PD-L1 and HIF-2α Upregulation in Head and Neck Paragangliomas after Embolization

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-2 alpha (median nuclear HIF-2 alpha positivity: 40%) as compared to HNPGLs without embolization (median nuclear HIF-2 alpha positivity: 0%). Our findings suggest, that hypoxia leads to the upregulation of both PD-L1 and HIF-2 alpha in HNPGLs, and may thus facilitate targeted treatment with HIF-2 alpha 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-2 alpha 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 alpha 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 alpha. 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 alpha (median nuclear HIF-2 alpha positivity: 40%) as compared to HNPGLs without prior embolization (median nuclear HIF-2 alpha 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 alpha in HNPGLs, and could thus facilitate targeted treatment with HIF-2 alpha and checkpoint inhibitors in the case of inoperable, locally advanced, or metastatic disease.