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

Clin Cancer Res. 2017 Aug 1;23(15):4462-4472. doi: 10.1158/1078-0432.CCR-16-2601. Epub 2017 Mar 7.

Abstract

Purpose: 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.Experimental Design:In situ 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.Results: 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 (P = 0.0448). MYC and MYCN control the expression of PD-L1 in neuroblastoma cells both in vitro and in vivo Consistently, abundance of PD-L1 transcript correlates with MYC expression in primary neuroblastoma.Conclusions: 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. Clin Cancer Res; 23(15); 4462-72. ©2017 AACR.

MeSH terms

  • 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
  • Lymphocyte Activation Gene 3 Protein
  • 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

Substances

  • (+)-JQ1 compound
  • Antigens, CD
  • Azepines
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • MYC protein, human
  • MYCN protein, human
  • N-Myc Proto-Oncogene Protein
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Proto-Oncogene Proteins c-myc
  • Triazoles
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, human