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Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: relationship with the hypoxic response, immune evasion and malignant behaviour.

Title: Programmed cell death ligands expression in phaeochromocytomas and paragangliomas: relationship with the hypoxic response, immune evasion and malignant behaviour.
Authors: Pinato, DJ
Black, J
Trousil, S
Dina, R
Trivedi, P
Mauri, F
Sharma, R
Item Type: Journal Article
Abstract: Background: The hypoxic response underlies the pathogenesis and malignant behaviour of PCC/PGL. Regulation of PD-1 receptor-ligand signalling, a therapeutically actionable driver of the anti-tumour immune response, is a hypoxic-driven trait across malignancies. We evaluated the prognostic role of PD ligands in association with biomarkers of hypoxia and angiogenesis in patients with PCC/PGL. Methods: Tissue microarrays sections including consecutive cases diagnosed between 1983-2011 were stained for PD-L1 & 2, hypoxia inducible factor 1a (Hif-1a), Carbonic Anhydrase IX (CaIX), Vascular Endothelial Growth Factor-A (VEGF-A). We explored the biologic significance of PD ligands expression using gene set enrichment analysis (GSEA) on The Cancer Genome Atlas (TCGA) for PCC/PGL (n=184). Results: In total, 100 patients, 10% malignant, 64% PCC, 29% familial with a median tumour size of 4.7 cm (range 1-14) were included. Median follow-up was 4.7 years. We found PD-L1 expression in 18% of PCC/PGL, which was independent of adverse pathological features including capsular (CI), vascular invasion (VI), necrosis (N) and expression of biomarkers of hypoxia. PD-L2 expression (16%) strongly correlated with CI, VI, N and malignant behaviour (p<0.05) and was associated with stronger Hif-1a and CaIX immunolabeling (p<0.01). PD-L2 was predictive of shorter survival (162 versus 309 months, HR 3.1 95%CI 1.1-9.2, p=0.02). GSEA on TGCA samples confirmed enrichment of transcripts involved in hypoxia and anti-cancer immunity. Conclusions: We report for the first time PD ligands expression in PCC/PGL with a distinctive prognostic, clinico-pathologic and immuno-biologic role. These findings support a potential therapeutic role for PD-1/PD-L1 targeted checkpoint inhibitors in these tumours.
Issue Date: 4-Aug-2017
Date of Acceptance: 14-Jul-2017
URI: http://hdl.handle.net/10044/1/50128
DOI: https://dx.doi.org/10.1080/2162402X.2017.1358332
ISSN: 2162-4011
Publisher: Taylor & Francis
Journal / Book Title: OncoImmunology
Volume: 6
Issue: 11
Copyright Statement: © 2017 David J. Pinato, James R. Black, Sebastian Trousil, Roberto E. Dina, Pritesh Trivedi, Francesco A. Mauri, and Rohini Sharma. Published with license by Taylor & Francis Group, LLC This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sponsor/Funder: The Academy of Medical Sciences
Funder's Grant Number: N/A
Keywords: Science & Technology
Life Sciences & Biomedicine
Oncology
Immunology
Phaeochromocytoma
Paraganglioma
PD-L1
PD-L2
prognosis
CHECKPOINT INHIBITORS
NEUROENDOCRINE TUMORS
THERAPY
CHEMOTHERAPY
CANCER
SURVIVAL
CYCLOPHOSPHAMIDE
VINCRISTINE
DACARBAZINE
MUTATIONS
Publication Status: Published
Article Number: e1358332
Appears in Collections:Division of Surgery
Division of Cancer
Department of Medicine
Faculty of Medicine



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