Abstract
BackgroundEpigenetic changes of lung adenocarcinoma (LUAD) have been reported to be a relevant factor in tumorigenesis and cancer progression. However, the molecular mechanisms responsible for DNA methylation patterns in the tumor immune-infiltrating microenvironment and in cancer immunotherapy remain unclear.MethodsWe conducted a global analysis of the DNA methylation modification pattern (DMP) and immune cell-infiltrating characteristics of LUAD patients based on 21 DNA methylation regulators. A DNA methylation score (DMS) system was constructed to quantify the DMP model in each patient and estimate their potential benefit from immunotherapy.ResultsTwo DNA methylation modification patterns able to distinctly characterize the immune microenvironment characterization were identified among 513 LUAD samples. A lower DMS, characterized by increased CTLA-4/PD-1/L1 gene expression, greater methylation modifications, and tumor mutation burden, characterized a noninflamed phenotype with worse survival. A higher DMS, characterized by decreased methylation modification, a greater stromal-relevant response, and immune hyperactivation, characterized an inflamed phenotype with better prognosis. Moreover, a lower DMS indicated an increased mutation load and exhibited a poor immunotherapeutic response in the anti-CTLA-4/PD-1/PD-L1 cohort.ConclusionEvaluating the DNA methylation modification pattern of LUAD patients could enhance our understanding of the features of tumor microenvironment characterization and may promote more favorable immunotherapy strategies.
Highlights
The global DNA methylation is strongly associated with growth selection and uncontrolled cell proliferation in multiple cancer types [1, 2]
We identified two independent DNA methylation patterns (DMPs) by unsupervised consensus clustering the expression of 21 DNA methylation regulator-related genes, which we defined as methylation regulators
To investigate whether these genetic variants influenced the gene expression of regulators in cancer samples, we compared the expression of the 21 DNA methylation regulators between normal and Lung adenocarcinoma (LUAD) samples and found that regulators with significant genetic mutation as well as copy number variation (CNV) amplification were significantly higher expressed in cancer groups (Figures 1B–E), indicating that the regulator gene mutation and the alternation of CNV could be risk factors leading to the multiperturbation of the translation of DNA methylation regulators
Summary
The global DNA methylation is strongly associated with growth selection and uncontrolled cell proliferation in multiple cancer types [1, 2]. The expression and function of those methyltransferases has been reported to be partly responsible for immunomodulation and might have an impact on DNA methylation modification patterns in human cancers [4, 5]. As a result of an increasing number of studies focusing on tumor immune cell infiltrations and DNA epigenetic modification, crucial immune cell types and methyltransferase subsets in tumor growth, metastasis, and outcome have gradually been identified [7,8,9,10]. The molecular mechanisms responsible for DNA methylation patterns in the tumor immune-infiltrating microenvironment and in cancer immunotherapy remain unclear
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