Ferroptosis Regulators and Tumor Microenvironment Immune Cell Infiltration Characterization in Adrenocortical Carcinoma

Abstract Background Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and lacking effective systemic treatment options. Recent studies showed that ferroptosis play a prominent role in the initiation and development of cancer. Nonetheless, the potential roles of ferroptosis regulators in the prognosis and tumor microenvironment immunomodulator factors expression remain not fully study. Methods TCGA and GEO ACC datasets were used to investigate the relationship between ferroptosis regulators with prognosis and clinical features. Consensus clustering analysis was performed to divided ACC patients into different ferroptosis subgroups. A ferroptosis scoring system was established for individual ACC using principal component analysis algorithms. The correlation between ferroptosis score and tumor microenvironment immune cell infiltration was analyzed. Results Twenty ferroptosis regulators were differentially expressed in ACC and 17 ferroptosis regulators were closely related to the prognosis of ACC. Three ferroptosis subgroups (Cluster A, B, and C) were determined based on the expression of ferroptosis regulators. Cluster C is preferentially associated with favorable OS, PFS, upregulated antigen-presenting genes expression, and higher immune cell infiltration. GSEA also indicated that Cluster C was prominently related to immune fully activation including chemokine signaling pathway, natural killer cell-mediated cytotoxicity, T cell receptor signaling pathway, and Toll-like receptor signaling pathway. A ferroptosis scoring system was constructed and it could serve as an independent prognostic factor for ACC. The ferroptosis scores were significantly correlated with TMB, immune-checkpoint genes expression, and tumor microenvironment immune cell infiltration in ACC. Further analyses indicated that the ferroptosis score integrated with TMB, immune-checkpoint genes expression, and CD4+ T cell infiltration, could predict the prognosis of ACC. Furthermore, a nomogram was constructed to monitor the prognosis of individual ACC patient. RNA isolation and reverse transcription‑quantitative PCR (RT-qPCR) demonstrated significant differences in the expression levels of ACSL4, FANCD2 and SLC7A1 between ACC and normal tissues. Conclusion Our study demonstrated ferroptosis regulators were significantly associated with the prognosis, clinical characteristics, immune-checkpoint genes expression, and tumor microenvironment immune cell infiltration in ACC. This current study provided comprehensive evidence for further research on ferroptosis regulators in ACC and provides new enlightenment for epigenetic regulation of antitumor immune response.