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Single cell profiling of γδ hepatosplenic T-cell lymphoma unravels tumor cell heterogeneity associated with disease progression

Wei Song, Haixi Zhang, Fan Yang, Kiichi Nakahira, Cheng Wang, Keqian Shi, View ORCID ProfileRuoyu Zhang
doi: https://doi.org/10.1101/2022.01.17.476575
Wei Song
1Faculty of Life science and Technology, Kunming University of Science and Technology, Kunming, 650500, Yunnan, P.R. China
2School of Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, P.R. China
4Department of Radiology, The First People’s Hospital of Yunnan Province, Kunming, 650032, Yunnan, P.R. China
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Haixi Zhang
3Department of Hematology, The First People’s Hospital of Yunnan Province, Kunming, 650032, Yunnan, P.R. China
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Fan Yang
2School of Medicine, Kunming University of Science and Technology, Kunming, 650500, Yunnan, P.R. China
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Kiichi Nakahira
5Department of Pharmacology, Nara Medical University, Kashihara, Nara, 634-8521, Japan
6Division of Pulmonary and Critical Care Medicine, Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, New York, 10065, USA
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Cheng Wang
7Innovec Biotherapeutics, Inc. Beijing, 102206, P.R. China
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Keqian Shi
3Department of Hematology, The First People’s Hospital of Yunnan Province, Kunming, 650032, Yunnan, P.R. China
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  • For correspondence: zry0510@gmail.com shikeqian1@outlook.com
Ruoyu Zhang
7Innovec Biotherapeutics, Inc. Beijing, 102206, P.R. China
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  • ORCID record for Ruoyu Zhang
  • For correspondence: zry0510@gmail.com shikeqian1@outlook.com
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Abstract

Hepatosplenic T-cell lymphoma (HSTCL), mostly derived from γδ T cells, is a rare but very aggressive lymphoma with poor outcomes. The molecular pathogenesis driving HSTCL is largely unknown while only limited treatment options are available. In this study, by performing paired single cell RNA-seq and T cell receptor (TCR) sequencing on biopsies from a HSTCL patient pre- and post-chemotherapy treatments, we characterized unique gene expressing signatures of malignant γδ T cells, with a set of marker genes were newly identified in HSTCL (AREG, PLEKHA5, VCAM1 etc.). Although the malignant γδ T cells were expanded from a single TCR clonotype according to their TCR identities, they evolved into two transcriptional distinct tumor subtypes during the disease progression. The Tumor_1 subtype was dominant in pre-treatment samples with highly aggressive phenotypes. While the Tumor_2 had relative mild cancer hallmark signatures but expressed genes associated with tumor survival signal and drug resistance (IL32, TOX2, AIF1, AKAP12 etc.), and finally became the main tumor subtype post-treatment. We further dissected the tumor microenvironment of the HSTCL and noticed that CD8 memory T cells were clonal expanded post-treatment. In addition, we discovered dynamically rewiring cell-cell interaction networks during the treatment. The tumor cells had reduced communications with the microenvironment post-treatment. Our study reveals heterogenous and dynamic tumor and microenvironment underlying pathogenesis of HSTCL and may contribute to identify novel targets for diagnosis and cure of HSTCL in the future.

Competing Interest Statement

RZ is a paid consultant of Innovec Biotherapeutics. CW is the co-founder of Innovec Biotherapeutics.

Footnotes

  • Key points:

    1. A single cell atlas was established for γδ hepatosplenic T-cell lymphoma

    2. Tumor cell heterogeneity was revealed and may associate with disease progression and drug resistance

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 18, 2022.
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Single cell profiling of γδ hepatosplenic T-cell lymphoma unravels tumor cell heterogeneity associated with disease progression
Wei Song, Haixi Zhang, Fan Yang, Kiichi Nakahira, Cheng Wang, Keqian Shi, Ruoyu Zhang
bioRxiv 2022.01.17.476575; doi: https://doi.org/10.1101/2022.01.17.476575
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Single cell profiling of γδ hepatosplenic T-cell lymphoma unravels tumor cell heterogeneity associated with disease progression
Wei Song, Haixi Zhang, Fan Yang, Kiichi Nakahira, Cheng Wang, Keqian Shi, Ruoyu Zhang
bioRxiv 2022.01.17.476575; doi: https://doi.org/10.1101/2022.01.17.476575

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