PD-L1 Is a Therapeutic Target of the Bromodomain Inhibitor JQ1 and, Combined with HLA Class I, a Promising Prognostic Biomarker in Neuroblastoma.
Details
Serval ID
serval:BIB_5ABCC0C44EDC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
PD-L1 Is a Therapeutic Target of the Bromodomain Inhibitor JQ1 and, Combined with HLA Class I, a Promising Prognostic Biomarker in Neuroblastoma.
Journal
Clinical cancer research
ISSN
1078-0432 (Print)
ISSN-L
1078-0432
Publication state
Published
Issued date
01/08/2017
Peer-reviewed
Oui
Volume
23
Number
15
Pages
4462-4472
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
<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> .
Keywords
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
Yes
Create date
14/03/2017 11:23
Last modification date
21/08/2019 6:35