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- Title
PD-L1 and HIF-2α Upregulation in Head and Neck Paragangliomas after Embolization.
- Authors
Fischer, Alessa; Maccio, Umberto; Wang, Katharina; Friemel, Juliane; Broglie Daeppen, Martina A.; Vetter, Diana; Lehmann, Kuno; Reul, Astrid; Robledo, Mercedes; Hantel, Constanze; Bechmann, Nicole; Pacak, Karel; Zitzmann, Kathrin; Auernhammer, Christoph J.; Grossman, Ashley B.; Beuschlein, Felix; Nölting, Svenja
- Abstract
Simple Summary: In solid tumors, hypoxia activates pathways associated with tumor progression and induces alterations in the immune microenvironment such as the upregulation of programmed cell death-ligand 1 (PD-L1). Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors which are all considered to have metastatic potential independent of their initial clinical presentation. However, the relationship between hypoxia and PD-L1 regulation in PPGLs is still largely unexplored. We show that PD-L1 expression in head and neck paragangliomas (HNPGLs) undergoing 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%). Consistently, significantly more HNPGLs with embolization were positive for the hypoxia-marker HIF-2α (median nuclear HIF-2α positivity: 40%) as compared to HNPGLs without embolization (median nuclear HIF-2α positivity: 0%). Our findings suggest, that hypoxia leads to the upregulation of both PD-L1 and HIF-2α in HNPGLs, and may thus facilitate targeted treatment with HIF-2α and checkpoint inhibitors. Hypoxia 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-2α and of PD-L1 in a PPGL-cohort with and without embolization as potential biomarkers that may predict the response to treatment with HIF-2α 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-2α. 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-2α (median nuclear HIF-2α positivity: 40%) as compared to HNPGLs without prior embolization (median nuclear HIF-2α 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-2α in HNPGLs, and could thus facilitate targeted treatment with HIF-2α and checkpoint inhibitors in the case of inoperable, locally advanced, or metastatic disease.
- Subjects
PROTEINS; KRUSKAL-Wallis Test; PROGRAMMED death-ligand 1; IMMUNE checkpoint inhibitors; IMMUNOHISTOCHEMISTRY; HEAD &; neck cancer; THERAPEUTIC embolization; PEARSON correlation (Statistics); COMPARATIVE studies; CHI-squared test; DESCRIPTIVE statistics; PHEOCHROMOCYTOMA; RESEARCH funding; PARAGANGLIOMA; DATA analysis software; TUMOR markers; HYPOXEMIA; CELL death
- Publication
Cancers, 2023, Vol 15, Issue 21, p5199
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers15215199