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

IF 3.9 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Frontiers in Endocrinology Pub Date : 2025-03-10 eCollection Date: 2025-01-01 DOI:10.3389/fendo.2025.1502117

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.

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在肾上腺皮质癌中，Wnt/β-catenin通路激活与糖皮质激素分泌有关，但与免疫细胞浸润无直接关系。

背景：在晚期肾上腺皮质癌（ACC）中，免疫检查点抑制（ICI）的应答率仅为~15%。糖皮质激素（GC）的分泌和Wnt/β-catenin通路的激活被认为有助于肿瘤免疫细胞的低浸润。转录因子淋巴细胞增强因子1 （LEF-1）转导β-连环蛋白（CTNNB1）介导的转录激活。目的：了解Wnt/β-catenin通路激活和糖皮质激素受体（GR）信号在ACC免疫冷肿瘤微环境中的作用。方法：采用半定量免疫组化（IHC）方法检测59例ACC患者的β-catenin （CTNNB1）、LEF-1、GR和T细胞标志物CD3、CD4、CD8、foxp3。58例ACC组织标本中354个免疫相关基因的靶向RNA表达分析。与临床资料的相关分析。结果：核LEF-1与CTNNB1蛋白在ACC组织中的表达呈正相关（Pearson R2 = 0.1283, p=0.0046）。LEF-1的高、中、低表达率分别为24.1%、53.2%和19.3%，CTNNB1的高、中、低表达率分别为30.6%、43.5%和19.3%。我们发现在gc分泌肿瘤中较高的LEF-1表达与无活性肿瘤在GR表达方面没有区别。IHC评估的T细胞标记物与Wnt/β-catenin通路标记物的表达无关。在RNA水平上，高表达LEF-1的肿瘤显示37个转录本的显著下调（包括8个参与抗原呈递的转录本）。在这个队列中，高水平的LEF-1表达与较差的总生存率相关。结论：Lef-1表达可作为ACC中激活的Wnt/β-catenin信号传导的生物标志物。Wnt/β-catenin通路激活与ACC中免疫细胞标记物的减少无关，但与GC分泌有关，可能与肿瘤抗原呈递有关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Frontiers in Endocrinology Medicine-Endocrinology, Diabetes and Metabolism

CiteScore

5.70

自引率

9.60%

发文量

3023

审稿时长

14 weeks

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.