Wnt/β-catenin pathway activation is associated with glucocorticoid secretion in adrenocortical carcinoma, but not directly with immune cell infiltration

Front Endocrinol (Lausanne). 2025 Mar 10:16:1502117. doi: 10.3389/fendo.2025.1502117. eCollection 2025.

Abstract

Background: In advanced adrenocortical carcinoma (ACC), the response rate to immune checkpoint inhibition (ICI) is only ~15%. Glucocorticoid (GC) secretion and the activation of the Wnt/β-catenin pathway have been suggested to contribute to low tumour immune cell infiltration. The transcription factor lymphoid enhancer factor 1 (LEF-1) transduces β-catenin (CTNNB1)-mediated transcriptional activation.

Objective: To understand the contribution of Wnt/β-catenin pathway activation and glucocorticoid receptor (GR) signalling to the immunologically cold ACC tumour microenvironment.

Methods: Semi-quantitative immunohistochemistry (IHC) of β-catenin (CTNNB1), LEF-1, GR and T cell markers CD3, CD4, CD8, Fox P3 in 59 ACC samples. Targeted RNA expression analysis of 354 immune-related genes in 58 additional ACC tissue specimens. Correlative analyses with clinical data.

Results: Nuclear LEF-1 and CTNNB1 protein expression were positively correlated in ACC tissue (Pearson R2 = 0.1283, p=0.0046). High, moderate and low protein expression was detected in 24.1%, 53.2% and 19.3% of samples for LEF-1, and 30.6%, 43.5% and 19.3% for CTNNB1, respectively. We found higher LEF-1 expression in GC-secreting tumours which did not differ from inactive tumours in terms of GR expression. T cell markers, as evaluated by IHC, were not associated with expression of Wnt/β-catenin pathway markers. At RNA level, tumours with high LEF-1 expression showed significant downregulation of 37 transcripts (including 8 involved in antigen presentation). High LEF-1 expression levels correlated with worse overall survival in this cohort. This was not the case for CTNNB1 and GR.

Conclusion: Lef-1 expression is useful as a biomarker of activated Wnt/β-catenin signalling in ACC. Wnt/β-catenin pathway activation was not associated with reduced immune cell markers in ACC but GC secretion and may be related to tumoural antigen presentation.

Keywords: LEF-1; adrenocortical carcinoma; glucocorticoid receptor; hypercortisolism; immune cell infiltration; immunohistochemistry; marker; prognosis.

MeSH terms

  • Adrenal Cortex Neoplasms* / immunology
  • Adrenal Cortex Neoplasms* / metabolism
  • Adrenal Cortex Neoplasms* / pathology
  • Adrenocortical Carcinoma* / immunology
  • Adrenocortical Carcinoma* / metabolism
  • Adrenocortical Carcinoma* / pathology
  • Adult
  • Aged
  • Female
  • Glucocorticoids* / metabolism
  • Humans
  • Lymphocytes, Tumor-Infiltrating* / immunology
  • Lymphocytes, Tumor-Infiltrating* / metabolism
  • Lymphoid Enhancer-Binding Factor 1 / metabolism
  • Male
  • Middle Aged
  • Receptors, Glucocorticoid / metabolism
  • Tumor Microenvironment / immunology
  • Wnt Signaling Pathway*
  • beta Catenin* / metabolism

Substances

  • beta Catenin
  • Lymphoid Enhancer-Binding Factor 1
  • CTNNB1 protein, human
  • Glucocorticoids
  • LEF1 protein, human
  • Receptors, Glucocorticoid

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. P.S. received funding from the Else Kröner-Fresenius-Stiftung as part of the clinician scientist program “RISE – Rare Important Syndromes in Endocrinology”. This research was supported by the German Research Foundation (project number 314061271).