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Programmed cell death ligands expression drives immune tolerogenesis across the diverse subtypes of neuroendocrine tumours

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Title: Programmed cell death ligands expression drives immune tolerogenesis across the diverse subtypes of neuroendocrine tumours
Authors: Pinato, DJ
Vallipuram, A
Evans, JS
Wong, C
Zhang, H
Brown, M
Dina, RE
Trivedi, P
Akarca, AU
Marafioti, T
Mauri, FA
Sharma, R
Item Type: Journal Article
Abstract: INTRODUCTION: A comprehensive characterisation of the tumour microenvironment is lacking in neuroendocrine tumours (NETs), where programmed cell death-1 receptor-ligand (PD-1/PD-L1) inhibitors are undergoing efficacy testing. OBJECTIVE: We investigated drivers of cancer-related immunosuppression across NETs of various sites and grade using multi-parameter immunohistochemistry and targeted transcriptomic profiling. METHODS: Tissue microarrays (n=102) were stained for PD-L1 & 2, Indoleamine-deoxygenase-1 (IDO-1) and evaluated in relationship to functional characteristics of tumor-infiltrating T-lymphocytes (TILs) and biomarkers of hypoxia/angiogenesis. PD-L1 expression was tested in circulating tumour cell (CTCs, n=12) to evaluate its relationship with metastatic dissemination. RESULTS: PD-L1 expression was highest in lung NETs (n=30, p=0.007), whereas PD-L2 was highest in pNETs (n=53, p<0.001) with no correlation with grade or hypoxia/angiogenesis. PD-L1+ NETs (n=26, 25%) had greater CD4+/FOXP3+ and CD8+/PD1+ TILs (p<0.001) and necrosis (p=0.02). CD4+/FOXP3+ infiltrate was highest PD-L1/IDO-1 co-expressing tumours (p=0.006). Grade 3 well-differentiated NETs had lower CD4+/FOXP3+ and CD8+/PD1+ TILs density (p<0.001) and Nanostring immune-profiling revealed enrichment of macrophage-related transcripts in cases with poorer prognosis. We identified PD-L1(+) CTC subpopulations in 75% of evaluated patients (n=12). CONCLUSIONS: PD-L1 expression correlates with T-cell exhaustion independent of tumour hypoxia and is enhanced in a subpopulation of CTCs, suggesting its relevance to the progression of NETs. These findings support a potential therapeutic role for PD-L1 inhibitors in a subset of NETs.
Issue Date: 25-Feb-2020
Date of Acceptance: 21-Feb-2020
URI: http://hdl.handle.net/10044/1/81860
DOI: 10.1159/000506745
ISSN: 0028-3835
Publisher: Karger Publishers
Start Page: 465
End Page: 474
Journal / Book Title: Neuroendocrinology: international journal for basic and clinical studies on neuroendocrine relationships
Volume: 111
Copyright Statement: © 2020 S. Karger AG, Basel.
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: RDB01 79560
Keywords: Neuroendocrine tumours
1103 Clinical Sciences
1109 Neurosciences
Endocrinology & Metabolism
Publication Status: Published
Conference Place: Switzerland
Online Publication Date: 2020-02-25
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Faculty of Medicine