Single cell transcriptome analysis reveals disease-defining T cell subsets in the tumor microenvironment of classic Hodgkin lymphoma

Tomohiro Aoki, Lauren C Chong, Katsuyoshi Takata, Katy Milne, Monirath Hav, Anthony Colombo, Elizabeth A Chavez, Michael Nissen, Xuehai Wang, Tomoko Miyata-Takata, Vivian Lam, Elena Vigano, Bruce W Woolcock, Adele Telenius, Michael Yu Li, Shannon Healy, Chanel Ghesquiere, Daniel Kos, Talia Goodyear, Johanna VeldmanAllen W Zhang, Jubin Kim, Saeed Saberi, Jiarui Ding, Pedro Farinha, Andrew P Weng, Kerry J Savage, David W Scott, Gerald Krystal, Brad H Nelson, Anja Mottok, Akil Merchant, Sohrab P Shah, Christian Steidl

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    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.

    Original languageEnglish
    Pages (from-to)407-421
    Number of pages17
    JournalCancer discovery
    Volume10
    Issue number3
    Early online date19-Dec-2019
    DOIs
    Publication statusPublished - Mar-2020

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