{"doi":"10.3389/fonc.2022.1045517","title":"PD-L1 expression and association with genetic background in pheochromocytoma and paraganglioma","abstract":"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 IgG4κ 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.","journal":"Frontiers in Oncology","year":2022,"id":273355,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9567,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":372489,"name":"Ondřej Uher","orcid":"0000-0003-3978-9822","position":1,"is_corresponding":false},{"id":377912,"name":"Leah Meuter","orcid":null,"position":2,"is_corresponding":false},{"id":786918,"name":"Suman Ghosal","orcid":"0000-0002-3772-2336","position":3,"is_corresponding":false},{"id":698364,"name":"Sara Talvacchio","orcid":"0009-0006-6969-4735","position":4,"is_corresponding":false},{"id":484972,"name":"Mayank Patel","orcid":"0000-0002-6609-5394","position":5,"is_corresponding":false},{"id":459089,"name":"Jiřı́ Neužil","orcid":"0000-0002-2478-2460","position":6,"is_corresponding":false},{"id":435576,"name":"A. Jha","orcid":"0000-0002-1489-2471","position":7,"is_corresponding":false},{"id":246732,"name":"Katerina Hadrava Vanova","orcid":"0000-0002-8868-6013","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T00:27:52.048702Z","pmid":"36439433","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}