Constitutive AP-1 activity and EBV infection induce PD-l1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: Implications for targeted therapy

Michael R. Green, Scott Rodig, Przemyslaw Juszczynski, Jing Ouyang, Papiya Sinha, Evan O'Donnell, Donna Neuberg, Margaret A. Shipp

Research output: Contribution to journalArticle

297 Citations (Scopus)

Abstract

Purpose: 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. Experimental Design: 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.

Original languageEnglish (US)
Pages (from-to)1611-1618
Number of pages8
JournalClinical Cancer Research
Volume18
Issue number6
DOIs
StatePublished - Mar 15 2012

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Epstein-Barr Virus Infections
Lymphoproliferative Disorders
Transcription Factor AP-1
Hodgkin Disease
Cell Death
Ligands
Human Herpesvirus 4
Therapeutics
CD274 Antigen
Programmed Cell Death 1 Receptor
Neoplasms
Reed-Sternberg Cells
Transformed Cell Line
Gene Dosage
Antigen-Presenting Cells
T-Cell Antigen Receptor
Diploidy
Cell Survival
Membrane Proteins
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Constitutive AP-1 activity and EBV infection induce PD-l1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders : Implications for targeted therapy. / Green, Michael R.; Rodig, Scott; Juszczynski, Przemyslaw; Ouyang, Jing; Sinha, Papiya; O'Donnell, Evan; Neuberg, Donna; Shipp, Margaret A.

In: Clinical Cancer Research, Vol. 18, No. 6, 15.03.2012, p. 1611-1618.

Research output: Contribution to journalArticle

Green, Michael R. ; Rodig, Scott ; Juszczynski, Przemyslaw ; Ouyang, Jing ; Sinha, Papiya ; O'Donnell, Evan ; Neuberg, Donna ; Shipp, Margaret A. / Constitutive AP-1 activity and EBV infection induce PD-l1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders : Implications for targeted therapy. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 6. pp. 1611-1618.
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abstract = "Purpose: 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. Experimental Design: 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.",
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T1 - Constitutive AP-1 activity and EBV infection induce PD-l1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders

T2 - Implications for targeted therapy

AU - Green, Michael R.

AU - Rodig, Scott

AU - Juszczynski, Przemyslaw

AU - Ouyang, Jing

AU - Sinha, Papiya

AU - O'Donnell, Evan

AU - Neuberg, Donna

AU - Shipp, Margaret A.

PY - 2012/3/15

Y1 - 2012/3/15

N2 - Purpose: 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. Experimental Design: 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.

AB - Purpose: 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. Experimental Design: 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.

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