Microenvironmental immune cell alterations across the spectrum of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma

Christos Panayi; Ayse U Akarca; Alan D Ramsay; Ananth G Shankar; Brunangelo Falini; Miguel A Piris; David Linch; Teresa Marafioti

doi:10.3389/fonc.2023.1267604

Microenvironmental immune cell alterations across the spectrum of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma

Front Oncol. 2023 Oct 3:13:1267604. doi: 10.3389/fonc.2023.1267604. eCollection 2023.

Authors

Christos Panayi¹, Ayse U Akarca², Alan D Ramsay¹, Ananth G Shankar³, Brunangelo Falini⁴, Miguel A Piris⁵, David Linch⁶, Teresa Marafioti^{1

2}

Affiliations

¹ Department of Cellular Pathology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.
² University College London (UCL) Cancer Institute, University College London, London, United Kingdom.
³ Children and Young People's Cancer Services, University College London Hospitals NHS Foundation Trust, London, United Kingdom.
⁴ Institute of Hematology and Center for Haemato-Oncological Research (CREO), University of Perugia and Santa Maria della Misericordia Hospital, Perugia, Italy.
⁵ Pathology Department, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain.
⁶ Research Department of Haematology, Cancer Institute, University College London, London, United Kingdom.

Abstract

Background: The clinicopathological spectrum of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), also known as nodular lymphocyte predominant B-cell lymphoma, partially overlaps with T-cell/histiocyte-rich large B-cell lymphoma (THRLCBL). NLPHL histology may vary in architecture and B-cell/T-cell composition of the tumour microenvironment. However, the immune cell phenotypes accompanying different histological patterns remain poorly characterised.

Methods: We applied a multiplexed immunofluorescence workflow to identify differential expansion/depletion of multiple microenvironmental immune cell phenotypes between cases of NLPHL showing different histological patterns (as described by Fan et al, 2003) and cases of THRLBCL.

Results: FOXP3-expressing T-regulatory cells were conspicuously depleted across all NLPHL cases. As histology progressed to variant Fan patterns C and E of NLPHL and to THRLBCL, there were progressive expansions of cytotoxic granzyme-B-expressing natural killer and CD8-positive T-cells, PD1-expressing CD8-positive T-cells, and CD163-positive macrophages including a PDL1-expressing subset. These occurred in parallel to depletion of NKG2A-expressing natural killer and CD8-positive T-cells.

Discussion: These findings provide new insights on the immunoregulatory mechanisms involved in NLPHL and THLRBCL pathogenesis, and are supportive of an increasingly proposed biological continuum between these two lymphomas. Additionally, the findings may help establish new biomarkers of high-risk disease, which could support a novel therapeutic program of immune checkpoint interruption targeting the PD1:PDL1 and/or NKG2A:HLA-E axes in the management of high-risk NLPHL and THRLBCL.

Keywords: T-cell/histiocyte-rich large B-cell lymphoma; immune checkpoints; lymphoma biology; multispectral immunofluorescence; nodular lymphocyte predominant Hodgkin lymphoma (NLPHL); tumor microenvironment.

Grants and funding

This investigation was supported by the University College London Hospitals NHS Foundation Trust’s Department of Cellular Pathology Research Fund (2021).