Programmed Cell Death Ligand Expression Drives Immune Tolerogenesis across the Diverse Subtypes of Neuroendocrine Tumours
© 2020 S. Karger AG, Basel..
INTRODUCTION: A comprehensive characterization 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 grades using multi-parameter immunohistochemistry and targeted transcriptomic profiling.
METHODS: Tissue microarrays (n = 102) were stained for PD-L1 and 2 and indoleamine deoxygenase-1 (IDO-1) and evaluated in relationship to functional characteristics of tumour-infiltrating T-lymphocytes (TILs) and biomarkers of hypoxia/angiogenesis. PD-L1 expression was tested in circulating tumour cells (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 pancreatic NETs (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 had the highest PD-L1/IDO-1 co-expressing tumours (p = 0.006). Grade 3 well-differentiated NETs had lower CD4+/FOXP3+ and CD8+/PD1+ TIL 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:111 |
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| Enthalten in: |
Neuroendocrinology - 111(2021), 5 vom: 20., Seite 465-474 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pinato, David J [VerfasserIn] |
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| Links: |
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| Themen: |
B7-H1 Antigen |
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| Anmerkungen: |
Date Completed 17.11.2021 Date Revised 17.11.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1159/000506745 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM306904128 |
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| 100 | 1 | |a Pinato, David J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Programmed Cell Death Ligand Expression Drives Immune Tolerogenesis across the Diverse Subtypes of Neuroendocrine Tumours |
| 264 | 1 | |c 2021 | |
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| 500 | |a Date Completed 17.11.2021 | ||
| 500 | |a Date Revised 17.11.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2020 S. Karger AG, Basel. | ||
| 520 | |a INTRODUCTION: A comprehensive characterization 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 | ||
| 520 | |a OBJECTIVE: We investigated drivers of cancer-related immunosuppression across NETs of various sites and grades using multi-parameter immunohistochemistry and targeted transcriptomic profiling | ||
| 520 | |a METHODS: Tissue microarrays (n = 102) were stained for PD-L1 and 2 and indoleamine deoxygenase-1 (IDO-1) and evaluated in relationship to functional characteristics of tumour-infiltrating T-lymphocytes (TILs) and biomarkers of hypoxia/angiogenesis. PD-L1 expression was tested in circulating tumour cells (CTCs, n = 12) to evaluate its relationship with metastatic dissemination | ||
| 520 | |a RESULTS: PD-L1 expression was highest in lung NETs (n = 30, p = 0.007), whereas PD-L2 was highest in pancreatic NETs (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 had the highest PD-L1/IDO-1 co-expressing tumours (p = 0.006). Grade 3 well-differentiated NETs had lower CD4+/FOXP3+ and CD8+/PD1+ TIL 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) | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Neuroendocrine tumours | |
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| 650 | 4 | |a PD-L1 | |
| 650 | 4 | |a PD-L2 | |
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| 650 | 7 | |a CD274 protein, human |2 NLM | |
| 650 | 7 | |a Programmed Cell Death 1 Ligand 2 Protein |2 NLM | |
| 650 | 7 | |a Programmed Cell Death 1 Receptor |2 NLM | |
| 700 | 1 | |a Vallipuram, Anu |e verfasserin |4 aut | |
| 700 | 1 | |a Evans, Joanne S |e verfasserin |4 aut | |
| 700 | 1 | |a Wong, Clement |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Hua |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Matthew |e verfasserin |4 aut | |
| 700 | 1 | |a Dina, Roberto E |e verfasserin |4 aut | |
| 700 | 1 | |a Trivedi, Pritesh |e verfasserin |4 aut | |
| 700 | 1 | |a Akarca, Ayse U |e verfasserin |4 aut | |
| 700 | 1 | |a Marafioti, Teresa |e verfasserin |4 aut | |
| 700 | 1 | |a Mauri, Francesco A |e verfasserin |4 aut | |
| 700 | 1 | |a Sharma, Rohini |e verfasserin |4 aut | |
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