Molecular Characterization of the Clinical and Tumor Immune Microenvironment Signature of 5-methylcytosine-Related Regulators in non-small Cell Lung Cancer

Abstract

Background: DNA methylation is an important epigenetic modification, among which 5-methylcytosine methylation (5mC) is generally associated with tumorigenesis. Nonetheless, the potential roles of 5mC regulators in the tumor microenvironment (TME) remain unclear.Methods: The 5mC modification patterns of 1,374 lung adenocarcinoma samples were analyzed systematically. The correlation between the 5mC modification and tumor microenvironment cell infiltration was further assessed. The 5mCscore was developed to evaluate tumor mutation burden, immune check-point inhibitor response, and the clinical prognosis of individual tumors.Results: Three 5mC modification patterns were established based on the clinical characteristics of 21 5mC regulators. According to the differential expression of 5mC regulators, three distinct 5mC gene cluster were also identified, which showed distinct TME immune cell infiltration patterns and clinical prognoses. The 5mCscore was constructed to evaluate the tumor mutation burden, immune check-point inhibitor response, and prognosis characteristics. We found that patients with a low 5mCscore had significant immune cell infiltration and increased clinical benefit.Conclusion: This study indicated that the 5mC modification is involved in regulating TME infiltration remodeling. Targeting 5mC modification regulators might be a novel strategy to treat lung cancer.

Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets

“…The research team found that both the therapeutic benefit and immune cell infiltration were increased in patients with a low 5mC score. 186 Similar studies also found that the group with a high 5mC score was associated with limited cancer immunotherapy sensitivity, and a low 5mC score was associated with a better response to immunotherapy in patients with bladder cancer (BLCA) and lung squamous cell carcinoma (LUSC). 187 These results suggest that the 5mC score may serve as a biomarker for predicting the prognosis of cancer patients and gauging the efficacy of cancer treatments.…”

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

“…For example, in CD4 + T cells from patients with SLE, the levels of the m 5 C writer NSUN2 and methylated m 5 C genes were found to be decreased ( 13 ). In cutaneous melanoma, lung adenocarcinoma, lung squamous cell carcinoma, and other cancer types, bioinformatic analysis have shown that m 5 C regulators modulate the tumor immune microenvironment, act as immunotherapy indicators and were related to patients’ prognosis ( 14 – 19 , 22 , 60 – 64 ). These studies firmly proved that m 5 C regulators were differentially expressed and modulated the immunotherapy response in multiple cancers.…”

Epigenetic targets to enhance antitumor immune response through the induction of tertiary lymphoid structures

“…In an extensive study by Liu et al., modifications in the 5mC signature were observed to mediate TME remodeling in lung cancer tissues. Furthermore, the study found that patients with low methylation levels had higher levels of TIL and enhanced clinical response ( 84 ). In another study, the methylation of the promoter region of the Egfl7 gene within the tumor stroma inhibited the expression of CCL2.…”