Molecular phenotypic linkage between N6-methyladenosine methylation and tumor immune microenvironment in hepatocellular carcinoma

PurposeThe crucial role of N-6-methyladenosine (m(6)A) methylation in anti-tumor immunity and immunotherapy has been broadly depicted. However, the molecular phenotypic linkages between m(6)A modification pattern and immunological ecosystem are expected to be disentangled in hepatocellular carcinoma (HCC), for immunotherapeutic unresponsiveness circumvention and combination with promising drug agents.MethodsModification patterns of m(6)A methylation were qualitatively dissected according to the large-scale HCC samples profiling. We then determined the immune phenotypic linkages by systematically evaluating their tumor microenvironment composition, immune/stromal-relevant signature, immune checkpoints correlation, and prognostic value. Individual quantification of m(6)A methylation pattern was achieved by m(6)Ascore construction, intensified by longitudinal single-cell analysis of immunotherapy cohort and validated by the transcriptomic profiles of our in-hospital GDPH-HCC cohort. Candidate therapeutic agents were also screened out.ResultsThree distinct m(6)A methylation patterns were determined in high accordance with inflamed-, excluded-, and desert-immunophenotype. To be precise, Immune-inflamed high-m(6)Ascore group was characterized by activated immunity with favorable prognosis. Stromal activation and absence of immune cell infiltration were observed in low-m(6)Ascore phenotype, linked to impaired outcome. Patients with low-m(6)Ascore demonstrated diminished responses and clinical benefits for cohorts receiving immunotherapy. The above credible linkage between m(6)A methylation pattern and tumor immune microenvironment was robustly validated in our GDPH-HCC cohort. Single-cell dynamic change of m(6)A methylation level in exhausted CD8 T cell and fibroblast was depicted in immunotherapy cohort fore and art. Derived from m(6)A methylation pattern, seven potential frontline drug agents were recognized as promising choice for high-m(6)Ascore patients.ConclusionOur work bridged the credible linkage between epigenetics and anti-tumor immunity in HCC, unraveling m(6)A modification pattern as immunological indicator and predictor for immunotherapy. Individualized m(6)Ascore facilitated strategic choices to maximize therapy-responsive possibility.