m6A regulator-mediated methylation modification patterns and tumor microenvironment infiltration characterization in...

There is increasing evidence of the epigenetic regulation of the immune response in cancer. However, the specific functions and mechanisms of RNA N6-methyladenosine (m6A) modification in the cell infiltration in the hepatocellular carcinoma (HCC) tumor microenvironment (TME) is unknown.

We systematically analyzed the m6A-modification patterns of 371 HCC samples based on 23 m6A regulators, and determined their correlation with TME cell-infiltrating characteristics. Principal-component analysis algorithms was used to calculate the m6Ascore and clarify the m6A-modification patterns of individual tumors.

Three different m6A-modification patterns were identified in HCC, wherein the m6Acluster B and m6Acluster A had the best and worst prognosis, respectively. These three patterns had different TME cell infiltration characteristics and biological behavior. An m6A-scoring signature was constructed to evaluate the m6A-modification patterns within individual tumors. A low m6Ascore was associated with a low overall survival and high clinical stage. Moreover, the m6A-scoring signature was characterized by distinct immunotherapeutic landscapes; a high m6A score indicated a higher immune checkpoint inhibitor score in the anti-PD-1 treatment alone, anti-CTLA-4 treatment alone, or combined anti-CTLA-4/PD-1 treatment cohorts, which reflected significant treatment and clinical benefits.

Our study highlights the significant role of the m6A modification in the HCC TME. A scoring signature to clarify the individual m6A-modification pattern would help us understand the HCC TME infiltration characterization and, thus, would guide the selection of more effective immunotherapeutic strategies.