m6A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer

Wei Chong; Liang Shang; Jin Liu; Zhen Fang; Fengying Du; Hao Wu; Yang Liu; Zhe Wang; Yang Chen; Shengtao Jia; Liming Chen; Leping Li; Hao Chen

doi:10.7150/thno.52717

m⁶A regulator-based methylation modification patterns characterized by distinct tumor microenvironment immune profiles in colon cancer

Theranostics. 2021 Jan 1;11(5):2201-2217. doi: 10.7150/thno.52717. eCollection 2021.

Authors

Wei Chong^{1

2

3}, Liang Shang^{1

2

3}, Jin Liu⁴, Zhen Fang^{2

3}, Fengying Du^{2

3}, Hao Wu^{2

3}, Yang Liu^{2

3}, Zhe Wang⁵, Yang Chen⁶, Shengtao Jia⁷, Liming Chen⁸, Leping Li^{1

2

3}, Hao Chen⁹

Affiliations

¹ Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, 250021, China.
² 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 Gastroenterology, 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 center for Cancer; Key Laboratory of Cancer Prevention and Therapy; Tianjin's Clinical Research Center for Cancer, Tianjin, China.
⁷ Department of Tumor Cell Biology, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and 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, Qilu Hospital of Shandong University, Jinan, Shandong, 250021, China.

Abstract

Recent studies have highlighted the biological significance of RNA N⁶-methyladenosine (m⁶A) modification in tumorigenicity and progression. However, it remains unclear whether m⁶A 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 colon 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 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, 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 infiltration. 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 three 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 promote more effective immunotherapy strategies.

Keywords: Colon cancer; Immune profiles; Immunotherapy; Tumor microenvironment; m6A modification.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / chemistry
Biomarkers, Tumor / genetics*
Biomarkers, Tumor / immunology
Colonic Neoplasms / drug therapy
Colonic Neoplasms / genetics
Colonic Neoplasms / immunology*
Colonic Neoplasms / pathology
DNA Methylation*
Gene Expression Regulation, Neoplastic*
Humans
Lymphocytes, Tumor-Infiltrating / immunology*
Transcriptome
Tumor Microenvironment / immunology*

Substances

Biomarkers, Tumor
N-methyladenosine
Adenosine