Fischer, AlessaMaccio, UmbertoWang, KatharinaFriemel, JulianeBroglie Daeppen, Martina AVetter, DianaLehmann, KunoReul, AstridRobledo Batanero, MercedesHantel, ConstanzeBechmann, NicolePacak, KarelZitzmann, KathrinAuernhammer, Christoph JGrossman, Ashley BBeuschlein, FelixNölting, Svenja2024-09-162024-09-162023-10-29Cancers (Basel) . 2023 ;15(21):5199.2072-6694https://hdl.handle.net/20.500.12105/23098Hypoxia activates pathways associated with tumor progression, metastatic spread, and alterations in the immune microenvironment leading to an immunosuppressive phenotype. In particular, the upregulation of PD-L1, a target for therapy with checkpoint inhibitors, is well-studied in several tumors. However, the relationship between hypoxia and PD-L1 regulation in pheochromocytomas and paragangliomas (PPGL), and especially in paragangliomas treated with embolization, is still largely unexplored. We investigated the expression of the hypoxia-marker HIF-2? and of PD-L1 in a PPGL-cohort with and without embolization as potential biomarkers that may predict the response to treatment with HIF-2? and checkpoint inhibitors. A total of 29 tumor samples from 25 patients who were operated at a single center were included and analyzed utilizing immunohistochemistry (IHC) for PD-L1 and HIF-2?. Embolization prior to surgery was performed in seven (24%) tumors. PD-L1 expression in tumor cells of head and neck paragangliomas (HNPGLs) receiving prior embolization (median PD-L1 positivity: 15%) was significantly higher as compared to PD-L1 expression in HNPGLs without prior embolization (median PD-L1 positivity: 0%) (p = 0.008). Consistently, significantly more HNPGLs with prior embolization were positive for HIF-2? (median nuclear HIF-2? positivity: 40%) as compared to HNPGLs without prior embolization (median nuclear HIF-2? positivity: 0%) (p = 0.016). Our results support the hypothesis that embolization with subsequent hypoxia leads to the upregulation of both PD-L1 and HIF-2? in HNPGLs, and could thus facilitate targeted treatment with HIF-2? and checkpoint inhibitors in the case of inoperable, locally advanced, or metastatic disease.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 Internacional37958373152110.3390/cancers15215199Cancersopen access