title: Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy.
abstract: OBJECTIVE
  Programmed cell death ligand 1 (PD-L1) is a molecule expressed on antigen-presenting cells that engages the PD-1 receptor on T cells and inhibits T-cell receptor signaling. The PD-1 axis can be exploited by tumor cells to dampen host antitumor immune responses and foster tumor cell survival. PD-1 blockade has shown promise in multiple malignancies but should be directed toward patients in whom it will be most effective. In recent studies, we found that the chromosome 9p24.1 amplification increased the gene dosage of PD-L1 and its induction by JAK2 in a subset of patients with classical Hodgkin lymphoma (cHL). However, cHLs with normal 9p24.1 copy numbers also expressed detectable PD-L1, prompting analyses of additional PD-L1 regulatory mechanisms.
  
  
  METHODS
  Herein, we utilized immunohistochemical, genomic, and functional analyses to define alternative mechanisms of PD-L1 activation in cHL and additional EBV(+) lymphoproliferative disorders.
  
  
  RESULTS
  We identified an AP-1-responsive enhancer in the PD-L1 gene. In cHL Reed-Sternberg cells, which exhibit constitutive AP-1 activation, the PD-L1 enhancer binds AP-1 components and increases PD-L1 promoter activity. In addition, we defined Epstein-Barr virus (EBV) infection as an alternative mechanism for PD-L1 induction in cHLs with diploid 9p24.1. PD-L1 was also expressed by EBV-transformed lymphoblastoid cell lines as a result of latent membrane protein 1-mediated, JAK/STAT-dependent promoter and AP-1-associated enhancer activity. In addition, more than 70% of EBV(+) posttransplant lymphoproliferative disorders expressed detectable PD-L1.
  
  
  CONCLUSIONS
  AP-1 signaling and EBV infection represent alternative mechanisms of PD-L1 induction and extend the spectrum of tumors in which to consider PD-1 blockade.
authors.affiliation: Dana-Farber Cancer Institute, MA, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.forename: Scott
authors.initials: S
authors.lastname: Rodig
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Juszczynski
authors.forename: Jing
authors.initials: J
authors.lastname: Ouyang
authors.forename: Papiya
authors.initials: P
authors.lastname: Sinha
authors.forename: Evan
authors.initials: E
authors.lastname: O'Donnell
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Shipp
mesh_terms: D060890:B7-H1 Antigen / Q000378:metabolism*; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000235:genetics; D002899:Chromosomes, Human, Pair 9; D004742:Enhancer Elements, Genetic; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D006689:Hodgkin Disease / Q000235:genetics* / Q000276:immunology / Q000821:virology; D006801:Humans; D007165:Immunosuppression Therapy; D008232:Lymphoproliferative Disorders / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014763:Viral Matrix Proteins / Q000494:pharmacology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D018808:Transcription Factor AP-1; D014763:Viral Matrix Proteins