The immune cell infiltrate in the tumour microenvironment of phaeochromocytomas and paragangliomas

Tufton, Nicola; Berney, Daniel M.; Drake, William M; Parvanta, Laila; Chapple, J. Paul; Akker, Scott

doi:10.1530/erc-22-0020

Cited by 10 publications

(9 citation statements)

References 32 publications

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“…A recent study on the tumor immune microenvironment of PPGLs is consistent with this notion since the lowest proportion of cytotoxic Tlymphocytes in PPGLs has been associated with SDHB mutations (29). This further suggests that reduced immune cells presence in tumors corresponds to higher risk of their metastatic behavior (29,30). In our cohort, one patient with SDHB germline variant received immunotherapy (nivolumab and ipilimumab), besides other treatments, however, the patient had metastatic, progressive disease at the time of these therapies and very soon afterwards progressed, without indication of significant stabilization.…”

Section: Discussionsupporting

confidence: 60%

“…Since PD-L1 expression can represent a T cellmediated inflamed tumor microenvironment (25-28), lower expression in the pseudohypoxia cluster most likely correlates to a lower T cell involvement/immune activation. A recent study on the tumor immune microenvironment of PPGLs is consistent with this notion since the lowest proportion of cytotoxic Tlymphocytes in PPGLs has been associated with SDHB mutations (29). This further suggests that reduced immune cells presence in tumors corresponds to higher risk of their metastatic behavior (29,30).…”

Section: Discussionsupporting

confidence: 57%

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

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionsupporting

confidence: 57%

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

et al. 2022

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“…Moreover, both mast cells, Th1 cells and B cells had strongly positive relation to TIL, and TIL had positive correlation with macrophages. Although no signi cant difference was found in macrophages in our study, PPGLs is usually presented a more prominent macrophage signature, with Th1 suppressed [40][41][42]. Consequently, furtherly analysis for different types of macrophages may needed in this study.…”

Section: Discussioncontrasting

confidence: 54%

Chromatin Regulators as Prognostic Biomarkers In Patients With Pheochromocytomas And Paragangliomas

Kong,

Tang,

Wang

et al. 2023

Preprint

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Chromatin regulators participated in tumorigenesis of various cancers while less research about its relationships with pheochromocytomas and paragangliomas. The aim of our study was to discover potential chromatin regulators as biomarkers for pathogenesis as well as prognosis of pheochromocytomas and paragangliomas. In this study, we explored expression patterns of pheochromocytomas and paragangliomas from the Gene Expression Omnibus database and 870 manually curated verified chromatin regulators. Then 185 differentially expressed chromatin regulators were verified which biological function were explored using Gene Ontology，Disease Ontology，Moreover, Kyoto Encyclopedia of Genes and Genomes pathways enrichment analysis. Besides protein-protein interaction network indicated 10 Hub genes. Their diagnostic performance as well as related drugs were valued by Receiver Operating Characteristics analysis, The Drug Signature Databases separately. Then we use TISIDB database to verify the relationship between 10 Hub genes and immune infiltration of pheochromocytomas and paragangliomas. Finally, 2 key genes were screened after Kaplan-Meier survival analysis and miRNA regulatory network was constructed based on Key genes by TargetScan microRNA 2017 in the Enrichr platform and TargetScanHuman (version8.0) platform. In conclusion, we identified 10 chromatin regulatorsespecially EZH2 and TAF7 which had high diagnostic performance and their functions were complicated in tumorigenesis of pheochromocytomas and paragangliomas. Likewise, the immune infiltration of pheochromocytomas and paragangliomas was intrinsically complex and these Hub genes mainly had negative correlation with immune infiltrating cells as well as immune infiltrating functions. Consequently, these chromatin regulators verified in our research could help to a further evaluation in pathogenesis and prognosis of pheochromocytomas and paragangliomas. Trial registration None

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“…In this work, three out of four Pheo/PGL tumours with mutations in genes encoding for the SDH subunits showed the highest levels of CD163 compared with tumours harbouring different mutations. Very recently, Tufton and colleagues confirmed the presence of macrophages, lymphocytes and neutrophils by immunohistochemistry on Pheo/PGL tumour samples (76). They not only found a higher proportion of immune cells with a predominance of macrophages, in tumour tissue compared with non-neoplastic adrenal medulla tissue, but also a higher proportion of M2:M1 macrophages and T-helper lymphocytes in aggressive tumours compared with indolent ones.…”

Section: Tumour Associated Macrophagesmentioning

confidence: 90%

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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The immune cell infiltrate in the tumour microenvironment of phaeochromocytomas and paragangliomas

Cited by 10 publications

References 32 publications

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

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

Chromatin Regulators as Prognostic Biomarkers In Patients With Pheochromocytomas And Paragangliomas

Tumour microenvironment in pheochromocytoma and paraganglioma

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