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PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by BRAFV600E Mutation

SIMPLE SUMMARY: This study was conducted to investigate the prognostic significance of programmed death-ligand 1 (PD-L1) expression in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC) patients and to explore the correlation of PD-L1 and BRAFV600E mutations in PTC tumors and cell li...

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Autores principales: Siraj, Abdul K., Parvathareddy, Sandeep Kumar, Pratheeshkumar, Poyil, Divya, Sasidharan Padmaja, Al-Sobhi, Saif S., Al-Dayel, Fouad, Al-Kuraya, Khawla S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867170/
https://www.ncbi.nlm.nih.gov/pubmed/33535609
http://dx.doi.org/10.3390/cancers13030555
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author Siraj, Abdul K.
Parvathareddy, Sandeep Kumar
Pratheeshkumar, Poyil
Divya, Sasidharan Padmaja
Al-Sobhi, Saif S.
Al-Dayel, Fouad
Al-Kuraya, Khawla S.
author_facet Siraj, Abdul K.
Parvathareddy, Sandeep Kumar
Pratheeshkumar, Poyil
Divya, Sasidharan Padmaja
Al-Sobhi, Saif S.
Al-Dayel, Fouad
Al-Kuraya, Khawla S.
author_sort Siraj, Abdul K.
collection PubMed
description SIMPLE SUMMARY: This study was conducted to investigate the prognostic significance of programmed death-ligand 1 (PD-L1) expression in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC) patients and to explore the correlation of PD-L1 and BRAFV600E mutations in PTC tumors and cell lines. We found PD-L1 over-expression in PTC patients and it was significantly associated with aggressive clinico-pathological parameters and BRAF mutation. PTC patients with co-existing PD-L1 over-expression and BRAF mutation had a poor disease-free survival. In vitro studies showed that BRAF inhibition induces PD-L1 expression in BRAF-mutated PTC cell lines via mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway activation. Silencing of PD-L1 in BRAF-mutated cell lines significantly attenuated cell growth. Our data suggest that PD-L1 could represent a useful prognostic marker for risk stratification in Middle Eastern PTC and that a programmed cell death protein 1 (PD-1)/PD-L1 inhibitor could be a potential therapeutic option for aggressive PTC cancers, such as the tall cell variant, BRAF mutation-positive patients that are unresponsive to standard PTC treatment. ABSTRACT: PD-L1 inhibition is a promising therapeutic target whose efficacy has been demonstrated in several cancers. Immunohistochemistry was performed to assess PD-L1 protein expression in PTC. We further conducted in vitro analysis to investigate the role of PD-L1 in regulating BRAFV600E in PTC cell lines. PD-L1 over-expression was noted in 32.4% (473/1458) of cases and significantly associated with aggressive clinico-pathological parameters. Importantly, PD-L1 was found to be an independent poorer prognostic marker. We also found PD-L1 to be significantly associated with BRAF mutation and patients with co-existing PD-L1 over-expression and BRAF mutation had a poor disease-free survival compared to patients with BRAF mutation alone. In vitro analysis showed high expression of PD-L1 in BRAF-mutated PTC cell lines compared to a BRAF wild-type cell line. Inhibition of BRAF using vemurafenib induced PD-L1 expression in BRAF-mutated cell lines without affecting cell growth. Knockdown of PD-L1 in BRAF-mutated cell lines significantly decreased the cell growth and induced apoptosis. Our data suggest that PD-L1 might represent a useful prognostic marker in Middle Eastern PTC and PD-L1 inhibition could be a potential therapeutic option for aggressive PTC cancers, such as the tall cell variant, BRAF mutation-positive patients that are unresponsive to standard treatment.
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spelling pubmed-78671702021-02-07 PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by BRAFV600E Mutation Siraj, Abdul K. Parvathareddy, Sandeep Kumar Pratheeshkumar, Poyil Divya, Sasidharan Padmaja Al-Sobhi, Saif S. Al-Dayel, Fouad Al-Kuraya, Khawla S. Cancers (Basel) Article SIMPLE SUMMARY: This study was conducted to investigate the prognostic significance of programmed death-ligand 1 (PD-L1) expression in a large cohort of Middle Eastern papillary thyroid carcinoma (PTC) patients and to explore the correlation of PD-L1 and BRAFV600E mutations in PTC tumors and cell lines. We found PD-L1 over-expression in PTC patients and it was significantly associated with aggressive clinico-pathological parameters and BRAF mutation. PTC patients with co-existing PD-L1 over-expression and BRAF mutation had a poor disease-free survival. In vitro studies showed that BRAF inhibition induces PD-L1 expression in BRAF-mutated PTC cell lines via mitogen-activated protein kinase kinase/extracellular-signal-regulated kinase (MEK/ERK) pathway activation. Silencing of PD-L1 in BRAF-mutated cell lines significantly attenuated cell growth. Our data suggest that PD-L1 could represent a useful prognostic marker for risk stratification in Middle Eastern PTC and that a programmed cell death protein 1 (PD-1)/PD-L1 inhibitor could be a potential therapeutic option for aggressive PTC cancers, such as the tall cell variant, BRAF mutation-positive patients that are unresponsive to standard PTC treatment. ABSTRACT: PD-L1 inhibition is a promising therapeutic target whose efficacy has been demonstrated in several cancers. Immunohistochemistry was performed to assess PD-L1 protein expression in PTC. We further conducted in vitro analysis to investigate the role of PD-L1 in regulating BRAFV600E in PTC cell lines. PD-L1 over-expression was noted in 32.4% (473/1458) of cases and significantly associated with aggressive clinico-pathological parameters. Importantly, PD-L1 was found to be an independent poorer prognostic marker. We also found PD-L1 to be significantly associated with BRAF mutation and patients with co-existing PD-L1 over-expression and BRAF mutation had a poor disease-free survival compared to patients with BRAF mutation alone. In vitro analysis showed high expression of PD-L1 in BRAF-mutated PTC cell lines compared to a BRAF wild-type cell line. Inhibition of BRAF using vemurafenib induced PD-L1 expression in BRAF-mutated cell lines without affecting cell growth. Knockdown of PD-L1 in BRAF-mutated cell lines significantly decreased the cell growth and induced apoptosis. Our data suggest that PD-L1 might represent a useful prognostic marker in Middle Eastern PTC and PD-L1 inhibition could be a potential therapeutic option for aggressive PTC cancers, such as the tall cell variant, BRAF mutation-positive patients that are unresponsive to standard treatment. MDPI 2021-02-01 /pmc/articles/PMC7867170/ /pubmed/33535609 http://dx.doi.org/10.3390/cancers13030555 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Siraj, Abdul K.
Parvathareddy, Sandeep Kumar
Pratheeshkumar, Poyil
Divya, Sasidharan Padmaja
Al-Sobhi, Saif S.
Al-Dayel, Fouad
Al-Kuraya, Khawla S.
PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by BRAFV600E Mutation
title PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by BRAFV600E Mutation
title_full PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by BRAFV600E Mutation
title_fullStr PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by BRAFV600E Mutation
title_full_unstemmed PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by BRAFV600E Mutation
title_short PD-L1 Is an Independent Prognostic Marker in Middle Eastern PTC and Its Expression Is Upregulated by BRAFV600E Mutation
title_sort pd-l1 is an independent prognostic marker in middle eastern ptc and its expression is upregulated by brafv600e mutation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867170/
https://www.ncbi.nlm.nih.gov/pubmed/33535609
http://dx.doi.org/10.3390/cancers13030555
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