Wnt/β-catenin pathway activation is associated with glucocorticoid secretion in adrenocortical carcinoma, but not directly with immune cell infiltration.
Tanja Maier, Laura-Sophie Landwehr, Alexandra Triebig, Stefan Kircher, Marc P Schauer, Thomas Knösel, Silviu Sbiera, Paul Schwarzlmueller, Petra Zimmermann, Martin Reincke, Isabel Weigand, Martin Fassnacht, Matthias Kroiss
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引用次数: 0
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.
期刊介绍:
Frontiers in Endocrinology is a field journal of the "Frontiers in" journal series.
In today’s world, endocrinology is becoming increasingly important as it underlies many of the challenges societies face - from obesity and diabetes to reproduction, population control and aging. Endocrinology covers a broad field from basic molecular and cellular communication through to clinical care and some of the most crucial public health issues. The journal, thus, welcomes outstanding contributions in any domain of endocrinology.
Frontiers in Endocrinology publishes articles on the most outstanding discoveries across a wide research spectrum of Endocrinology. The mission of Frontiers in Endocrinology is to bring all relevant Endocrinology areas together on a single platform.