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, Scott J. Rodig*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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-L11 HRS cells, PD-L11 TAMs, and PD-11 T cells remain undefined. We used multiplex immunofluorescence and digital image analysis to examine the topography of PD-L11 and PD-11 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-L11 TAMs, which physically colocalize with PD-L11 HRS cells in a microenvironmental niche. PD-L11 TAMs are enriched for contacts with T cells, and PD-L11 HRS cells are enriched for contacts with CD41 T cells, a subset of which are PD-11. Our data define a unique topology of cHL in which PD-L11 TAMs surround HRS cells and implicate CD41 T cells as a target of PD-1 blockade.

Original languageEnglish
Pages (from-to)2420-2430
Number of pages11
Issue number22
Publication statusPublished - 30 Nov 2017

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