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Original research
Isoformic PD-1-mediated immunosuppression underlies resistance to PD-1 blockade in hepatocellular carcinoma patients
  1. Zhiwu Tan1,2,
  2. Mei Sum Chiu1,
  3. Xinxiang Yang3,
  4. Ming Yue4,
  5. Tan To Cheung3,
  6. Dongyan Zhou1,2,
  7. Yuewen Wang3,
  8. Anthony Wing-Hung Chan5,
  9. Chi Wing Yan1,
  10. Ka Yi Kwan1,
  11. Yik Chun Wong1,
  12. Xin Li1,
  13. Jingying Zhou6,
  14. Ka Fai To5,
  15. Jiye Zhu3,
  16. Chung Mau Lo3,
  17. Alfred Sze-Lok Cheng6,
  18. Stephen Lam Chan7,
  19. Li Liu1,2,
  20. You-Qiang Song4,
  21. Kwan Man3,
  22. Zhiwei Chen1,2
  1. 1AIDS Institute and Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, State Key Laboratory of Emerging Infectious Diseases, The University of Hong Kong, Hong Kong SAR, People’s Republic of China
  2. 2Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong SAR, People’s Republic of China
  3. 3Department of Surgery, HKU-SZH & School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People’s Republic of China
  4. 4School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, People’s Republic of China
  5. 5Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of China
  6. 6School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of China
  7. 7Department of Clinical Oncology and State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, The Chinese University of Hong Kong, Hong Kong SAR, People’s Republic of China
  1. Correspondence to Prof. Zhiwei Chen, (lead contact), AIDS Institute and Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People’s Republic of China; zchenai{at}hku.hk; Dr. Zhiwu Tan, AIDS Institute and Department of Microbiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People’s Republic of China; zwtan{at}hku.hk; Prof. Kwan Man, Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, People’s Republic of China; kwanman{at}hku.hk

Abstract

Objective Immune checkpoint blockade (ICB) has improved cancer treatment, yet why most hepatocellular carcinoma (HCC) patients are resistant to PD-1 ICB remains elusive. Here, we elucidated the role of a programmed cell death protein 1 (PD-1) isoform, Δ42PD-1, in HCC progression and resistance to nivolumab ICB.

Design We investigated 74 HCC patients in three cohorts, including 41 untreated, 28 treated with nivolumab and 5 treated with pembrolizumab. Peripheral blood mononuclear cells from blood samples and tumour infiltrating lymphocytes from tumour tissues were isolated for immunophenotyping. The functional significance of Δ42PD-1 was explored by single-cell RNA sequencing analysis and validated by functional and mechanistic studies. The immunotherapeutic efficacy of Δ42PD-1 monoclonal antibody was determined in HCC humanised mouse models.

Results We found distinct T cell subsets, which did not express PD-1 but expressed its isoform Δ42PD-1, accounting for up to 71% of cytotoxic T lymphocytes in untreated HCC patients. Δ42PD-1+ T cells were tumour-infiltrating and correlated positively with HCC severity. Moreover, they were more exhausted than PD-1+ T cells by single T cell and functional analysis. HCC patients treated with anti-PD-1 ICB showed effective PD-1 blockade but increased frequencies of Δ42PD-1+ T cells over time especially in patients with progressive disease. Tumour-infiltrated Δ42PD-1+ T cells likely sustained HCC through toll-like receptors-4-signalling for tumourigenesis. Anti-Δ42PD-1 antibody, but not nivolumab, inhibited tumour growth in three murine HCC models.

Conclusion Our findings not only revealed a mechanism underlying resistance to PD-1 ICB but also identified anti-Δ42PD-1 antibody for HCC immunotherapy.

  • hepatocellular carcinoma
  • immunotherapy
  • T lymphocytes
  • inflammation
  • clinical trials

Data availability statement

The scRNA-seq data have been deposited in GEO under accession code GSE155736. Other data are available on reasonable request.

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Data availability statement

The scRNA-seq data have been deposited in GEO under accession code GSE155736. Other data are available on reasonable request.

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Footnotes

  • Contributors ZC conceived and supervised the study. ZT and ZC designed the experiments, analyzed data and wrote the manuscript. KM coordinated clinical teams and experiments. ZT, MSC, DZ, CWY, KYK, YCW, XL and LL performed experiments. ZT, MY and Y-QS analyzed the scRNA-seq data. XY, TTC, YW, AW-HC, JZhou, KFT, JZhu, CML, AS-LC, SLC and KM provided HCC patients samples. KM and AS-LC provided critical comments and discussions.

  • Funding This work was undertaken with grant support from the Hong Kong Research Grant Council (TRS: T11-706/18-N, GRF: 17115818, 17104919 to ZC; TRS: T12-703/19-R to KM; GRF: 17121219 to TTC), the Hong Kong Health and Medical Research Fund (HMRF: 03142666, 04151266 and 05162326), University Development Fund and Li Ka Shing Faculty of Medicine Matching Fund from HKU to the AIDS Institute, and HKU Platform Technology Fund on Humanized Mice.

  • Competing interests None declared.

  • 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.

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