Topological analysis reveals a PD-L1-associated microenvironmental niche for Reed-Sternberg cells in Hodgkin lymphoma

Blood. 2017 Nov 30;130(22):2420-2430. doi: 10.1182/blood-2017-03-770719. Epub 2017 Sep 11.


Signaling between programmed cell death protein 1 (PD-1) and the PD-1 ligands (PD-L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade antitumor immunity in classical Hodgkin lymphoma (cHL). Copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2) contribute to robust PD-L1 and PD-L2 expression by HRS cells. PD-L1 is also expressed by nonmalignant tumor-associated macrophages (TAMs), but the relationships among PD-L1+ HRS cells, PD-L1+ TAMs, and PD-1+ T cells remain undefined. We used multiplex immunofluorescence and digital image analysis to examine the topography of PD-L1+ and PD-1+ cells in the tumor microenvironment (TME) of cHL. We find that the majority of PD-L1 in the TME is expressed by the abundant PD-L1+ TAMs, which physically colocalize with PD-L1+ HRS cells in a microenvironmental niche. PD-L1+ TAMs are enriched for contacts with T cells, and PD-L1+ HRS cells are enriched for contacts with CD4+ T cells, a subset of which are PD-1+ Our data define a unique topology of cHL in which PD-L1+ TAMs surround HRS cells and implicate CD4+ T cells as a target of PD-1 blockade.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / analysis*
  • Fluorescent Antibody Technique
  • Hodgkin Disease / pathology*
  • Humans
  • Macrophages / pathology
  • Programmed Cell Death 1 Receptor / analysis
  • Reed-Sternberg Cells / pathology*
  • T-Lymphocytes / pathology
  • Tumor Microenvironment*


  • B7-H1 Antigen
  • CD274 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor