factor of PAAD and could be a potential indicator to predict the response to immunotherapy.Conclusion: This study comprehensively evaluated the features of m6A modification patterns in PAAD. m6A modification patterns play a non-negligible role in the TIME of PAAD. m6Ascore provides a more holistic understanding of m6A modification in PAAD, and will help clinicians predict the prognosis and response to immunotherapy.

METTL3 enhances pancreatic ductal adenocarcinoma progression and gemcitabine resistance through modifying DDX23 mRNA N6 adenosine methylation

“…Aberrant m6A modification caused by the dysregulation of methyltransferases, demethylases, m6A-binding proteins, etc., is involved in the carcinogenesis of various cancers, including pancreatic cancer [13]. In addition, m6A modifications were reported to actively participate in the tumor microenvironment of pancreatic adenocarcinoma [14][15][16][17]. Thus, targeting methyltransferases such as METTL3 or their target transcripts seems to be a promising approach for pancreatic cancer therapeutics [18,19], and there have been evidence supporting it.…”

m6A methylation modification and immune cell infiltration: implications for targeting the catalytic subunit m6A-METTL complex in gastrointestinal cancer immunotherapy

“…Furthermore, early-stage pancreatic cancer often exhibits suppressed tumor immunity, hindering the effectiveness of immunotherapy in improving survival outcomes for PC patients (117). Liu et al found that in pancreatic ductal adenocarcinoma (PDAC), high METTL3/14 expression was significantly and positively associated with the enrichment of activated NK cells and mast cells (118). Specifically, within the CD4 + T cell subpopulation, METTLE3 was found to be negatively correlated with Th2 and Th17 cells, which regulate inflammatory responses, while it was positively correlated with Th1 and Tfh cells, known for their crucial role in tumor immunotherapy.…”

Focus on Therapeutic Options for Surgically Resectable Pancreatic Adenocarcinoma Based on Novel Biomarkers

“…Moreover, scoring systems based on the measurement of metabolites such as N6methyladenosine (m6A) could serve as independent prognostic factors for predicting the response to immunotherapy and assessing modifications in immune cell infiltration, including Tregs, CD8, and CD4 [45][46][47].…”