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

Christopher D. Carey, Daniel Gusenleitner, Mikel Lipschitz, Margaretha G.M. Roemer, Edward C. Stack, Evisa Gjini, Xihao Hu, Robert Redd, Gordon J. Freeman, Donna Neuberg, F. Stephen Hodi, Xiaole Shirley Liu, Margaret A. Shipp and Scott J. Rodig

Key points

  • Regionally localized PD-L1+ macrophages form a specialized microenvironmental niche for Hodgkin Reed-Sternberg cells in cHL.


Signaling between programmed cell death protein 1 (PD-1) and the programmed cell death -1 ligands (PD-1 ligands, PD-L1, PD-L2) is essential for malignant Hodgkin Reed-Sternberg (HRS) cells to evade anti-tumor 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 non-malignant tumor-associated macrophages (TAMs) but the relationships between 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 co-localize 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.

  • Submitted March 21, 2017.
  • Accepted August 18, 2017.