title: PD-L1 Is a Therapeutic Target of the Bromodomain Inhibitor JQ1 and, Combined with HLA Class I, a Promising Prognostic Biomarker in Neuroblastoma.
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 situIHC 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 bothin vitroandin vivoConsistently, 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.
authors.affiliation: Immuno-Oncology Laboratory, Oncohaematology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Melaiu
authors.affiliation: Fondazione Bruno Kessler, Trento, Italy.|Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Mina
authors.affiliation: Fondazione Bruno Kessler, Trento, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Chierici
authors.affiliation: Pathology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Boldrini
authors.affiliation: Fondazione Bruno Kessler, Trento, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Jurman
authors.affiliation: Immuno-Oncology Laboratory, Oncohaematology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Romania
authors.affiliation: Immuno-Oncology Laboratory, Oncohaematology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Valerio
authors.initials: V
authors.lastname: D'Alicandro
authors.affiliation: Pathology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Benedetti
authors.affiliation: Paediatric Haematology/Oncology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Aurora
authors.initials: A
authors.lastname: Castellano
authors.affiliation: Children's Cancer Institute Australia, Lowy Cancer Research Center, University of New South Wales, Randwich, New South Wales, Australia.
authors.forename: Tao
authors.initials: T
authors.lastname: Liu
authors.affiliation: Fondazione Bruno Kessler, Trento, Italy.
authors.forename: Cesare
authors.initials: C
authors.lastname: Furlanello
authors.affiliation: Paediatric Haematology/Oncology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.|University of Pavia, Pavia, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Immuno-Oncology Laboratory, Oncohaematology Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. doriana.fruci@opbg.net.
authors.forename: Doriana
authors.initials: D
authors.lastname: Fruci
mesh_terms: D000293:Adolescent; D000328:Adult; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001381:Azepines / Q000008:administration & dosage; D060890:B7-H1 Antigen / Q000235:genetics* / Q000276:immunology; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005805:Genes, MHC Class I / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007223:Infant; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D000071447:N-Myc Proto-Oncogene Protein / Q000235:genetics* / Q000276:immunology; D009447:Neuroblastoma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000276:immunology; D014230:Triazoles / Q000008:administration & dosage; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: C561695:(+)-JQ1 compound; D015703:Antigens, CD; D001381:Azepines; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C489427:MYC protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human