ECEESPE2025 Poster Presentations Adrenal and Cardiovascular Endocrinology (169 abstracts)
Exploring the impact of pathogenic variants and cortisol secretion on M2-like tumor-associated macrophage polarization in adrenocortical adenomas
Rosa Catalano 1,2 , Giacomo Cristofolini 1,3 , Ali Kerim Secener 4 , Laura-Sophie Landwehr 1 , Mario Detomas 1 , Marc Schauer 1 , Otilia Kimpel 1 , Sabine Herterich 5 , Stefan Kircher 6 , Cristina Ronchi 7 , Silviu Sbiera 1 , Erika Peverelli 2,8 , Giovanna Mantovani 2,8 , Martin Fassnacht 1 & Barbara Altieri 1,9
1University Hospital, University of Würzburg, Division of Endocrinology and Diabetes, Department of Internal Medicine I, Würzburg, Germany; 2University of Milan, Department of Clinical Sciences and Community Health, Milan, Italy; 3Humanitas University, Division Department of Biomedical Sciences, MIlan, Italy; 4Max Delbrück Center for Molecular Medicine, Berlin, Germany; 5Central Laboratory University Hospital Würzburg, Würzburg, Germany; 6University of Würzburg, Institute of Pathology, Würzburg, Germany; 7University of Birmingham, Department of Metabolism and System Science, Birmingham, UK; 8Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Milan, Italy; 9University Hospital, University of Würzburg, Bavarian Cancer Research Center (BZKF), Würzburg, Germany
JOINT2754
Background: Prevalence of M2-macrophages has been described in normal and tumor adrenal tissues, likely modulated by cortisol autocrine/paracrine effects. However, their infiltration in adrenocortical adenomas (ACA) and comparison with normal adrenal glands (NAG) remain poorly characterized. This study aimed to evaluate tumor-associated macrophages (TAM) in ACA and assess the impact of ACA-pathogenic variants (PVs) and cortisol hypersecretion on their polarization.
Methods: Immunohistochemistry for CD163 and CD206 (M2-specific markers), and CD68 (pan-macrophage marker) was performed. Immunostaining was quantified using QuPath-0.5.1 pixel classification (thresholds 0.15–0.30) and expressed as mean percentage of positive pixels. PV in CTNNB1, PRKACA, and GNAS were detected by Sanger sequencing from matched fresh-frozen ACA. Associations between TAM, clinicopathological features, PV status, hormone levels and circulating monocytes were analyzed. Additionally, myeloid transcriptomic profiles from single-nucleus RNA sequencing (snRNA-Seq) data (DOI:10.1002/ctm2.1798) were examined using Seurat R package and differential gene expression analysis.
Results: A cohort of 103 ACA and 8 NAG-adjacent to ACA was analyzed. In ACA, CD163 staining was higher than CD206 and CD68 (6.83% vs. 1.62% and 1.71%, P<0.001). Conversely, in NAG CD206 was higher than CD68 (8.41% vs. 5.6%, P=0.008), but similar to CD163. Matched ACA-NAG comparisons revealed in ACA reduced CD206 (2.3% vs. 7.46%, P=0.008) and CD68 (2.14% vs. 4.43%, P=0.012), while CD163 remained unchanged, resulting in an increased CD163/CD206 ratio in ACA (2.28% vs. 0.76%, P=0.017). Same result was found at snRNA-Seq levels for CD206 (1.21 in ACA vs 1.48 in NAG, P<0.001), without difference in CD163. ACA harbouring CTNNB1 and PRKACA/GNAS PVs had a higher CD163/CD68 ratio compared to PV negative cases (60% vs 33%, P=0.022), an association observed exclusively in women, suggesting potential sex-specific differences in macrophage infiltration. ACA with PRKACA PVs showed lower CD206 (0.5% vs. 1.79%, P=0.003) and, consequently, higher CD163/CD206 ratio (17.4% vs 3.2%, P=0.002) than those without. These results were consistent when considering cortisol-producing ACA only. Similarly, low CD206 was found also at snRNA-Seq in ACA with PRKACA PV (0.73 vs 1.27, P=0.003). Finally, CD68 inversely correlated with 24 h-urinary free cortisol (ρ=−0.245, P=0.04), with lower CD68 in patients with overt Cushing’s syndrome (P=0.018). No correlation between number of circulating monocytes and TAM was found.
Conclusion: This study provides a comprehensive characterization of M2-like TAM in ACA, revealing distinct macrophage infiltration with higher CD163/CD206 ratio compared to NAG. TAM polarization is influenced by PVs and cortisol excess, with sex-specific differences, offering new insights into ACA microenvironment
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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