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

Wenhao Xu; Xi Tian; Wangrui Liu; Aihetaimujiang Anwaier; Jiaqi Su; Wenkai Zhu; Fangning Wan; Guohai Shi; Gaomeng Wei; Yuanyuan Qu; Hailiang Zhang; Dingwei Ye

doi:10.3389/fonc.2021.709579

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

Front Oncol. 2021 Jul 6:11:709579. doi: 10.3389/fonc.2021.709579. eCollection 2021.

Authors

Wenhao Xu^{1

2}, Xi Tian^{1

2}, Wangrui Liu³, Aihetaimujiang Anwaier^{1

2}, Jiaqi Su^{1

2}, Wenkai Zhu^{1

2}, Fangning Wan^{1

2}, Guohai Shi^{1

2}, Gaomeng Wei³, Yuanyuan Qu^{1

2}, Hailiang Zhang^{1

2}, Dingwei Ye^{1

2}

Affiliations

¹ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
³ Department of Urology, Affiliated Hospital of Youjiang Medical College for Nationalities, Baise, China.

Abstract

Background: This 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).

Methods: The 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.

Results: Prognostic 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 score^Low group (cluster 1&2) have significantly elevated TIDE score compared with m⁶A score^High 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 score^High group in 368 patients receiving ICTs from testing IMvigor210 (n = 292) and validation FUSCC (n = 55) cohorts.

Conclusion: Our 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.

Keywords: N6-methyladenosine; clear cell renal cell carcinoma; immunotherapies; m6A modification subclasses; tumor microenvironment.