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
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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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