Steroid Phenotype Stratification Reveals Distinct HLA Expression Signatures in Adrenocortical Carcinoma

Area of Science:

• Immunology
• Oncology
• Endocrinology

Background:

• Adrenocortical carcinoma (ACC) is a rare cancer.
• Steroid excess in ACC may promote immune evasion.
• The link between steroid production and antigen presentation is unclear.

Purpose of the Study:

• Investigate the relationship between steroid phenotype, HLA expression, and the tumor microenvironment (TME) in ACC.
• Determine the impact of these factors on patient outcomes.
• Validate findings in an independent cohort.

Main Methods:

• Immunoinformatics analysis of TCGA-ACC cohort (n=79).
• Assessment of steroid phenotype, HLA expression, TME, and patient survival.
• Validation in ENSAT-ACC cohort (n=44) using molecular subtypes.

Main Results:

• Two distinct immunological profiles emerged based on steroid production.
• High steroid production (HSP) linked to suppressed HLA and "cold" TME.
• Low steroid production (LSP) associated with elevated HLA, T-cell infiltration, and immune checkpoints ("hot" but exhausted TME).
• HLA downregulation in HSP-like (C1A) and survival advantage in LSP-like (C1B) phenotypes confirmed.

Conclusions:

• Steroid phenotype is a key regulator of immune escape in ACC.
• LSP phenotype (C1B) identifies tumors likely to respond to immune checkpoint blockade.
• Stratification by steroid phenotype may serve as a biomarker for patient selection.