Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1783648242231148544 |
---|---|
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. |
format | Online Article Text |
id | pubmed-7867170 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT sirajabdulk pdl1isanindependentprognosticmarkerinmiddleeasternptcanditsexpressionisupregulatedbybrafv600emutation AT parvathareddysandeepkumar pdl1isanindependentprognosticmarkerinmiddleeasternptcanditsexpressionisupregulatedbybrafv600emutation AT pratheeshkumarpoyil pdl1isanindependentprognosticmarkerinmiddleeasternptcanditsexpressionisupregulatedbybrafv600emutation AT divyasasidharanpadmaja pdl1isanindependentprognosticmarkerinmiddleeasternptcanditsexpressionisupregulatedbybrafv600emutation AT alsobhisaifs pdl1isanindependentprognosticmarkerinmiddleeasternptcanditsexpressionisupregulatedbybrafv600emutation AT aldayelfouad pdl1isanindependentprognosticmarkerinmiddleeasternptcanditsexpressionisupregulatedbybrafv600emutation AT alkurayakhawlas pdl1isanindependentprognosticmarkerinmiddleeasternptcanditsexpressionisupregulatedbybrafv600emutation |