m6A Regulator-Mediated Methylation Modification Model Predicts Prognosis, Tumor Microenvironment Characterizations and Response to Immunotherapies of Clear Cell Renal Cell Carcinoma

Abstract

BackgroundThis study aims to establish an N6-methyladenosine (m6A) RNA methylation regulators-mediated methylation model and explore its role in predicting prognostic accuracy of immune contexture and characterizations of clear cell renal cell carcinoma (ccRCC).MethodsThe m6A modification subclasses (m6AMS) were identified by unsupervised cluster analysis and three clusters were determined by consensus clustering algorithm in a discovering cohort. Testing and real-world validation cohorts were used to identify predictive responses for immune checkpoint therapies (ICTs) of m6AMS.ResultsPrognostic implications landscape of m6A regulators in cancers and its differential expression levels in ccRCC patients were identified. Based on discovering cohort, ccRCC were automatically divided into three m6AMS, and cluster 3 showed significant worse survival than cluster 1/2. Importantly, it was found that the immune checkpoint molecules expression was significantly elevated in cluster 3. Besides, m6A scoreLow group (cluster 1&2) have significantly elevated TIDE score compared with m6A scoreHigh group (cluster 3). There was conspicuous tertiary lymphoid tissue, aggressive phenotype, elevated glycolysis, expression of PD-L1, abundance of CD8+ T cells, CD4+ FOXP3+ Treg cells and TCRn immune cells infiltration in the high m6A score group. Interestingly, there are significantly increased patients with clinical benefit in m6A scoreHigh group in 368 patients receiving ICTs from testing IMvigor210 (n = 292) and validation FUSCC (n = 55) cohorts.ConclusionOur discovery highlights the relationship between tumor epigenetic heterogeneity and immune contexture. Immune-rejection cluster 3 has pro-tumorigenic immune infiltration, and shows significant clinical benefits for ccRCC patients receiving ICTs, enabling patient selection for future clinical treatment.

N6-Methyladenosine-Related LncRNAs Are Potential Remodeling Indicators in the Tumor Microenvironment and Prognostic Markers in Osteosarcoma

“…Recently, N6-adenosine methylation has been found to play a critical role in the tumor immune microenvironment and to be associated with cancer prognosis ( 61 – 65 ). In fact, N6-adenosine methylation regulates not only the development or function of immune cells and other stromal cells within the TME, but also the responses of the TME to various stimuli, such as hypoxia, internal or external cellular stress, metabolic dysregulation, chronic inflammation, and TGF-β ( 66 , 67 ).…”

Tertiary lymphoid structures in cancer: immune mechanisms and clinical implications

“…Intratumoral and peritumoral TLS also have distinct functions. In intrahepatic cholangiocarcinoma, colorectal cancer, hepatocellular carcinoma, BC, and clear cell renal cell carcinoma, it has been suggested that peritumoral TLS is associated with a worse survival, whereas intratumoral TLS is associated with a favorable prognosis 9,84–87 . However, peritumoral TLS density is associated with higher maturity and anti‐PD‐1 reactivity in esophageal cancer 88 .…”

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

“…( 118 ) constructed an m 6 A score to accurately evaluate the m 6 A methylation pattern in ccRCC patients, which could be used to predict the anti-PD-1 treatment response in ccRCC. In ccRCC the high m 6 A score group had higher PD-L1 expression, larger numbers of CD8+ T cells and CD4+ FOXP3+ Treg cells, and higher levels of immune cell infiltration ( 119 ). Among patients receiving immune checkpoint therapies, the clinical benefits were significantly higher in patients with high m 6 A scores ( 119 ).…”

“…In ccRCC the high m 6 A score group had higher PD-L1 expression, larger numbers of CD8+ T cells and CD4+ FOXP3+ Treg cells, and higher levels of immune cell infiltration ( 119 ). Among patients receiving immune checkpoint therapies, the clinical benefits were significantly higher in patients with high m 6 A scores ( 119 ). The expressions of 17 m 6 A RNA methylation regulators were closely related to the immunity and malignant progression of papillary renal cell carcinoma ( 120 ).…”