PD-L1 Is a Therapeutic Target of the Bromodomain Inhibitor JQ1 and, Combined with HLA Class I, a Promising Prognostic Biomarker in Neuroblastoma.

Détails

ID Serval
serval:BIB_5ABCC0C44EDC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
PD-L1 Is a Therapeutic Target of the Bromodomain Inhibitor JQ1 and, Combined with HLA Class I, a Promising Prognostic Biomarker in Neuroblastoma.
Périodique
Clinical cancer research
Auteur(s)
Melaiu O., Mina M., Chierici M., Boldrini R., Jurman G., Romania P., D'Alicandro V., Benedetti M.C., Castellano A., Liu T., Furlanello C., Locatelli F., Fruci D.
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Statut éditorial
Publié
Date de publication
01/08/2017
Peer-reviewed
Oui
Volume
23
Numéro
15
Pages
4462-4472
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
<b>Purpose:</b> This study sought to evaluate the expression of programmed cell death-ligand-1 (PD-L1) and HLA class I on neuroblastoma cells and programmed cell death-1 (PD-1) and lymphocyte activation gene 3 (LAG3) on tumor-infiltrating lymphocytes to better define patient risk stratification and understand whether this tumor may benefit from therapies targeting immune checkpoint molecules. <b>Experimental Design:</b> <i>In situ</i> IHC staining for PD-L1, HLA class I, PD-1, and LAG3 was assessed in 77 neuroblastoma specimens, previously characterized for tumor-infiltrating T-cell density and correlated with clinical outcome. Surface expression of PD-L1 was evaluated by flow cytometry and IHC in neuroblastoma cell lines and tumors genetically and/or pharmacologically inhibited for MYC and MYCN. A dataset of 477 human primary neuroblastomas from GEO and ArrayExpress databases was explored for PD-L1, MYC, and MYCN correlation. <b>Results:</b> Multivariate Cox regression analysis demonstrated that the combination of PD-L1 and HLA class I tumor cell density is a prognostic biomarker for predicting overall survival in neuroblastoma patients ( <i>P</i> = 0.0448). MYC and MYCN control the expression of PD-L1 in neuroblastoma cells both <i>in vitro</i> and <i>in vivo</i> Consistently, abundance of PD-L1 transcript correlates with MYC expression in primary neuroblastoma. <b>Conclusions:</b> The combination of PD-L1 and HLA class I represents a novel prognostic biomarker for neuroblastoma. Pharmacologic inhibition of MYCN and MYC may be exploited to target PD-L1 and restore an efficient antitumor immunity in high-risk neuroblastoma. <i>Clin Cancer Res; 23(15); 4462-72. ©2017 AACR</i> .
Mots-clé
Adolescent, Adult, Antigens, CD/genetics, Antigens, CD/immunology, Azepines/administration & dosage, B7-H1 Antigen/genetics, B7-H1 Antigen/immunology, Biomarkers, Tumor/genetics, Cell Line, Tumor, Child, Child, Preschool, Female, Gene Expression Regulation, Neoplastic/drug effects, Genes, MHC Class I/genetics, Genes, MHC Class I/immunology, Humans, Infant, Lymphocytes, Tumor-Infiltrating/drug effects, Lymphocytes, Tumor-Infiltrating/pathology, Male, Middle Aged, Molecular Targeted Therapy, N-Myc Proto-Oncogene Protein/genetics, N-Myc Proto-Oncogene Protein/immunology, Neuroblastoma/drug therapy, Neuroblastoma/genetics, Neuroblastoma/immunology, Neuroblastoma/pathology, Prognosis, Programmed Cell Death 1 Receptor/genetics, Proto-Oncogene Proteins c-myc/genetics, Proto-Oncogene Proteins c-myc/immunology, Triazoles/administration & dosage
Pubmed
Web of science
Open Access
Oui
Création de la notice
14/03/2017 11:23
Dernière modification de la notice
21/08/2019 6:35
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