Abstract
N6-methyladenosine (m6A) RNA methylation has been shown to have prognostic value in cancer. Nonetheless, its potential role regarding immunity, metabolism, and stemness in soft tissue sarcoma (STS) remains unknown. We comprehensively estimated the m6A modification patterns and corresponding immunity, metabolism, and stemness characteristics based on 568 STS samples and 21 m6A regulators. The m6Ascore was constructed to quantify m6A modification patterns in individuals using machine learning algorithms. Two distinct m6A modification patterns among the STS patients were identified, which exhibited differences in prognosis, immune cell infiltration, metabolic pathways, stemness, somatic mutation, and copy number variation. Thereafter, immunity-, metabolism-, and stemness phenotype-related genes associated with m6A modification were identified. Furthermore, patients with lower m6Ascores had increased antitumor immune responses, survival benefit under immunotherapy, tumor mutation burden, immunogenicity, and response to anti-PD-1/L1 immunotherapy. Immunotherapy sensitivity was validated using the IMvigor210 dataset. STS patients with lower m6Ascore might be more sensitive to docetaxel and gemcitabine. Finally, pan-cancer analysis illustrated the significant correlations of m6Ascore with clinical outcomes, immune cell infiltration, metabolism, and stemness. This study revealed that m6A modification plays an important role in immunity, metabolism, and stemness in STS. Evaluating the m6A modification pattern and development of m6Ascore may help to guide more effective immunotherapy and chemotherapy strategies.
Highlights
Soft tissue sarcoma (STS) is a type of malignant tumor that originates from mesenchymal tissues
We revealed two m6A modification patterns with distinct characteristics of immunity, metabolism, and stemness, which suggested that m6A modification might regulate immune microenvironment, metabolism processes, and tumor cell stemness to contribute to different behaviors of soft tissue sarcoma (STS)
In addition to TMB, we further studied other immunogenic biomarkers and found that intratumor heterogeneity (LOH), DNA damage including homologous recombination deficiency (HRD), tumor neoantigen burden (TNB), intratumor heterogeneity (ITH), and aneuploidy were significantly negatively correlated with m6Ascore (Figure 4G)
Summary
Soft tissue sarcoma (STS) is a type of malignant tumor that originates from mesenchymal tissues. Immunotherapy is a promising cancer treatment, its response rate remains low [5] This is especially the case in STS, due to its extensive heterogeneity and unclear characterization of the tumor microenvironment (TME) in the molecular subtypes. Research has highlighted that m6A modification plays an important role in cancer biology and tumor stemness [16]. From this perspective, analysis of m6A modification could broaden the understanding of the mechanisms underlying STS occurrence and progression, while providing new insights into the clinical use of immunotherapy. Multiomics and clinical data of 568 STS samples were used to comprehensively identify distinct m6A modification patterns, and three important tumor characteristics (immunity, metabolism, and stemness) were assessed. A pan-cancer analysis illustrated significant correlations of m6Ascore with prognosis, immune cell infiltration, metabolism, and stemness in other cancers, which indicated that it may help to guide the use of immunotherapy and chemotherapy in other cancers
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