PD-L1 and CD8+PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy
PD-L1 and CD8+PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy
Recent monoclonal antibody trials targeting the PD1/PD-L1 immune-checkpoint pathway have shown remarkable success in treating adult malignancies, with PD-L1-expressing tumors showing the most objective response. However, little is known as to whether pediatric cancers have also adopted this immune evasion mechanism. We evaluated 115 pediatric tumors (taken at diagnosis) for PD-L1 expression and the presence of CD8+ tumor-infiltrating lymphocytes (TILs). Tumors with >5% PD-L1 membrane staining were scored positive. The presence of CD8+ TILs expressing PD-1 was assessed using dual-labeling immunohistochemistry. Data were evaluated against clinical demographics. The proportion of PD-L1+ tumors was 86% for alveolar rhabdomyosarcoma (12/14), 72% for high-risk neuroblastoma (31/43), 57% for Ewing's sarcoma (8/14), 50% for embryonal rhabdomyosarcoma (8/16) and 47% for osteosarcoma (7/15). Increased proportions of CD8+ TILs significantly correlated with PD-1 expression. When grouped by cancer type, those with the highest proportion of PD-L1 positivity showed poorest survival. PD-L1+ patients with a particularly high frequency of CD8+ TILs (but not those with low numbers CD8+ TILs) had significantly better survival compared to PD-L1 negative patients. This study reveals the presence of an active PD-L1 pathway in a high proportion of pediatric cancers, as demonstrated by strong PD-L1 positivity and the presence of PD-1 expressing CD8+ TILs. In addition, patients with high proportions of CD8+ TILs showed better survival, suggesting that bolstering CD8+ T-cell responses through PD-1/PD-L1 blockade would be a viable treatment strategy, providing support for expediting these targeted immunotherapies in children.
Chowdhury, Ferdousi
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Dunn, Stuart
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Mitchell, Simon
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Mellows, Toby
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Ashton-Key, Margaret
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Gray, Juliet
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Chowdhury, Ferdousi
0af499d4-17c5-40cf-9426-0d509ab82595
Dunn, Stuart
e6fd3eb2-4487-45ed-b9d7-948febd5b7ea
Mitchell, Simon
30c9565d-df31-4a55-9397-62dab28445c1
Mellows, Toby
92bddc4c-d95e-4348-aec0-da4fd6474190
Ashton-Key, Margaret
5111ac18-7d4f-4ef0-9c71-0a44c37aaed4
Gray, Juliet
12d5e17c-97bb-4d6d-8fc4-3914b730ed42
Chowdhury, Ferdousi, Dunn, Stuart, Mitchell, Simon, Mellows, Toby, Ashton-Key, Margaret and Gray, Juliet
(2015)
PD-L1 and CD8+PD1+ lymphocytes exist as targets in the pediatric tumor microenvironment for immunomodulatory therapy.
OncoImmunology, 4 (10).
(doi:10.1080/2162402X.2015.1029701).
Abstract
Recent monoclonal antibody trials targeting the PD1/PD-L1 immune-checkpoint pathway have shown remarkable success in treating adult malignancies, with PD-L1-expressing tumors showing the most objective response. However, little is known as to whether pediatric cancers have also adopted this immune evasion mechanism. We evaluated 115 pediatric tumors (taken at diagnosis) for PD-L1 expression and the presence of CD8+ tumor-infiltrating lymphocytes (TILs). Tumors with >5% PD-L1 membrane staining were scored positive. The presence of CD8+ TILs expressing PD-1 was assessed using dual-labeling immunohistochemistry. Data were evaluated against clinical demographics. The proportion of PD-L1+ tumors was 86% for alveolar rhabdomyosarcoma (12/14), 72% for high-risk neuroblastoma (31/43), 57% for Ewing's sarcoma (8/14), 50% for embryonal rhabdomyosarcoma (8/16) and 47% for osteosarcoma (7/15). Increased proportions of CD8+ TILs significantly correlated with PD-1 expression. When grouped by cancer type, those with the highest proportion of PD-L1 positivity showed poorest survival. PD-L1+ patients with a particularly high frequency of CD8+ TILs (but not those with low numbers CD8+ TILs) had significantly better survival compared to PD-L1 negative patients. This study reveals the presence of an active PD-L1 pathway in a high proportion of pediatric cancers, as demonstrated by strong PD-L1 positivity and the presence of PD-1 expressing CD8+ TILs. In addition, patients with high proportions of CD8+ TILs showed better survival, suggesting that bolstering CD8+ T-cell responses through PD-1/PD-L1 blockade would be a viable treatment strategy, providing support for expediting these targeted immunotherapies in children.
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Accepted/In Press date: 11 March 2015
e-pub ahead of print date: 27 May 2015
Organisations:
Cancer Sciences
Identifiers
Local EPrints ID: 396805
URI: http://eprints.soton.ac.uk/id/eprint/396805
ISSN: 2162-402X
PURE UUID: 20b911bd-db3b-4fe2-bef7-beb5e7111e6b
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Date deposited: 14 Jun 2016 12:46
Last modified: 15 Mar 2024 03:16
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Author:
Ferdousi Chowdhury
Author:
Stuart Dunn
Author:
Simon Mitchell
Author:
Toby Mellows
Author:
Margaret Ashton-Key
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