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

Abstract

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 (P = 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.

• Authors: Tomohiro Aoki, Lauren C Chong, Katsuyoshi Takata, Katy Milne, Ashley Marshall, Elizabeth A Chavez, Tomoko Miyata-Takata, Susana Ben-Neriah, Doria Unrau, Adele Telenius, Merrill Boyle, Andrew P Weng, Kerry J Savage, David W Scott, Pedro Farinha, Sohrab P Shah, Brad H Nelson, Christian Steidl
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 118 Issue 41 (10 12 2021) ISSN: 1091-6490 [Electronic] United States
• PMID: 34615710 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 the Author(s). Published by PNAS.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• CXCL13 protein, human
• CXCR5 protein, human
• Chemokine CXCL13
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, CXCR5

Topics

• B-Lymphocytes (metabolism)
• B7-H1 Antigen (metabolism)
• Chemokine CXCL13 (metabolism)
• Fluorescent Antibody Technique
• Hodgkin Disease (pathology)
• Humans
• Lymph Nodes (cytology)
• Programmed Cell Death 1 Receptor (metabolism)
• RNA-Seq
• Receptors, CXCR5 (metabolism)
• Reed-Sternberg Cells (pathology)
• Single-Cell Analysis
• T-Lymphocytes, Helper-Inducer (metabolism)
• Tumor Microenvironment (immunology)