Comprehensive Analysis of 5-Methylcytosine (m5C) Regulators and the Immune Microenvironment in Pancreatic Adenocarcinoma to Aid Immunotherapy

Abstract

BackgroundPancreatic adenocarcinoma (PAAD) is one of the most malignant cancers and has a poor prognosis. As a critical RNA modification, 5-methylcytosine (m5C) has been reported to regulate tumor progression, including PAAD progression. However, a comprehensive analysis of m5C regulators in PAAD is lacking.MethodsIn the present study, PAAD datasets were obtained from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and ArrayExpress databases. The expression pattern of m5C regulators were analyzed and patients were divided into different m5C clusters according to consensus clustering based on m5C regulators. Additionally, m5C differentially expressed genes (DEGs) were determined using Limma package. Based on m5C DEGs, patients were divided into m5C gene clusters. Moreover, m5C gene signatures were derived from m5C DEGs and a quantitative indicator, the m5C score, was developed from the m5C gene signatures.ResultsOur study showed that m5C regulators were differentially expressed in patients with PAAD. The m5C clusters and gene clusters based on m5C regulators and m5C DEGs were related to immune cell infiltration, immune-related genes and patient survival status, indicating that m5C modification play a central role in regulating PAAD development partly by modulating immune microenvironment. Additionally, a quantitative indicator, the m5C score, was also developed and was related to a series of immune-related indicators. Moreover, the m5C score precisely predicted the immunotherapy response and prognosis of patients with PAAD.ConclusionIn summary, we confirmed that m5C regulators regulate PAAD development by modulating the immune microenvironment. In addition, a quantitative indicator, the m5C score, was developed to predict immunotherapy response and prognosis and assisted in identifying PAAD patients suitable for tailored immunotherapy strategies.

Identification and Validation of a m5C RNA Modification-Related Gene Signature for Predicting Prognosis and Immunotherapeutic Efficiency of Gastric Cancer

“…It has been reported that m5C modifcation is involved in immune microenvironment regulation, and the tumor immune microenvironment plays a role in the efect of m5C regulators on patient prognosis [54]. ALYREF, the Aly/REF nuclear export factor, functions as an m5C reader; its expression levels were signifcantly associated with immune infltrating cells, such as B cells, macrophages, NK cells, and dendritic cells [55].…”

Vital roles of m5C RNA modification in cancer and immune cell biology

“…In contrast, NSUN6 ( 31 ) and DNMT3A ( 131 ) have inhibitory effects on pancreatic cancer and suppress the proliferation of cancerous cells, but the mechanisms remain to be elucidated. m 5 C modification profoundly influences the tumor immune microenvironment ( 130 , 144 ), interfering with the infiltration of CD8+ T cells and upregulating PD-L1 expression ( 130 ). Risk models based on m 5 C-related lncRNAs have also been constructed to provide prognostic information ( 145 ).…”

RNA Modifications Meet Tumors

“…; (3) extracellular matrix (ECM) and other secretory molecules: growth factors, cytokines, chemokines, and extracellular vesicles (EVs); (4) Blood and lymphatic vascular networks. 10–13 The relationship between RNA modifications and the tumor microenvironment, especially the role of m 6 A and m 5 C modifications, has been described in many kinds of cancer subtypes such as lung adenocarcinoma, 88 , 89 pancreatic carcinoma 90 , 91 and CRC; 92 , 93 however, these studies are not in-depth and very few in number ( Figure 1 ).…”