PD-L1 expression and association with genetic background in pheochromocytoma and paraganglioma

0565106 - BTÚ 2023 RIV CH eng J - Článek v odborném periodiku
Vanova, K. H. - Uher, O. - Meuter, L. - Ghosal, S. - Talvacchio, S. - Patel, M. - Neužil, Jiří - Pacak, K.
PD-L1 expression and association with genetic background in pheochromocytoma and paraganglioma.
Frontiers in Oncology. Roč. 12, NOV 11 2022 (2022), č. článku 1045517. ISSN 2234-943X. E-ISSN 2234-943X
Institucionální podpora: RVO:86652036
Klíčová slova: neuroendocrine tumors * immunotherapy * pheochromocytoma * paraganglioma * programmed death ligand 1
Obor OECD: Oncology
Impakt faktor: 4.7, rok: 2022
Způsob publikování: Open access
https://www.frontiersin.org/articles/10.3389/fonc.2022.1045517/full

Metastatic pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors associated with poor prognosis and limited therapeutic options. Recent advances in oncology-related immunotherapy, specifically in targeting of programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathways, have identified a new treatment potential in a variety of tumors, including advanced and rare tumors. Only a fraction of patients being treated by immune checkpoint inhibitors have shown to benefit from it, displaying a need for strategies which identify patients who may most likely show a favorable response. Building on recent, promising outcomes in a clinical study of metastatic PPGL using pembrolizumab, a humanized IgG4 kappa monoclonal antibody targeting the PD-1/PD-L1 pathway, we examined PD-L1 and PD-L2 expression in relation to oncogenic drivers in our PPGL patient cohort to explore whether expression can predict metastatic potential and/or be considered a predictive marker for targeted therapy. We evaluated RNA expression in the NIH cohort of 48 patients with known genetic predisposition (sporadic, pseudohypoxia: SDHB, VHL, EPAS1, EGLN1, kinase signaling: RET, NF1) and 6 normal medulla samples (NAM). For comparison, 72 PPGL samples from The Cancer Genome Atlas (TCGA) were used for analysis of gene expression based on the variant status (pseudohypoxia: SDHB, VHL, EPAS1, EGLN1, kinase signaling: NF1, RET). Expression of PD-L1 was elevated in the PPGL cohort compared to normal adrenal medulla, aligning with the TCGA analysis, whereas PD-L2 was not elevated. However, expression of PD-L1 was lower in the pseudohypoxia cluster compared to the sporadic and the kinase signaling subtype cluster, suggesting that sporadic and kinase signaling cluster PPGLs could benefit from PD-1/PD-L1 therapy more than the pseudohypoxia cluster. Within the pseudohypoxia cluster, expression of PD-L1 was significantly lower in both SDHB- and non-SDHB-mutated tumors compared to sporadic tumors. PD-L1 and PD-L2 expression was not affected by the metastatic status. We conclude that PD-L1 and PD-L2 expression in our cohort of PPGL tumors was not linked to metastatic behavior, however, the presence of PPGL driver mutation could be a predictive marker for PD-L1-targeted therapy and an important feature for further clinical studies in patients with PPGL.
Trvalý link: https://hdl.handle.net/11104/0337807