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Research Articles

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 Viganò, Bruce W. Woolcock, Adèle Telenius, Michael Y. Li, Shannon Healy, Chanel Ghesquiere, Daniel Kos, Talia Goodyear, Johanna Veldman, Allen 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 and Christian Steidl
Tomohiro Aoki
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Lauren C. Chong
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Katsuyoshi Takata
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Katy Milne
3Deeley Research Centre, British Columbia Cancer, Vancouver, British Columbia, Canada.
4Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
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Monirath Hav
5Cedars-Sinai Medical Center, Los Angeles, California.
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Anthony Colombo
5Cedars-Sinai Medical Center, Los Angeles, California.
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Elizabeth A. Chavez
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Michael Nissen
6Terry Fox Laboratory, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Xuehai Wang
6Terry Fox Laboratory, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Tomoko Miyata-Takata
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Vivian Lam
6Terry Fox Laboratory, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Elena Viganò
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Bruce W. Woolcock
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Adèle Telenius
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Michael Y. Li
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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Shannon Healy
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Chanel Ghesquiere
3Deeley Research Centre, British Columbia Cancer, Vancouver, British Columbia, Canada.
4Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
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Daniel Kos
3Deeley Research Centre, British Columbia Cancer, Vancouver, British Columbia, Canada.
4Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
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Talia Goodyear
3Deeley Research Centre, British Columbia Cancer, Vancouver, British Columbia, Canada.
4Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
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Johanna Veldman
7Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
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Allen W. Zhang
8Department of Molecular Oncology, British Columbia Cancer, Vancouver, British Columbia, Canada.
9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Jubin Kim
6Terry Fox Laboratory, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Saeed Saberi
8Department of Molecular Oncology, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Jiarui Ding
8Department of Molecular Oncology, British Columbia Cancer, Vancouver, British Columbia, Canada.
10Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
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Pedro Farinha
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Andrew P. Weng
6Terry Fox Laboratory, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Kerry J. Savage
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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David W. Scott
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Gerald Krystal
6Terry Fox Laboratory, British Columbia Cancer, Vancouver, British Columbia, Canada.
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Brad H. Nelson
3Deeley Research Centre, British Columbia Cancer, Vancouver, British Columbia, Canada.
4Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia, Canada.
11Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
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Anja Mottok
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
12Institute of Human Genetics, Ulm University and Ulm University Medical Center, Ulm, Germany.
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Akil Merchant
5Cedars-Sinai Medical Center, Los Angeles, California.
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Sohrab P. Shah
2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
8Department of Molecular Oncology, British Columbia Cancer, Vancouver, British Columbia, Canada.
9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Christian Steidl
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
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  • For correspondence: CSteidl@bccancer.bc.ca
DOI: 10.1158/2159-8290.CD-19-0680 Published March 2020
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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.

See related commentary by Fisher and Oh, p. 342.

This article is highlighted in the In This Issue feature, p. 327

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Cancer Discov 2020;10:406–21

  • Received June 12, 2019.
  • Revision received November 13, 2019.
  • Accepted December 13, 2019.
  • Published first December 19, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 10 (3)
March 2020
Volume 10, Issue 3
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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 Viganò, Bruce W. Woolcock, Adèle Telenius, Michael Y. Li, Shannon Healy, Chanel Ghesquiere, Daniel Kos, Talia Goodyear, Johanna Veldman, Allen 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 and Christian Steidl
Cancer Discov March 1 2020 (10) (3) 406-421; DOI: 10.1158/2159-8290.CD-19-0680

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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 Viganò, Bruce W. Woolcock, Adèle Telenius, Michael Y. Li, Shannon Healy, Chanel Ghesquiere, Daniel Kos, Talia Goodyear, Johanna Veldman, Allen 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 and Christian Steidl
Cancer Discov March 1 2020 (10) (3) 406-421; DOI: 10.1158/2159-8290.CD-19-0680
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