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

Vanova, Katerina Hadrava; Uher, Ondřej; Meuter, Leah; Ghosal, Suman; Talvacchio, Sara; Patel, Mayank; Neužil, Jiřı́; Pacák, Karel

doi:10.3389/fonc.2022.1045517

Cited by 4 publications

(5 citation statements)

References 36 publications

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“…Within the pseudohypoxia cluster, expression of PD-L1 was significantly lower in both SDHB- and non-SDHB-mutated tumours compared with sporadic tumours. PD-L1 and PD-L2 expression was not linked to metastatic behaviour, however, the presence of Pheo/PGL driver mutation could be a predictive marker for PD-L1-targeted therapy and an important feature for further clinical studies in patients with Pheo/PGL ( 178 ).…”

Section: Immune Phenotype Of Pheo/pglmentioning

confidence: 96%

“…Very recently, Hadrava Vanova et al. examined PD-L1 and PD-L2 expression in relation to oncogenic drivers in their Pheo/PGL patient cohort to explore whether expression can predict metastatic potential and/or be considered a predictive marker for targeted therapy ( 178 ). They found that the expression of PD-L1 was elevated in the Pheo/PGL cohort compared with normal adrenal medulla, whereas PD-L2 was not elevated.…”

Section: Immune Phenotype Of Pheo/pglmentioning

confidence: 99%

“…The results of the phase II clinical trial of pembrolizumab, a humanized anti-PD-1 monoclonal antibody, in patients with progressive metastatic Pheo/PGL, indicate that this drug has modest anti-neoplastic activity with an acceptable safety profile (177). Very recently, Hadrava Vanova et al examined PD-L1 and PD-L2 expression in relation to oncogenic drivers in their Pheo/PGL patient cohort to explore whether expression can predict metastatic potential and/or be considered a predictive marker for targeted therapy (178). They found that the expression of PD-L1 was elevated in the Pheo/PGL cohort compared with normal adrenal medulla, whereas PD-L2 was not elevated.…”

Section: Immune Phenotype Of Pheo/pglmentioning

confidence: 99%

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Tumour microenvironment in pheochromocytoma and paraganglioma

et al. 2023

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Pheochromocytomas and Paragangliomas (Pheo/PGL) are rare catecholamine-producing tumours derived from adrenal medulla or from the extra-adrenal paraganglia respectively. Around 10–15% of Pheo/PGL develop metastatic forms and have a poor prognosis with a 37% of mortality rate at 5 years. These tumours have a strong genetic determinism, and the presence of succinate dehydrogenase B (SDHB) mutations are highly associated with metastatic forms. To date, no effective treatment is present for metastatic forms. In addition to cancer cells, the tumour microenvironment (TME) is also composed of non-neoplastic cells and non-cellular components, which are essential for tumour initiation and progression in multiple cancers, including Pheo/PGL. This review, for the first time, provides an overview of the roles of TME cells such as cancer-associated fibroblasts (CAFs) and tumour-associated macrophages (TAMs) on Pheo/PGL growth and progression. Moreover, the functions of the non-cellular components of the TME, among which the most representatives are growth factors, extracellular vesicles and extracellular matrix (ECM) are explored. The importance of succinate as an oncometabolite is emerging and since Pheo/PGL SDH mutated accumulate high levels of succinate, the role of succinate and of its receptor (SUCNR1) in the modulation of the carcinogenesis process is also analysed. Further understanding of the mechanism behind the complicated effects of TME on Pheo/PGL growth and spread could suggest novel therapeutic targets for further clinical treatments.

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Section: Immune Phenotype Of Pheo/pglmentioning

confidence: 96%

Section: Immune Phenotype Of Pheo/pglmentioning

confidence: 99%

Section: Immune Phenotype Of Pheo/pglmentioning

confidence: 99%

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Tumour microenvironment in pheochromocytoma and paraganglioma

et al. 2023

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“…In our cohort, PD-L1 and HIF-2α positivity were not associated with cluster 1A PV (pseudo-hypoxia) or cluster 2 PVs when corrected for embolization status. An analysis of 48 PPGL patients in combination with a cohort from "The Cancer Genome Atlas" (TCGA) selected on the presence of matched PV (n = 72) even revealed decreased mRNA expression of the PD-L1 gene in the pseudo-hypoxia cluster 1 compared to the kinase signaling cluster 2 [29].…”

Section: Effect Of Embolization/hypoxia On Pd-l1 Expression In Ppglsmentioning

confidence: 99%

“…PD-L1 expression on tumor cells-in addition to tumor mutational burden (TMB) and microsatellite instability (MSI) -is a widely used biomarker to predict the response to immunotherapy with antibodies blocking the PD-L1/PD1 axis [28]. However, PD-L1 expression and its association with HIF-α expression in different subgroups of PPGLs is not well studied, and has especially not yet been studied in the context of embolization-induced hypoxia [29][30][31].…”

Section: Introductionmentioning

confidence: 99%

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

Fischer,

Maccio,

Wang

et al. 2023

Cancers

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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.

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Platelet-Lymphocyte and Neutrophil-Lymphocyte Ratios Are Prognostic Markers for Pheochromocytomas and Paragangliomas

Yang

et al. 2023

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Preoperative inflammatory markers, such as the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and lymphocyte-monocyte ratio (LMR), have recently been proposed as prognostic markers in different tumors. However, their predictive values in patients with pheochromocytomas and paragangliomas (PPGLs) are uncertain. The present study aimed to investigate the prognostic significance of these biomarkers in PPGL patients. Objective We assessed whether inflammatory biomarkers are associated with poor prognosis for PPGLs. Design Data from 1247 consecutive PPGL patients between 2002 and 2020 were evaluated. The preoperative inflammatory markers were evaluated. The prognostic roles were identified by X-tile software, Kaplan–Meier curves, and Cox regression models. Results A total of 728 patients were included in the analysis, with a median follow-up of 63 months (IQR, 31–111 months), 31 individuals died, 28 patients developed metastases and 12 patients developed recurrence. Our study showed that death were observed significantly more frequently in patients with high NLR(≥3.5) and high PLR (≥217.4) group than with low NLR(<3.5) (P=0.003) and low PLR(<217.4) group (P=0.005). Elevated NLR (≥3.5) and elevated PLR (≥217.4) was significantly associated with decreased overall survival (OS) (P=0.005), elevated PLR (≥238.3) was significantly associated with decreased Metastasis-free survival (MFS) (P=0.021). Cox models illustrated that NLR and PLR were independent prognostic factors for OS, and PLR was an independent prognostic factor for MFS. Conclusions Both elevated NLR and PLR are associated with poor prognosis in PPGLs. They are convenient predictive markers that could be used in daily clinical practice.

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

Cited by 4 publications

References 36 publications

Tumour microenvironment in pheochromocytoma and paraganglioma

Tumour microenvironment in pheochromocytoma and paraganglioma

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

Platelet-Lymphocyte and Neutrophil-Lymphocyte Ratios Are Prognostic Markers for Pheochromocytomas and Paragangliomas

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