N6-methyladenosine Regulator-Mediated Immune Genes Identify Breast Cancer Immune Subtypes and Predict Immunotherapy Efficacy

Abstract

Breast cancer (BRCA) is a heterogeneous malignancy closely related to the tumor microenvironment (TME) cell infiltration. N6-methyladenosine (m6A) modification of mRNA plays a crucial regulator in regulating the immune microenvironment of BRCA. Immunotherapy represents a paradigm shift in BRCA treatment; however, lack of an appropriate approach for treatment evaluation is a significant issue in this field. In this study, we attempted to establish a prognostic signature of BRCA based on m6A-related immune genes and to investigate the potential association between prognosis and immunotherapy. We comprehensively evaluated the m6A modification patterns of BRCA tissues and non-tumor tissues from The Cancer Genome Atlas and the modification patterns with TME cell-infiltrating characteristics. Overall, 1,977 TME-related genes were identified in the literature. Based on LASSO and Cox regression analyses, the m6A-related immune score (m6A-IS) was established to characterize the TME of BRCA and predict prognosis and efficacy associated with immunotherapy. We developed an m6A-IS to effectively predict immune infiltration and the prognosis of patients with BRCA. The prognostic score model represented robust predictive performance in both the training and validation cohorts. The low-m6A-IS group was characterized by enhanced antigen presentation and improved immune checkpoint expression, further indicating sensitivity to immunotherapy. Compared with the patients in the high-score group, the overall survival rate after treatment in the low-score group was significantly higher in the testing and validation cohorts. We constructed an m6A-IS system to examine the ability of the m6A signature to predict the infiltration of immune cells of the TME in BRCA, and the m6A-IS system acted as an independent prognostic biomarker that predicts the response of patients with BRCA in immunotherapy.

N6-methyladenosine (m6A) writer METTL3 accelerates the apoptosis of vascular endothelial cells in high glucose

“…M 6 A modification has been proposed to be participated in cardiovascular physiological and pathological processes [ [18] , [19] , [20] ]. However, the vital roles of m 6 A writer METTL3 in high glucose exposure vascular endothelial cells are unknown [ 21 , 22 ].…”

N6-methyladenosine modified AFAP1-AS1 accelerates hepatocellular carcinoma proliferation and migration via miR-195-5p/KIAA1429 feedback loop

“…Using a bioinformatics approach, present study was performed to conduct the genome-wide comparison of HCC [20,21]. Moreover, the prediction tools indicated that there were remarkable m 6 A modi ed sites on AFAP1-AS1 RNA sequences.…”

N6‐methyladenosine modification participates in neoplastic immunoregulation and tumorigenesis

“…The suppression of m6A modification mediated by METTL3 and METTL14 was demonstrated to connect with immune system and tumor microenvironment through increasing the production of cytokines and chemokines including IFN-γ, CXCL9, and CXCL10, accompanied by an enhanced response to immunotherapy (L. immune evasion (Tallima et al, 2021). It was demonstrated that m6A modification is associated with the expression of MHC-related antigenpresenting molecules, such as human leukocyte antigen (HLA) (M. M. Zhang et al, 2021). This suggests that there is a potential immune escape mechanism, which is involved by m6A modification.…”

“…Major histocompatibility complex (MHC) Class I protein expresses on the surface of tumor cells, and the defection of MHC Class I leads to immune evasion (Tallima et al, 2021). It was demonstrated that m6A modification is associated with the expression of MHC‐related antigen‐presenting molecules, such as human leukocyte antigen (HLA) (M. M. Zhang et al, 2021). This suggests that there is a potential immune escape mechanism, which is involved by m6A modification.…”