PD-L1 and HIF-2α Upregulation in Head and Neck Paragangliomas after Embolization.
Alessa FischerUmberto MaccioKatharina WangJuliane FriemelMartina A Broglie DaeppenDiana VetterKuno LehmannAstrid ReulMercedes RobledoConstanze HantelNicole BechmannKarel PacakKathrin ZitzmannChristoph Josef AuernhammerAshley B GrossmanFelix BeuschleinSvenja NöltingPublished in: Cancers (2023)
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.
Keyphrases
- endothelial cells
- poor prognosis
- squamous cell carcinoma
- dna damage
- locally advanced
- cell proliferation
- small cell lung cancer
- cell cycle
- signaling pathway
- stem cells
- radiation therapy
- mesenchymal stem cells
- mass spectrometry
- long non coding rna
- drug delivery
- bone marrow
- high resolution
- cancer therapy
- atrial fibrillation
- cell therapy
- study protocol
- phase ii study
- double blind
- high speed