Background: N6-methyladenosine (m6A) modification is considered to be the most significant and abundant mRNA modification and constitutes a critical mechanism of epigenetic regulation in various tumors. However, the potential influences of these m6A regulators on the tumor immune microenvironment (TIME) and immunotherapy in hepatocellular carcinoma (HCC) remain unknown.
Methods: We systematically analyzed the expressions and genetic alterations of 38 m6A regulators in HCC from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) database. We used unsupervised clustering algorithm to divide the samples into three patterns based on the expression profiles of mRNA modifications. Next, we constructed the m6A score model to performed association analysis for m6Ascore and clinical characteristics, total mutation burden (TMB), and the efficacy of immunotherapy.
Results: We demonstrated that the expression of m6A regulators were associated with patient survival and the infiltration of immune cells. We identified two RNA modification patterns and assigned m6Ascore to each individual. Patients with a low m6Ascore had a better survival rate than those with a high m6Ascore, and patients with a high TMB and high m6Ascore had a worse survival rate. In addition, patients in the high m6Ascore group had higher PD-L1 expression than the low m6Ascore group. The low m6Ascore group showed higher immune checkpoint inhibitor responses, including anti-CTLA-4 therapy, anti-PD-1, or a combination of both, than the high m6Ascore group.
Conclusions: Our results revealed the potential function of these mRNA modifcations in TIME, and identified their therapeutic value in immunotherapy.