# Steroid Phenotype Stratification Reveals Distinct HLA Expression Signatures in Adrenocortical Carcinoma

## TL;DR

This study shows that steroid hormone levels in adrenocortical tumors affect immune system interactions, with high steroid tumors evading the immune system and low steroid tumors being more responsive to immunotherapy.

## Contribution

The study identifies steroid phenotype as a novel biomarker for immune response and treatment response in adrenocortical carcinoma.

## Key findings

- High steroid production tumors show lower HLA expression and a 'cold' immune environment.
- Low steroid production tumors have higher HLA expression and increased immune cell infiltration.
- LSP tumors show a survival advantage and may benefit more from immunotherapy.

## Abstract

Adrenocortical carcinoma is a rare and aggressive cancer often characterized by excess steroid hormone production. We used computational methods to analyze molecular data from patients to investigate whether steroids influence how the immune system recognizes the tumor. Our analysis suggests that tumors stratified by steroid production levels interact with the immune system differently. Tumors producing high levels of steroids show lower levels of the genes that help the immune system recognize cancer, potentially facilitating evasion of the body’s defenses. In contrast, tumors with low steroid production maintain high levels of these genes and are associated with increased immune cell infiltration. This analysis may help explain why patients with high steroid production often have worse outcomes. Our findings suggest that patients with low steroid production might be better candidates for immunotherapies, highlighting the potential of hormone profiles to guide personalized cancer treatment.

Background: Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy where endogenous steroid excess may foster immune evasion. However, whether this hormonal axis directly modulates the antigen presentation machinery remains unclear. Methods: We applied an immunoinformatics approach to the TCGA-ACC cohort (n = 79) to investigate relationships among steroid phenotype, HLA expression, tumor microenvironment (TME), and patient outcome. Key findings were assessed in an independent validation cohort (ENSAT-ACC, n = 44) using C1A/C1B molecular subtypes corresponding to the steroid phenotypes. Results: Stratification by steroid phenotype revealed two distinct immunological profiles. The high steroid production (HSP) phenotype was associated with suppressed HLA expression and a lymphocyte-depleted “cold” TME. In contrast, the low steroid production (LSP) phenotype displayed elevated HLA expression, enriched T-cell infiltration, and upregulation of immune checkpoints (e.g., PDCD1, CTLA4), consistent with an inflamed but exhausted TME. The core signature of HLA downregulation in the HSP-like phenotype (C1A) and the significant survival advantage of the LSP-like phenotype (C1B) were confirmed in the validation cohort, demonstrating biological robustness despite platform and sample size differences. Conclusions: These findings identify the steroid phenotype as a critical regulator of immune escape in ACC. Our results support incorporating this stratification as a biomarker for patient selection, identifying LSP tumors as the subgroup most likely to benefit from immune checkpoint blockade due to their “hot” yet exhausted microenvironment.