Single-cell profiling reveals the importance of CXCL13/CXCR5 axis biology in lymphocyte-rich classic Hodgkin lymphoma

Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironm...

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Published in:	Proceedings of the National Academy of Sciences - PNAS 2021-10, Vol.118 (41), p.1
Main Authors:	Aoki, Tomohiro, Chong, Lauren C, Takata, Katsuyoshi, Milne, Katy, Marshall, Ashley, Chavez, Elizabeth A, Miyata-Takata, Tomoko, Ben-Neriah, Susana, Unrau, Doria, Telenius, Adele, Boyle, Merrill, Weng, Andrew P, Savage, Kerry J, Scott, David W, Farinha, Pedro, Shah, Sohrab P, Nelson, Brad H, Steidl, Christian
Format:	Article
Language:	eng
Subjects:	B-Lymphocytes - metabolism B7-H1 Antigen - metabolism Biological Sciences CD4 antigen Chemokine CXCL13 - metabolism Chemokines Crosstalk CXCL13 protein CXCR5 protein Fluorescent Antibody Technique Gene sequencing Hodgkin Disease - pathology Hodgkin's lymphoma Humans Immune system Immunofluorescence Lymph nodes Lymph Nodes - cytology Lymphocytes Lymphocytes B Lymphocytes T Lymphoma PD-1 protein Programmed Cell Death 1 Receptor - metabolism Receptors, CXCR5 - metabolism Reed-Sternberg Cells - pathology RNA-Seq Sclerosis Single-Cell Analysis Spatial analysis T-Lymphocytes, Helper-Inducer - metabolism Tumor microenvironment Tumor Microenvironment - immunology
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Summary:	Lymphocyte-rich classic Hodgkin lymphoma (LR-CHL) is a rare subtype of Hodgkin lymphoma. Recent technical advances have allowed for the characterization of specific cross-talk mechanisms between malignant Hodgkin Reed-Sternberg (HRS) cells and different normal immune cells in the tumor microenvironment (TME) of CHL. However, the TME of LR-CHL has not yet been characterized at single-cell resolution. Here, using single-cell RNA sequencing (scRNA-seq), we examined the immune cell profile of 8 cell suspension samples of LR-CHL in comparison to 20 samples of the mixed cellularity (MC, 9 cases) and nodular sclerosis (NS, 11 cases) subtypes of CHL, as well as 5 reactive lymph node controls. We also performed multicolor immunofluorescence (MC-IF) on tissue microarrays from the same patients and an independent validation cohort of 31 pretreatment LR-CHL samples. ScRNA-seq analysis identified a unique CD4 helper T cell subset in LR-CHL characterized by high expression of Chemokine C-X-C motif ligand 13 (CXCL13) and PD-1. PD-1 CXCL13 T cells were significantly enriched in LR-CHL compared to other CHL subtypes, and spatial analyses revealed that in 46% of the LR-CHL cases these cells formed rosettes surrounding HRS cells. MC-IF analysis revealed CXCR5 normal B cells in close proximity to CXCL13 T cells at significantly higher levels in LR-CHL. Moreover, the abundance of PD-1 CXCL13 T cells in the TME was significantly associated with shorter progression-free survival in LR-CHL ( = 0.032). Taken together, our findings strongly suggest the pathogenic importance of the CXCL13/CXCR5 axis and PD-1 CXCL13 T cells as a treatment target in LR-CHL.
ISSN:	0027-8424 1091-6490