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Hepatology
Original research
Distinct single-cell immune ecosystems distinguish true and de novo HBV-related hepatocellular carcinoma recurrences
  1. Shuling Chen1,2,3,
  2. Cheng Huang4,
  3. Guanrui Liao1,
  4. Huichuan Sun4,
  5. Yubin Xie3,
  6. Changyi Liao5,
  7. Jianping Wang6,
  8. Minghui He1,
  9. Huanjing Hu3,
  10. Zihao Dai1,3,
  11. Xiaoxue Ren5,
  12. Xuezhen Zeng3,
  13. Zhilong Lin1,
  14. Guo-Pei Zhang1,
  15. Wenxuan Xie1,
  16. Shunli Shen1,
  17. Shaoqiang Li1,
  18. Sui Peng3,6,7,
  19. Dong-Ming Kuang8,
  20. Qiang Zhao9,10,
  21. Dan G Duda11,
  22. Ming Kuang1
  1. 1Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
  2. 2Institute of Diagnostic and Interventional Ultrasound, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
  3. 3Precision Medicine Institute, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, People's Republic of China
  4. 4Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, People's Republic of China
  5. 5Department of Oncology, Cancer Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
  6. 6Department of Gastroenterology and Hepatology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
  7. 7Clinical Trials Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
  8. 8State Key Laboratory of Oncology in South China, Cancer Center, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
  9. 9Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, People's Republic of China
  10. 10Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, Guangzhou, Guangdong, People's Republic of China
  11. 11Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Professor Ming Kuang, The First Affiliated Hospital, Center of Hepato-Pancreato-Biliary Surgery, Sun Yat-Sen University, Guangzhou, Guangdong, China; kuangm{at}mail.sysu.edu.cn; Dr Dan G Duda; duda{at}steele.mgh.harvard.edu; Qiang Zhao; zhaoq37{at}mail.sysu.edu.cn

Abstract

Objective Revealing the single-cell immune ecosystems in true versus de novo hepatocellular carcinoma (HCC) recurrences could help the optimal development of immunotherapies.

Design We performed 5’and VDJ single-cell RNA-sequencing on 34 samples from 20 recurrent HCC patients. Bulk RNA-sequencing, flow cytometry, multiplexed immunofluorescence, and in vitro functional analyses were performed on samples from two validation cohorts.

Results Analyses of mutational profiles and evolutionary trajectories in paired primary and recurrent HCC samples using whole-exome sequencing identified de novo versus true recurrences, some of which occurred before clinical diagnosis. The tumour immune microenvironment (TIME) of truly recurrent HCCs was characterised by an increased abundance in KLRB1+CD8+ T cells with memory phenotype and low cytotoxicity. In contrast, we found an enrichment in cytotoxic and exhausted CD8+ T cells in the TIME of de novo recurrent HCCs. Transcriptomic and interaction analyses showed elevated GDF15 expression on HCC cells in proximity to dendritic cells, which may have dampened antigen presentation and inhibited antitumour immunity in truly recurrent lesions. In contrast, myeloid cells’ cross talk with T cells-mediated T cell exhaustion and immunosuppression in the TIME of de novo recurrent HCCs. Consistent with these findings, a phase 2 trial of neoadjuvant anti-PD-1 immunotherapy showed more responses in de novo recurrent HCC patients.

Conclusion True and de novo HCC recurrences occur early, have distinct TIME and may require different immunotherapy strategies. Our study provides a source for genomic diagnosis and immune profiling for guiding immunotherapy based on the type of HCC recurrence and the specific TIME.

  • hepatocellular carcinoma
  • surgical oncology

Data availability statement

Data are available on reasonable request. Data are available on reasonable request. The single-cell RNA sequencing, single-cell TCR sequencing, and bulk RNA sequencing data reported in this publication can be accessed under the Genome Sequence Archive (http://bigd.big.ac.cn/gsa-human, accession number HRA003039) on request.

http://dx.doi.org/10.1136/gutjnl-2022-328428

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    Data availability statement

    Data are available on reasonable request. Data are available on reasonable request. The single-cell RNA sequencing, single-cell TCR sequencing, and bulk RNA sequencing data reported in this publication can be accessed under the Genome Sequence Archive (http://bigd.big.ac.cn/gsa-human, accession number HRA003039) on request.

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    Footnotes

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    • SC, CH, GL, HS and YX contributed equally.

    • QZ, DGD and MK contributed equally.

    • Contributors Guarantor, MK; Conceptualisation, SC, DGD and MK; Methodology, SC, GL, YX, HH and MH; Investigation, SC, CH, HS, CL, JW, ZD, XR, XZ, ZL, G-PZ, QZ; Formal analysis, SC, GL, YX, CL, HH, MH and D-MK; Resource, CH, HS, WX, SS, SL, SP, and MK; Data curation, MK; Writing-original draft, SC; Writing-review and editing, SC, DGD and MK; Visualisation, SC, GL and YX; Supervision, QZ, DGD and MK; Funding acquisition, SC, DGD and MK.

    • Funding The work of the authors is supported by the National Natural Science Foundation of China (No. 82172047, 82130083), the National Science Fund for Distinguished Young Scholars (No. 81825013), the Guangdong Natural Science Foundation of Distinguished Youth Scholar (No. 2022B1515020060), the Guangdong Natural Science Foundation (No. 2021A1515010450), the Kelin Outstanding Young Scientist of the First Affiliated Hospital, Sun Yat-sen University (R08030), the Key Research and Development Plan of Guangzhou City (2022-06-08-04-3001-0010), US National Cancer Institute grants (No. R01CA260872, R01CA260857) and DoD PRCRP Impact Award W81XWH-19-1-0284.

    • Competing interests DGD received consultant fees from Innocoll, and has received research grants from Bayer, Surface Oncology, Exelixis and BMS. No reagents or support from these companies was used for this study. No potential conflicts of interest were disclosed by other authors.

    • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.