Constitutive AP-1 Activity and EBV Infection Induce PD-L1 in Hodgkin Lymphomas and Post-transplant Lymphoproliferative Disorders: Implications for Targeted Therapy

By Michael R. Green, S. Rodig, P. Juszczyński, Ouyang Jing, P. Sinha, Evan O’Donnell, D. Neuberg, M. Shipp. Clinical Cancer Research, 2012

661 citations recorded by the source corpus.

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. Clin Cancer Res; 18(6); 1611–8. ©2012 AACR.

Subfields: Oncology, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/26e3a0db12ded68b186e361daffb4bede180f800

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Oncology

Citations in the corpus

PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma (2014, neutral): “Complete response 4 (17) 1 (7) 0 3 (60)”
PD-L1 Expression is Characteristic of a Subset of Aggressive B-Cell Lymphomas and Virus-Associated Malignancies (2013, positive): “PD-L1, as a major ligand for PD-1, serves to suppress T-cell immunity – including immunity directed toward virally encoded antigens expressed in EBV-positive CHL (6).”
Regulatory mechanisms of PD-1/PD-L1 in cancers (2024, background): “…a transcriptional regulator composed of FOS, c-Jun, MAF, and ATF subunits, binds to the enhancer region of the PD-L1 gene located about 5 kb downstream of the transcription start site to participate in the transcriptional regulation of PD-L1, promoting its expression in Hodgkin’s lymphoma [223].”
Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma. (2017, neutral): “(%) 4 (2-12) 4 (1-11) 3 (2-10) 4 (1-12) Prior lines of therapy, No.”