Pan-Cancer Molecular Characterization of m6A Regulators and Immunogenomic Perspective on the Tumor Microenvironment

Abstract

PurposeN6-methyladenosine (m6A) methylation plays a critical role in diverse biological processes. However, knowledge regarding the constitution of m6A on tumor microenvironment (TME) and tumor-infiltrating lymphocytes (TILs) across cancer types is still lacking. We performed comprehensive immuno-genomic analyses to reveal molecular characterization of the m6A regulators and immune-related genes (IRGs) across TME and TIL heterogeneity.MethodsWe comprehensively analyzed the properties of m6A regulators in genomic profiles from The Cancer Genome Atlas (TCGA) according to expression perturbations of crucial IRGs, CD274, CD8A, GZMA, and PRF1. The four IRGs were proved to be reliable biomarkers of TILs and TME via CIBERSORT and ESTIMATE analyses, and their co-expression relationship was certified by TIMER analysis. Based on their median values, the samples from the pan-cancer tissues (N = 11,057) were classified into eight TME types. The RNA expression levels of 13 m6A regulators were compared across TME subtypes. Single-sample Gene Set Enrichment Analysis (ssGSEA) was also used to classify TME clusters, expression variants of IRGs and m6A regulators were verified among TME clusters. Meanwhile, the correlation between m6A regulators and tumor mutational burden (TMB) were tested. Finally, the impacts of IRGs and TME clusters in clinical characteristics and outcomes were revealed.ResultsCD274, CD8A, GZMA, and PRF1 showed similar TILs’ characteristics, of which the level of T cells CD8 and T cells CD4 memory activated are consistent with the expression levels of the four IRGs and higher immune infiltration. Besides, CD274, CD8A, GZMA, and PRF1 were positively correlated with the stromal score or immune score in almost all 33 tumor types. All of four IRGs showed impact between tumor pathological stages or clinical outcomes. Among TME type I to type IV, m6A regulators’ expression drift changed from high-level to low-level in ESCA, BLCA, HNSC, CESC, BRCA, and GBM. However among TME type V to type VIII, m6A regulators drew a shift from low-level to high-level expression in CESC, BLCA, ESCA, KIRP, HNSC, BRCA, KIRC, COAD, LAML, GBM, and KICH. In ssGSEA analyses, IRGs’ expression levels were elevated with the immune infiltration degree and m6A regulators’ expression level varied among three TIL subgroups. With different TMB levels, expression differences of m6A regulators were observed in BLCA, BRCA, COAD, LGG, LUAD, LUSC, STAD, THCA, and UCEC.ConclusionWe identified four crucial IRGs affecting TILs, TME characteristics and clinical parameters. Expression variants of m6A regulators among the subgroups of TME types and ssGSEA clusters suggested that m6A regulators may be essential factors for phenotypic modifications of IRGs and thus affecting TME characteristics across multiple tumor types.

N6-Methyladenosine RNA Modification in the Tumor Immune Microenvironment: Novel Implications for Immunotherapy

“…Most of the anticancer immune regulations rely on overcoming the continuous suppression of the adaptive immune response within the TME ( 43 ). Immune suppression is a typical feature of the TME, which involves the dysfunction of antigen presenting cells (APCs), recruitment or induction of large numbers of suppressive immune cells, such as CD4+ regulatory T cells (Tregs), dendritic cells (DCs), tumor-associated macrophages (TAMs), and myeloid cell-derived suppressor cells (MDSCs), and secretion of various cytokines ( Figure 2 ) ( 44 , 45 ).…”

Transcriptome Analyses Identify a Metabolic Gene Signature Indicative of Antitumor Immunosuppression of EGFR Wild Type Lung Cancers With Low PD-L1 Expression

“…The ssGSEA scores for most immune cell populations were obtained using the gene sets from Angelova et al (15). A total of 29 gene sets representing distinct immune cell populations were obtained: activated dendritic cells (aDCs), antigen-presenting cell (APC) co-inhibition, APC co-stimulation, B cells, CC chemokine receptor (CCR), CD8+ T cells, Checkpoint, Cytolytic activity, dendritic cells (DCs), human leukocyte antigen (HLA), interdigitating dendritic cells (iDCs), Inflammation-promoting, Macrophages, Mast cells, MHC class I, Neutrophils, NK cells, Parainflammation, plasmacytoid dendritic cells (pDCs), T cell-co-inhibition, T cell costimulation, T helper cells, follicular helper T cells (Tfh), Th1 cells, Th2 cells, tumor-infiltrating lymphocytes (TIL), regulatory T cells (Treg), Type I IFN Response, Type II IFN Response (16,17).…”

Characterization of m6A Regulator-Mediated Methylation Modification Patterns and Tumor Microenvironment Infiltration in Ovarian Cancer

“…TME components directly and indirectly affect multiple biological behaviors of cancer cells such as inhibiting apoptosis, inducing proliferation, avoiding hypoxia, inducing immune tolerance, et al ( Binnewies et al, 2018 ). The evidence suggests that m6A modification could build a TME favorable for the growth of cancer cells ( Zhu et al, 2021 ). For instance, Yi Jian et al found that ALKBH5 could promote the progression of OC in a simulated TME via NF-κB signaling ( Jiang et al, 2020 ).…”