BRAFV600E Expression in Thyrocytes Causes Recruitment of Immunosuppressive STABILIN-1 Macrophages

Catherine Spourquet; Ophélie Delcorte; Pascale Lemoine; Nicolas Dauguet; Axelle Loriot; Younes Achouri; Maija Hollmén; Sirpa Jalkanen; François Huaux; Sophie Lucas; Pierre Van Meerkeeck; Jeffrey A Knauf; James A Fagin; Chantal Dessy; Michel Mourad; Patrick Henriet; Donatienne Tyteca; Etienne Marbaix; Christophe E Pierreux

doi:10.3390/cancers14194687

BRAF^V600E Expression in Thyrocytes Causes Recruitment of Immunosuppressive STABILIN-1 Macrophages

Cancers (Basel). 2022 Sep 26;14(19):4687. doi: 10.3390/cancers14194687.

Authors

Catherine Spourquet¹, Ophélie Delcorte¹, Pascale Lemoine¹, Nicolas Dauguet², Axelle Loriot³, Younes Achouri⁴, Maija Hollmén⁵, Sirpa Jalkanen⁵, François Huaux⁶, Sophie Lucas^{7

8}, Pierre Van Meerkeeck⁷, Jeffrey A Knauf⁹, James A Fagin¹⁰, Chantal Dessy¹¹, Michel Mourad¹², Patrick Henriet¹, Donatienne Tyteca¹, Etienne Marbaix¹, Christophe E Pierreux¹

Affiliations

¹ CELL Unit, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
² CYTF Platform, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
³ CBIO Unit, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
⁴ Transgenesis Platform, Université Catholique de Louvain, 1200 Brussels, Belgium.
⁵ MediCity Research Laboratory and InFLAMES Flagship, University of Turku, 20500 Turku, Finland.
⁶ LTAP Unit, IREC, Université Catholique de Louvain, 1200 Brussels, Belgium.
⁷ GECE Unit, de Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
⁸ Walloon Excellence in Life Sciences and Biotechnology (WELBIO), 1300 Wavre, Belgium.
⁹ Department of Otolaryngology Head & Neck Surgery in the Cleveland Clinic Lerner, College of Medicine of Case Western Reserve University, Cleveland, OH 44106, USA.
¹⁰ Department of Medicine and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹¹ FATH & MORF Unit, IREC, Université Catholique de Louvain, 1200 Brussels, Belgium.
¹² Surgery and Abdominal Transplantation Division, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, 1200 Brussels, Belgium.

Abstract

Papillary thyroid carcinoma (PTC) is the most frequent histological subtype of thyroid cancers (TC), and BRAF^V600E genetic alteration is found in 60% of this endocrine cancer. This oncogene is associated with poor prognosis, resistance to radioiodine therapy, and tumor progression. Histological follow-up by anatomo-pathologists revealed that two-thirds of surgically-removed thyroids do not present malignant lesions. Thus, continued fundamental research into the molecular mechanisms of TC downstream of BRAF^V600E remains central to better understanding the clinical behavior of these tumors. To study PTC, we used a mouse model in which expression of BRAF^V600E was specifically switched on in thyrocytes by doxycycline administration. Upon daily intraperitoneal doxycycline injection, thyroid tissue rapidly acquired histological features mimicking human PTC. Transcriptomic analysis revealed major changes in immune signaling pathways upon BRAF^V600E induction. Multiplex immunofluorescence confirmed the abundant recruitment of macrophages, among which a population of LYVE-1+/CD206+/STABILIN-1+ was dramatically increased. By genetically inactivating the gene coding for the scavenger receptor STABILIN-1, we showed an increase of CD8+ T cells in this in situ BRAF^V600E-dependent TC. Lastly, we demonstrated the presence of CD206+/STABILIN-1+ macrophages in human thyroid pathologies. Altogether, we revealed the recruitment of immunosuppressive STABILIN-1 macrophages in a PTC mouse model and the interest to further study this macrophage subpopulation in human thyroid tissues.

Keywords: CD4/CD8 T cells; Stab1−/− mice; thyroid diseases.

Abstract

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