Comprehensive Analysis of Clinical Significance, Immune Infiltration and Biological Role of m6A Regulators in Early-Stage Lung Adenocarcinoma.

Bolun Zhou,Shugeng Gao

doi:10.3389/fimmu.2021.698236

Abstract

Recent publications have revealed that N6-methyladenosine (m6A) modification is critically involved in tumorigenesis and metastasis. However, the correlation of m6A modification and immune infiltration in early-stage lung adenocarcinoma (LUAD) is still uncertain. We performed NMF clustering based on 23 m6A regulators and identify three distinct m6A clusters and three m6A related genes clusters (m6A cluster-R) in early-stage LUAD. The immune infiltrating levels were calculated using CIBERSORT, MCPcounter and ssGSEA algorithms. And we established the m6A-predictive score to quantify m6A modified phenotypes and predict immunotherapeutic responses. Based on the TME characteristics, different immune profiles were also identified among three m6A gene-related clusters. And the m6A-R-C2 was related to a favorable overall survival (OS), whereas m6A-R-C3 had unfavorable overall survival. The m6A-predictive score was built according to the expression levels of m6A-related genes, and patients could be stratified into subgroups with low/high scores. Patients with high scores had poor overall survival, enhanced immune infiltration, high tumor mutation burden and increased level of somatic mutation. Besides, patients with high scores had unfavorable overall survival in the anti-PD-1 cohort, whereas the overall survival of high-score patients was better in the adoptive T cell therapy cohort. Our work highlights that m6A modification is closely related to immune infiltration in early-stage LUAD, which also contributes to the development of more effective immunotherapy strategies.

Highlights

Lung adenocarcinoma (LUAD) is one of the most prevalent cancers around the world, accounting for approximately 40% of lung cancer patients [1]
The somatic mutations of 23 m6A regulators were infrequent in early-stage LUAD. 92 of the 355 (25.9%) samples had the somatic mutations of m6A regulators, which primarily included missense mutations and nonsense mutations
We found that VIRMA, METTL3, RBM15, ELAVL1, HNRNPC, HNRNPA2B1, IGF2BP1, IGF2BP3, YTHDF1, YTHDF2, LRPPRC were highly expressed in tumors, while METTL14, ZC3H13 and FTO were mainly downregulated (Figure 1E)

Summary

Introduction

Lung adenocarcinoma (LUAD) is one of the most prevalent cancers around the world, accounting for approximately 40% of lung cancer patients [1]. With the rapid progress of various treatments, such as surgery, radiotherapy and chemotherapy, LUAD patients’ prognosis is still very poor [4,5,6]. Some radiological approaches, such as low-dose computerized tomography (CT), are implemented to screen for LUAD and truly reduced the mortality of patients, but radiological approaches cannot benefit every patient and the diagnostic accuracy still has room for improvement [7, 8]. We need an in-depth investigation of detailed molecular mechanisms to identify patients with a high probability of death, which may contribute to the precise treatment of patients with early-stage LUAD

Methods

Results

Conclusion