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Original article
Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy
  1. Yue Zhao1,
  2. Timothy Wai Ho Shuen2,
  3. Tan Boon Toh3,
  4. Xue Ying Chan1,
  5. Min Liu1,
  6. Sue Yee Tan1,
  7. Yong Fan4,
  8. Hechuan Yang5,
  9. Shridhar Ganpathi Lyer6,
  10. Glenn Kunnath Bonney6,
  11. Eva Loh7,
  12. Kenneth Tou En Chang7,
  13. Thiam Chye Tan8,
  14. Weiwei Zhai5,
  15. Jerry Kok Yen Chan9,10,
  16. Edward Kai-Hua Chow3,
  17. Cheng Ean Chee11,
  18. Guan Huei Lee12,
  19. Yock Young Dan12,
  20. Pierce Kah-Hoe Chow13,14,15,
  21. Han Chong Toh2,
  22. Seng Gee Lim12,
  23. Qingfeng Chen1,2,4,16
  1. 1 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore
  2. 2 Division of Medical Oncology, National Cancer Centre Singapore, Singapore
  3. 3 Cancer Science Institute of Singapore, National University of Singapore, Singapore
  4. 4 Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
  5. 5 Genome Institute of Singapore, Agency for Science, Technology and Research (A*STAR), Singapore
  6. 6 Division of Hepatobiliary and Liver Transplantation Surgery, National University Health System, Singapore
  7. 7 Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, Singapore
  8. 8 Department of Obstetrics and Gynaecology, KK Women’s and Children’s Hospital, Singapore
  9. 9 Department of Reproductive Medicine, KK Women’s and Children’s Hospital, Singapore
  10. 10 Experimental Fetal Medicine Group, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  11. 11 Department of Haematology-Oncology, National University Cancer Institute, Singapore
  12. 12 Division of Gastroenterology and Hepatology, National University Health System, Singapore, Singapore
  13. 13 Division of Surgical Oncology, National Cancer Center Singapore, Singapore
  14. 14 Department of Hepato-Pancreato-Biliary and Transplant Surgery, Singapore General Hospital, Singapore
  15. 15 Duke-NUS Graduate Medical School, Singapore
  16. 16 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  1. Correspondence to Dr Qingfeng Chen, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673; qchen{at}imcb.a-star.edu.sg

Abstract

Objective As the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing.

Design Patient-derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg−/− (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated.

Results Similar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid-derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab.

Conclusions Our work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy.

  • hepatocellular carcinoma
  • immunotherapy
  • immunology

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • Contributors YZ designed and performed experiments, analysed and interpreted data and prepared the manuscript. XYC, SYT and ML performed experiments and analysed data; TWHS, TBT, YF, HY, SGI, GKB, EL, KTEC, TCT, WZ, JKYC, EK-HC, CEC, GHL, YYD, PK-HC, HCT and SGL contributed research tools and reagents and prepared the manuscript. QC conceived the study, designed experiments, supervised the project and prepared the manuscript.

  • Funding This study was supported by the Industry Alignment Fund Cat 3 (IAF311020), Agency for Science, Technology and Research (A*STAR) Singapore, MOH Industry Alignment Fund Cat 2 (MOHIAFCAT2001), National Medical Research Council Singapore and by the Eradication of HBV TCR Program: NMRC/TCR/014-NUHS/2015 and NMRC/TCR/015-NCC/2016 National Medical Research Council Singapore. QC is also supported by the National Research Foundation Fellowship Singapore NRF-NRFF2017-03.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Singhealth, National Healthcare Group Research Ethics Committees of Singapore and Singapore General Hospital specifically approved this study (CIRB Ref: 2012/064/B, DSRB Reference Number: 2014/00231 and TCR Reference Number: 2016/2626).

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

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