Faculty, Staff and Student Publications

Language

English

Publication Date

11-1-2024

Journal

American Journal of Hematology

DOI

10.1002/ajh.27459

PMID

39152767

PMCID

PMC11469944

PubMedCentral® Posted Date

11-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

In classical Hodgkin lymphoma (cHL), responsiveness to immune-checkpoint blockade (ICB) is associated with specific tumor microenvironment (TME) and peripheral blood features. The role of ICB in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is not established. To gain insights into its potential in NLPHL, we compared TME and peripheral blood signatures between HLs using an integrative multiomic analysis. A discovery/validation approach in 121 NLPHL and 114 cHL patients highlighted >2-fold enrichment in programmed cell death-1 (PD-1) and T-cell Ig and ITIM domain (TIGIT) gene expression for NLPHL versus cHL. Multiplex imaging showed marked increase in intra-tumoral protein expression of PD-1+ (and/or TIGIT+) CD4+ T-cells and PD-1+CD8+ T-cells in NLPHL compared to cHL. This included T-cells that rosetted with lymphocyte predominant (LP) and Hodgkin Reed-Sternberg (HRS) cells. In NLPHL, intra-tumoral PD-1+CD4+ T-cells frequently expressed TCF-1, a marker of heightened T-cell response to ICB. The peripheral blood signatures between HLs were also distinct, with higher levels of PD-1+TIGIT+ in TH1, TH2, and regulatory CD4+ T-cells in NLPHL versus cHL. Circulating PD-1+CD4+ had high levels of TCF-1. Notably, in both lymphomas, highly expanded populations of clonal TIGIT+PD-1+CD4+ and TIGIT+PD-1+CD8+ T-cells in the blood were also present in the TME, indicating that immune-checkpoint expressing T-cells circulated between intra-tumoral and blood compartments. In in vitro assays, ICB was capable of reducing rosette formation around LP and HRS cells, suggesting that disruption of rosetting may be a mechanism of action of ICB in HL. Overall, results indicate that further evaluation of ICB is warranted in NLPHL.

Keywords

Humans, Hodgkin Disease, Programmed Cell Death 1 Receptor, Receptors, Immunologic, Male, Female, Tumor Microenvironment, Adult, Biomarkers, Tumor, Middle Aged, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Aged, Nodular Lymphocyte Predominant Hodgkin Lymphoma, Hodgkin Lymphoma, TIGIT, PD-1, immunotherapy

Published Open-Access

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