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Lookup NU author(s): Dr Alex Blain, Dr Christopher Bacon, Professor Vikki Rand, Professor Matthew CollinORCiD, Dr Christopher CareyORCiD
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© 2023 The American Society of HematologyClassic Hodgkin lymphoma (cHL) has a rich immune infiltrate, which is an intrinsic component of the neoplastic process. Malignant Hodgkin Reed-Sternberg cells (HRSCs) create an immunosuppressive microenvironment by the expression of regulatory molecules, preventing T-cell activation. It has also been demonstrated that mononuclear phagocytes (MNPs) in the vicinity of HRSCs express similar regulatory mechanisms in parallel, and their presence in tissue is associated with inferior patient outcomes. MNPs in cHL have hitherto been identified by a small number of canonical markers and are usually described as tumor-associated macrophages. The organization of MNP networks and interactions with HRSCs remains unexplored at high resolution. Here, we defined the global immune-cell composition of cHL and nonlymphoma lymph nodes, integrating data across single-cell RNA sequencing, spatial transcriptomics, and multiplexed immunofluorescence. We observed that MNPs comprise multiple subsets of monocytes, macrophages, and dendritic cells (DCs). Classical monocytes, macrophages and conventional DC2s were enriched in the vicinity of HRSCs, but plasmacytoid DCs and activated DCs were excluded. Unexpectedly, cDCs and monocytes expressed immunoregulatory checkpoints PD-L1, TIM-3, and the tryptophan-catabolizing protein IDO, at the same level as macrophages. Expression of these molecules increased with age. We also found that classical monocytes are important signaling hubs, potentially controlling the retention of cDC2 and ThExh via CCR1-, CCR4-, CCR5-, and CXCR3-dependent signaling. Enrichment of the cDC2-monocyte-macrophage network in diagnostic biopsies is associated with early treatment failure. These results reveal unanticipated complexity and spatial polarization within the MNP compartment, further demonstrating their potential roles in immune evasion by cHL.
Author(s): Stewart BJ, Fergie M, Young MD, Jones C, Sachdeva A, Blain A, Bacon CM, Rand V, Ferdinand JR, James KR, Mahbubani KT, Hook L, Jonas N, Coleman N, Saeb-Parsy K, Collin M, Clatworthy MR, Behjati S, Carey CD
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2023
Volume: 141
Issue: 19
Pages: 2343-2358
Print publication date: 11/05/2023
Online publication date: 07/02/2023
Acceptance date: 02/01/2023
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: Elsevier B.V.
URL: https://doi.org/10.1182/blood.2022015575
DOI: 10.1182/blood.2022015575
PubMed id: 36758207
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