Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma
- 1 March 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Discovery
- Vol. 10 (3), 406-421
- https://doi.org/10.1158/2159-8290.CD-19-0680
Abstract
Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma-specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma-associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3(+) T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3(+) T cells in the direct vicinity of MHC class II-deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma. SIGNIFICANCE: We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell-like immunosuppressive subset of LAG3(+) T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints.Other Versions
Funding Information
- Canadian Cancer Society Research Institute
- Terry Fox Research Institute
- Japanese Society for the Promotion of Science Uehara Memorial Foundation
- Kanae Foundation for the Promotion of Medical Science
- Michael Smith Foundation for Health Research
This publication has 48 references indexed in Scilit:
- Coexpression of CD49b and LAG-3 identifies human and mouse T regulatory type 1 cellsNature Medicine, 2013
- Interleukin-6 induces the generation of IL-10-producing Tr1 cells and suppresses autoimmune tissue inflammationJournal of Autoimmunity, 2013
- Results of a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or Refractory Hodgkin's LymphomaJournal of Clinical Oncology, 2012
- MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancersNature, 2011
- Densely Interconnected Transcriptional Circuits Control Cell States in Human HematopoiesisCell, 2011
- Tumor-Associated Macrophages and Survival in Classic Hodgkin's LymphomaThe New England Journal of Medicine, 2010
- CXCL12 enhances exogenous CD4+CD25+ T cell migration and prevents embryo loss in non-obese diabetic miceFertility and Sterility, 2009
- Pathogenesis of Classical and Lymphocyte-Predominant Hodgkin LymphomaAnnual review of pathology, 2009
- Expression of LAG-3 by tumor-infiltrating lymphocytes is coincident with the suppression of latent membrane antigen–specific CD8+ T-cell function in Hodgkin lymphoma patientsBlood, 2006
- Role of LAG-3 in Regulatory T CellsImmunity, 2004