结肠癌中以m6A调控因子为基础的甲基化修饰模式其特征是不同的肿瘤微环境免疫谱.pdf
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1、Theranostics 2021, Vol. 11, Issue 5 http:/www.thno.org 2201 Theranostics 2021; 11(5): 2201-2217. doi: 10.7150/thno.52717 Research Paper m6A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer Wei Chong1,2,3, Liang Shang1,
2、2,3, Jin Liu4, Zhen Fang2,3, Fengying Du2,3, Hao Wu2,3, Yang Liu2,3, Zhe Wang5, Yang Chen6, Shengtao Jia7, Liming Chen8, Leping Li1,2,3, Hao Chen9 1. Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China 2
3、. Department of Gastrointestinal Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250021, China 3. Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong, 250021, China 4. Department of Gastroenterolo
4、gy, Key Laboratory of Engineering of Shandong Province, Shandong Provincial Hospital, Jinan, Shandong, 250021, China 5. Tianjin Sino-US Diagnostics Co., Ltd, Tianjin, China 6. Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research cente
5、r for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjins Clinical Research Center for Cancer, Tianjin, China 7. Department of Tumor Cell Biology, National Clinical Research Center for Cancer, Tianjins Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and
6、 Hospital, Tianjin, China 8. Division of Gastroenterology, Department of Medicine, Center for Advanced Biomedical Imaging and Photonics, Beth Israel Deaconess Medical Center, Harvard University, Boston, 02215, MA, USA 9. Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qi
7、lu Hospital of Shandong University, Jinan, Shandong, 250021, China Corresponding authors: Dr. Hao Chen, Clinical Research Center of Shandong University, Clinical Epidemiology Unit, Qilu Hospital of Shandong University, Jinan, Shandong 250021, China. E-mail: ; . Prof. Leping Li, Department of Gastroi
8、ntestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China. E-mail: . The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https:/creativecommons.org/licenses/by/4.0
9、/). See http:/ for full terms and conditions. Received: 2020.09.01; Accepted: 2020.11.21; Published: 2021.01.01 Abstract Recent studies have highlighted the biological significance of RNA N6-methyladenosine (m6A) modification in tumorigenicity and progression. However, it remains unclear whether m6A
10、 modifications also have potential roles in immune regulation and tumor microenvironment (TME) formation. Methods: In this study, we curated 23 m6A regulators and performed consensus molecular subtyping with NMF algorithm to determine m6A modification patterns and the m6A-related gene signature in c
11、olon cancer (CC). The ssGSEA and CIBERSORT algorithms were employed to quantify the relative infiltration levels of various immune cell subsets. An PCA algorithm based m6Sig scoring scheme was used to evaluate the m6A modification patterns of individual tumors with an immune response. Results: Three
12、 distinct m6A modification patterns were identified among 1307 CC samples, which were also associated with different clinical outcomes and biological pathways. The TME characterization revealed that the identified m6A patterns were highly consistent with three known immune profiles: immune-inflamed,
13、 immune-excluded, and immune-desert, respectively. Based on the m6Sig score, which was extracted from the m6A-related signature genes, CC patients can be divided into high and low score subgroups. Patients with lower m6Sig score was characterized by prolonged survival time and enhanced immune infilt
14、ration. Further analysis indicated that lower m6Sig score also correlated with greater tumor mutation loads, PD-L1 expression, and higher mutation rates in SMGs (e.g., PIK3CA and SMAD4). In addition, patients with lower m6Sig scores showed a better immune responses and durable clinical benefits in t
15、hree independent immunotherapy cohorts. Conclusions: This study highlights that m6A modification is significantly associated with TME diversity and complexity. Quantitatively evaluating the m6A modification patterns of individual tumors will strengthen our understanding of TME characteristics and pr
16、omote more effective immunotherapy strategies. Key words: Colon cancer, m6A modification, Tumor microenvironment, Immune profiles, Immunotherapy Ivyspring International Publisher Theranostics 2021, Vol. 11, Issue 5 http:/www.thno.org 2202 Introduction Methylation of N6 adenosine (m6A), which is wide
17、ly observed in mRNAs, lncRNAs and miRNAs, is the most common type of RNA modification and plays crucial roles in multiple physiological processes and disease progression 1, 2. m6A modification is also a kind of dynamic and reversible process, which is controlled by different types of regulatory prot
18、eins: the methyltransferases (“writers”), the demethylases (“erasers”) and binding proteins (“readers”) 3. The expression and function of these regulatory proteins have great impacts on m6A modification, and investigation of these regulators can help understanding the mechanisms of m6A in gene regul
19、ation 4, 5. Increasing evidence has demonstrated that dysregulated expression and genetic changes of m6A regulators are correlated with malignant tumor progression and immunomodu-latory abnormalities 6-9. A comprehensive understanding of the genetic variation and expression perturbations underlying
20、cancer heterogeneity will further benefit the identification of RNA methylation-based therapeutic targets 10. Colon cancer (CC) is one of the most common malignancies and remains the primary cause of cancer death worldwide, and 30% - 50% of patients develop recurrence, metastasis and even death with
21、in 5 years of treatment 11, 12. Recently, with the increased understanding of the diversity and complexity of the tumor microenvironment contexture (including cancer cells, stromal cells, infiltrating immune cells, and secreted cytokines et al.), the crucial immune cell subsets in tumorigenesis and
22、metastasis have been gradual recognized 13-16. Indeed, assessment of the densities of lymphocyte populations (CD3 and cytotoxic CD8 T cells) at the tumor center and the tumor margin were demonstrated to play an important complementary role to the tumor staging system in relapse and mortality predict
23、ion in CC 17. Moreover, current immunotherapies represented by specific immune checkpoint inhibitors (ICIs), such as anti-CTLA-4 and anti-PD-1/L1, have achieved a marked durable response in CC treatment 18, 19. Evaluating immune infiltration based on the characteristics of the TME constitutes a crit
24、ical approach to predicting the response to existing ICIs and developing novel immunotherapeutic strategies 20-22. Current studies also proposed the novel concept of immune contexture, which classified CC tumors into three major immune coordination profiles (hot, excluded and cold) and represented d
25、ifferent TME characteristics and treatment options 23-25. Therefore, tumor immune phenotypes identified by comprehensively parsing the components of the tumor microenvironment will assist in guiding and predicting immunotherapeutic responsiveness 17, 26, 27. Recent studies revealed the interactions
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- 结肠癌 m6A 调控 因子 基础 甲基化 修饰 模式 特征 不同 肿瘤 环境 免疫
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