Identifying Immune-Specific Subtypes of Adrenocortical Carcinoma Based on Immunogenomic Profiling

Background: The tumor immune microenvironment (TIME) of adrenocortical carcinoma (ACC) is heterogeneous. However, a classification of ACC based on the TIME remains unexplored. Methods: We hierarchically clustered ACC based on the enrichment levels of twenty-three immune signatures to identify its immune-specific subtypes. Furthermore, we comprehensively compared the clinical and molecular profiles between the subtypes. Results: We identified two immune-specific subtypes of ACC: Immunity-H and Immunity-L, which had high and low immune signature scores, respectively. We demonstrated that this subtyping method was stable and reproducible by analyzing five different ACC cohorts. Compared with Immunity-H, Immunity-L had lower levels of immune cell infiltration, worse overall and disease-free survival prognosis, and higher tumor stemness, genomic instability, proliferation potential, and intratumor heterogeneity. Furthermore, the ACC driver gene CTNNB1 was more frequently mutated in Immunity-L than in Immunity-H. Several proteins, such as mTOR, ERCC1, Akt, ACC1, Cyclin_E1, beta-catenin, FASN, and GAPDH, were more highly expressed in Immunity-L than in Immunity-H. In contrast, p53, Syk, Lck, PREX1, and MAPK were more highly expressed in Immunity-H. Pathway and gene ontology analysis showed that the immune, stromal, and apoptosis pathways were highly enriched in Immunity-H, while the cell cycle, steroid biosynthesis, and DNA damage repair pathways were highly enriched in Immunity-L. Conclusions: ACC can be classified into two stable immune-related subtypes, which have significantly different antitumor responses, molecular characteristics, and clinical outcomes. This subtyping may provide clinical implications for prognostic and immunotherapeutic stratification of ACC.